Hindawi Publishing CorporationISRN EndocrinologyVolume 2013 Article ID 814690 16 pageshttpdxdoiorg1011552013814690

Review ArticleEstrogen Signaling and the Aging Brain Context-DependentConsiderations for Postmenopausal Hormone Therapy

Natasha N Mott and Toni R Pak

Department of Cell and Molecular Physiology Loyola University Chicago Stritch School of Medicine 2160 S First AvenueMaywood IL 60153 USA

Correspondence should be addressed to Toni R Pak tpaklumcedu

Received 12 April 2013 Accepted 21 May 2013

Academic Editors F Escobar-Jimenez H Galbo E Hajduch M Hiriart H-Q Qu and H Ueshiba

Copyright copy 2013 N N Mott and T R Pak This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Recent clinical studies have spurred rigorous debate about the benefits of hormone therapy (HT) for postmenopausal womenControversy first emerged based on a sharp increase in the risk of cardiovascular disease in participants of the Womenrsquos HealthInitiative (WHI) studies suggesting that decades of empirical research in animal models was not necessarily applicable to humansHowever a reexamination of the data from the WHI studies suggests that the timing of HT might be a critical factor and thatadvanced age andor length of estrogen deprivation might alter the bodyrsquos ability to respond to estrogens Dichotomous estrogeniceffects are mediated primarily by the actions of two high-affinity estrogen receptors alpha and beta (ER120572 amp ER120573) The expressionof the ERs can be overlapping or distinct dependent upon brain region sex age and exposure to hormone and during the time ofmenopause theremay be changes in receptor expression profiles post-translationalmodifications and proteinprotein interactionsthat could lead to a completely different environment for E

2to exert its effects In this review factors affecting estrogen-signaling

processes will be discussed with particular attention paid to the expression and transcriptional actions of ER120573 in brain regions thatregulate cognition and affect

1 Introduction

According to theCDC (2008) the average lifespan forwomenin the USA is sim81 years of age While the average lifespanhas been steadily increasing over the past century (sim48 yearsin 1900) the average age at which reproductive senescencemenopause occurs has remained relatively constant between45ndash55 years of age [1 2] Including the prepubescent yearsthis leaves women living about half of their lives withouthigh levels of circulating ovarian hormonesThe two primaryovarian hormones are 17120573-estradiol (E

2) and progesterone

both of which are required for female reproduction Manypositive anecdotal experiences are reported during times inthe reproductive cycle when E

2is high sparking further

investigation into the role of E2in various nonreproductive

processes including those pertaining to cognition andmoodThe vast majority of basic science studies have describedpositive effects of E

2on cognitive processes at a molecular

level and importantly older postmenopausal females exhibit

significant deficits when performing tasks that require theuse ofworkingmemory attentional processing and executivefunction [3ndash8] The natural aging process is coincidentwith menopause which confounds studies attempting todifferentiate between the molecular mechanisms specific tomenopause versus aging Therefore studies examining thephysiological and molecular functions of estrogen receptorsduring periods of estrogen deprivationwith respect to naturalaging are requisite to understanding how reintroducing estro-gens in aged postmenopausal women will affect neurologicalprocesses In spite of the wealth of studies investigating theeffects of HT on relevant health concerns there are still veryfew conclusive arguments for or against HT to ameliorateneurological issues Moreover it is very likely that the actionsof estrogens regulate opposing processes depending uponbrain region and genetic composition of neurons involvedcreating complex issues regarding the lack of specificity of E

2

treatment Nevertheless some insight into general functionsof E2in the brain can be gleaned from existing data that

2 ISRN Endocrinology

demonstrate that (1) there is a critical window of timesurrounding menopause for which HT can be beneficialsuggesting that aging is an important factor (2) progestinsare not likely to be beneficial for cognitive and affectiveneurological issues and (3) the type of estrogen used maybe crucial Given these important conclusions this reviewwill focus on the molecular mechanisms of E

2signaling in

the brain and how variables that might contribute to thesesignaling patterns can be altered by age

2 The Menopausal Transition E2

Decline andHealth Concerns

Menopause is defined by the Mayo Clinic as ldquothe permanentend of menstruation and fertility occurring 12 months afteryour last menstrual periodrdquo Menopause is marked by areduced oocyte number attributable to progressive atresiaof ovarian follicles and by declining circulating levels of E

2

and progestinsThe perimenopausal transition is typically 4ndash8 years during which most women experience symptomsincluding hot flushes night sweats mood swings sleepdisturbances vaginal dryness and atrophy as well as urinaryincontinence most of which are alleviated by hormone (E

2)

replacement therapy (HTET) Until recently a great dealof evidence suggested that estrogens have positive effects oncognition neuroprotection memory anxiety depression aswell as bone and cardiovascular health [5 9ndash13]

The paramount studies to present negative consequencesof HT were the Womenrsquos Health Initiative (WHI) and theancillary studies including the Womenrsquos Health InitiativeStudy on Cognitive Aging (WHISCA) and the WomenrsquosHealth Initiative Memory Study (WHIMS) Data from thesestudies showed that a combination therapy of conjugatedequine estrogenmedroxyprogesterone acetate (CEEMPA)increased risk for mild cognitive impairment and decreasedglobal cognitive functioning but CEE alone did not have anysignificant effect on cognitive functioning [14ndash16] Poststudyanalyses have revealedmany confounding factors in theWHIstudies ranging from the choice of a reference group to the ageof participants and the choice of ET used (CEE) [4 17 18] aswell as the use ofMPA which has been shown to have adverseeffects onmemory after one dose in adulthood [19]While theWHI studies showed negative or neutral effects of estrogentherapy many other basic science and observational studieshave shown just the opposite The Kronos Early EstrogenPrevention Study (KEEPS) recently announced findings thatsuggested that E

2therapy had a positive effect on mood

and memory Participants receiving CEE showed significantimprovement in symptoms of depression anxiety and atrend toward reduced feelings of angerhostility ImportantlyCEE treatment or Premarin (Wyeth-Ayerst Philadelphia PAUSA) is a mixture of several estrogenic compounds butprimarily estrone sulfate and ring B unsaturated estrogenssuch as equilin and equilenin which can differentially acti-vate ER isoforms as compared to E

2alone [20] Participants

receiving CEE self-reported a trend toward better recallof printed materials as compared to placebo and womenusing transdermal E

2tended to report fewer memory-related

complaints Another study performed a meta-analysis of 36randomized HT clinical trials (RCT) focusing on cognition[21] The length of treatment type of memory variety ofhormone and age of the participant were all variables thatdrastically altered the outcomes of each trial Results fromthe meta-analysis indicated that verbal memory was mostoften affected by HT and younger women tended to have abetter outcome in this categoryThere was also a trend towardworse outcomes onmemory tests in patients treatedwithCEEtreatment alone compared to those treated with biologicallyidentical E

2 Moreover treatment with estrogens alone (ie

absent cotreatment with progestins) was overall associatedwith positive results on memory tests In conclusion datafrom these clinical trials have revealed the importance ofusing bioidentical hormones for HT and that downstreamsignaling processes for memory and mood can be affected bythe choice of estrogen andor combination of hormones usedas therapeutics

3 Estrogen Receptor Signaling

Estrogen signaling is mediated primarily through two recep-tors (ER120572 and ER120573) ERs are class I members of thenuclear hormone superfamily of receptors deemed as aligand-inducible transcription factors [22] Classically ERswere thought to be localized in the cytoplasm bound tointracellular chaperone proteins until induced by ligandto translocate to the nucleus according to the two-stephypothesis coined by Jensen et al [23] Following ligandbinding ERs undergo a conformational change that allowsfor dimerization translocation to the nucleus and DNAbinding or association with other transcription factors toregulate gene transcription however we now know that ERsignaling is much more complex

For example ERs are involved in other ldquonongenomicrdquomolecular functions including RNA processing second-messenger signaling cascades and rapid dendritic spineformation in neurons Of particular importance in the brainthe discovery of rapid signaling processes implicates E

2

as a neuromodulator however local synthesis of E2has

been the subject of fervent debate While it is likely thatthere is de novo synthesis of E

2within the parenchyma

due to technical challenges the exact levels and changeswith age and circulating hormones have yet to be identified[24 25] It is also difficult to determine how local E

2may

affect ER action Most reports suggest an implicit role forlocal E

2at the synapse and membrane [26] but whether

nucleargenomic activities of ERs are affected has yet to beestablished Recent data from our laboratory demonstratethat E

2can alter miRNA-expression [27] and from others

have shown that ER120572 can associate with miRNA processingenzymes such as Drosha [28] Data from our laboratory(unpublished observations) and others have shown that ERsare involved in alternative splicing processes and one studyhas demonstrated direct interaction of phosphorylated ER120572with splicing factor (SF) 3a p120 that potentiates alternativesplicing through EGFE

2crosstalk [29]These relatively novel

ER functions may be explained by examining well-studied

ISRN Endocrinology 3

components of classic NR signaling such as the structuralproperties of the receptors

4 Structural Contributions to ER Activity

Class I nuclear receptors (NRs) including ER120572 and ER120573have a characteristic structure comprised of five functionaldomains labeled AndashE and a sixth domain (F) unique to ERs(Figure 1) The AB domain contains an activator function-1-(AF-1-) like domain that allows for associations with coregu-latory proteins and other transcription factors Notably theAB domain is the least conserved domain between ER120572and ER120573 (17 homology) and it may be responsible forthe observed ligand-independent actions of ER120573 [30] The Cdomain is a DNA-binding domain that allows the receptorto bind a specific DNA sequence called an Estrogen ResponseElement (ERE) to regulate transcription of genes containingthis sequence within their promoter region Two zinc fingersforming a helix-loop-helix structure allow for appropriatespacing (3 nucleotides) between an inverted hexameric palin-dromic repeat that is described as the canonical ERE Theexact nucleotide sequence of hormone response elements canvary and in part dictate the affinity an NR has to regulate aparticular gene [31] The D domain is a hinge-like region thatallows the receptor to undergo a conformational change onceactivated and also contains a nuclear localization sequenceThe best-studied region of ERs is the E domain also referredto as the ligand-binding domain (LBD) Characterizationusing X-ray crystallography has shown that the LBD consistsof 12 ordered alpha-helices that are essential for conferringligand specificity [32] The orientation of helix 12 is critical tothe conformation NRs adopt once bound to a particular typeof ligand and ultimately influence the ability of the receptorto bind other proteins and activate gene transcription Helix12 contains the core residues of the activator function-2 (AF-2) domain a short amphipathic conserved alpha-helix thatinteracts with coregulatory proteins through an LxxLLmotifAdjacent to the AF-2E domain is the less characterized Fdomain that is unique to ERs ER120572 has a larger F domain thanER120573 and the two receptors only share about 18 homologywithin this region ER120572 dimerization and interactions withcoregulators are altered when the F domain is deleted ormodified demonstrating that the F domain is a relevantstructure for ER120572 transcriptional regulation but a clear rolefor this domain for ER120573 has yet to be determined [33 34]Importantly naturally occurring human ER120573 splice variantshave altered E and F domains which can affect hormoneresponsiveness in tissues that express these variants

While the overall sequence homology between ER120572 andER120573 is greater than 60 the specific gene targets of eachreceptor appear to be vastly different For example a varietyof cancer cell models have identified an antiapoptotic prolif-erative role for ER120572 whereas ER120573 tends to promote apoptosisand regulate antiproliferative genes [35ndash38] It is well knownthat ER120572 and ER120573 are readily able to form heterodimerswhen expressed in the same cell adding another layer ofcomplexity to the regulation of estrogen responsive genesER120572 andER120573 both bindEREs but the affinity for one receptor

AB

AB

AB

AB

C

C

C

C

D

D

D

D

E

E

E

E

F

FhER1205731

hER1205732

hER1205734

hER1205735

(a)

AB

AB

AB

AB

AB

AB

C

C

C

C

C

C

D

D

D

D

D

D

E

E

E

E

E

E

F

F

F

F

F

F

rER1205731

rER1205731Δ3

rER1205731Δ4

rER1205732

rER1205732Δ3

rER1205732Δ4

(b)

Figure 1 Representative image of domains within human andrat ER120573 splice variants Human ER120573 splice variants (a) containtruncations and changes in amino acid sequence in the C-terminusE and F domains Rat ER120573 splice variants (b) contain an 18-amino-acid insert in the LBDE domain andor exon 34 exclusions in theDNA-binding domain

or the other can depend highly on the specificity of the DNAsequence being regulated and the ligands present [39ndash41]Therefore it is important to consider the overlap in ER120572 andER120573 preferred transcriptional response elements when bothreceptors are expressed in the same system

5 Expression of ERs in the BrainA Complex Story

The principal determinant of E2action is the expression

of ER120572 ER120573 their alternatively spliced variants or somecombination of each which is cell-type specific even withindistinct brain nuclei ER expression has been studied exten-sively yet there are few definitive statements that can bemade about the regulation of ER120573 expression It can benoted that ER expression profiles can vary throughout thelife-span in particular when there are dramatic changes incirculating hormone levels such as puberty and menopause(Figure 2) Not only can ER expression vary dependentupon sex age and E

2treatment but these factors can also

direct subcellular localization which ultimately dictates ERfunctions Accordingly contextual studies that map the exactcellular expression patterns of each receptor and their splice

4 ISRN Endocrinology

Perimenopause(40s50s)

Postmenopause(50s+)

Peripuberty(preteens)

E2

Cyclicity

ΔER expression withhormone cyclicity ΔER expression with age

and E2 declineuarr ER splice variants

Figure 2 Timeline showing factors affecting ER gene expressionthroughout the female life-span Brain ER gene expression patternsare altered with age sex and exposure to circulating hormoneCirculating hormones fluctuate with age most dramatically at thetime of puberty andmenopause therefore contributing to changes inER gene expression Additionally alternative splicing increases withage thus potentially diversifying the ER gene expression profile

variants are a critical first step in creating a comprehensiveexamination of E

2-regulated processes in any system

The female vertebrate reproductive organs tend to bedominated by the expression of ER120572 whereas ER120573 isexpressed largely in nonreproductive tissues ER120573 was firstcloned from prostate tissue [42] and it has since been shownto have the highest levels of expression in the central nervoussystem and cardiovascular tissue as well as lung kidneycolorectal tissue mammary tissue and the immune system[43] Consequently some of the most prominent phenotypicproblems observed in mice lacking a functional ESR2 gene(120573ERKO mice) are neurological deficits By contrast ER120572knockout mice have no gross brain-related phenotypes butthey exhibit decreased E

2-mediated neuroprotection follow-

ing an ischemic event [44] Overall the phenotypes observedin ER120572- and ER120573-null mouse models suggest that ER120573 ispotentially more important for mediating nonreproductiveE2-governed processes than ER120572ER120572 and ER120573 are coexpressed in some regions of the

hypothalamus such as the medial amygdala (MeA) the bednucleus of the stria terminalis (BNST) and the periaqueduc-tal grey area However ER120572 is predominant in hypothala-mic nuclei that control reproduction sexual behavior andappetite (eg arcuate (ARC) medial preoptic (MPoA) andventromedial (VM)) but ER120573 is the predominant isoform inthe nonreproductive associated nuclei (eg paraventricular(PVN) supraoptic (SON) and suprachiasmatic (SCN)) aswell as the hippocampus dorsal raphe nuclei cortex andcerebellum [45 46] In the hippocampus mRNA and proteinfor both ERs have been detected and are well established asmediating both genomic and nongenomic processes [47ndash49]Nuclear and extranuclear ER120573mRNA and immunoreactivity(IR) have been detected in principal cells as well as inmany other nuclei of cells within the ventral CA23 [4647] Although not as prevalent as ER120573 ER120572 has also beendetected in the hippocampus primarily within GABAergicinterneurons [47 49]

ER expression is also often found to be sexually dimor-phic As onewould expectmany regions of the hypothalamusexhibit a great deal of sexual dimorphism due in part to dif-ferences in sexual behavior and regulation of gonadotrophic

hormones but regions such as the BNST also display somesex-related differences in ER expression For example ER120572 inthe BNST can be induced in somatostatin-positive neurons ofmale but not female rats [50] ERs have also been shown tobe sexually dimorphic in the developing rodent hippocam-pus but not in adults [51 52] However one report identifiedER120573mRNA in the adult female but notmale rhesusmacaquebasal ganglia and hippocampus [53] Importantly a lacksexually dimorphic regional ER expression does not precludedifferential responses to estrogens as other effectormoleculescan alter estrogen-responsive processes

Expression of ERs can vary not only with chromosomalsex but also in response to the hormonalmilieu For instanceit is well accepted that ER120572 expression is autoregulated byE2 primarily through proteasomal degradation [54] but also

perhaps on a transcriptional level by E2-bound ER120573 [55]The

ER120573 gene (ESR2) promoter region has not been extensivelycharacterized but it has been shown to contain E

2-responsive

cis sequence-binding sites for Oct-1 and Sp-1 which interactwith ERs via trans factors suggesting a molecular mechanismfor E2-mediated autoregulation of its receptor There is also

an Alu repeat sequence that may contain an ERE that couldact as an ER-dependent enhancer [56] Conversely in vitroand in vivo studies investigating the effects of E

2on ER120573

expression have yielded inconsistent conclusions dependingupon cell type animal species and age For instance in theT47D human breast cancer cell line E

2upregulated ER120573 [57]

However ER120573 expression was decreased by E2in mammary

glands of lactating mice that coexpress ER120572 [58] ER120573 wasalso decreased in the PVN of rats subjected to OVX+ E

2[59]

Thus it appears that E2may regulate ER120572 and ER120573 however

this effect is highly dependent upon cell type and possiblyupon the coexpression of other ERs

In addition to sex and E2 aging also appears to influence

ER expression Overall decreased nuclear E2binding has

been reported in the hypothalamus and anterior pituitary ofaged female rats compared to young ones but the changein E2binding was not necessarily attributed to a decrease

in total ER expression [60 61] suggesting a shift in theratio of ERs andor subcellular localization While overallnuclear E

2binding within the hypothalamus may decrease

with age changes to ER expression patterns with age remaincontentious In general it appears that age alone does noteliminate ER120572 expression in the brain but regional specificityand E

2availability may be important factors [62 63] and an

increase in ESR promoter methylation has been correlatedwith age in other systems [64 65] One study reported variedmiddle age-specific reduction in hypothalamic ER with E

2

treatment [66] yet another study showed that E2decreased

hypothalamic ER expression significantly in all ages tested(3 11 and 20 months) [67] Specific to ER120572 a work byChakraborty and colleagues determined that immunoreac-tive cell numbers did not always change following OVXand E

2replacement Rather their study revealed that with

advanced age (24ndash26 months compared to 3-4 and 10ndash12months) the number of ER120572-positive cells was increased or itstayed the same in different hypothalamic nuclei [68] In thehippocampus ER120572 was decreased after long-term estrogendeprivation (LTED 10 weeks) regardless of E

2replacement

ISRN Endocrinology 5

following LTED but E2deprivation had no effect on ER120573

[11] The same report demonstrated decreased levels of ER120573in very old rats (24-month females compared to 3-monthdiestrus females) In general most reports suggest that agingdecreases ER120573 expression but like ER120572 this effect may behighly region specific An age-related decrease in ER120573 expres-sion in the brain is underscored by a corresponding increaseinCpGmethylation of the ESR2 promoter inmiddle-aged (9ndash12months) rats [69] Other reports describe decreases in ER120573protein and message in some areas but not in others [63 70]Taken together there are a number of reports attemptingto identify the parameters that control ER expression suchas age sex and response to E

2 however with such vast

deviations in expression with cell type there is still much tobe learned about expression of these receptors especially inbrain regions controlling nonreproductive behaviors

6 Alternative Splice Variants

Based upon the highly variable reports that differ in sexand age of animals as well as exposure to hormone it maybe possible that these studies are unknowingly detectingchanges in splice variant expression which could change E

2

responsiveness as well as downstream gene regulation Notonly can ERs heterodimerize to regulate gene transcriptionbut there are a number of alternatively spliced variants of eachreceptor that are endogenously expressed and that potentiallycontribute to the diverse tissue-specific actions of E

2 Alter-

native splicing of ERs alters inherent signaling properties ofthe receptor including ligand and DNA-binding affinitiesnuclear localization and dimerization depending on wherethe alternative splice site is encoded A number of ER splicevariant transcripts and other proteins have been identifiedin demented human brains breast and prostate and insome reports an increase in alternative splicing is correlatedwith pathology [71ndash75] Also interesting age alone mayincrease alternative splicing of some gene products [76] Theidentified ER120573 human splice variants are truncated at the C-terminus of the receptor (Figure 1(a)) however we providedexperimental evidence that the C-terminus of the receptoris not required for ER120573-mediated transcription especiallywith regard to the identified human splice variants [77]Unlike the human splice variants rodent ER120573 splice variantsidentified to date have been shown to have either an exoninclusion in the ligand-binding domain creating (rER1205732)or an exon deletion in the DNA-binding domain rER1205731Δ3or rER1205731Δ4 or both rER1205732Δ3 and rER1205732Δ4 (Figure 1(b))[37 78 79] Exon inclusion (rER1205732 variants) has been shownto produce a protein that binds E

2with a 35-fold decrease

in affinity In contrast ERs with exon 3 and 4 deletions areunable to bind DNA but they can still mediate transcriptionthrough proteinprotein interactions with other transcriptionfactors such as AP-1 and it can bind E

2as well as rER1205731

[37 80] Importantly the transcriptional functions of rER1205731are significantly altered when coexpressed with other splicevariants likely due to a weaker interaction with coactivatorproteins [81 82] Despite lower E

2binding andor lack of

DNA binding the rodent and human splice variants retain a

constitutive ligand-independent transcriptional function atboth basic and complex promoters [77 83 84] suggestingthat these splice variants have an important endogenousbiological function Indeed unliganded ER1205731 or apo-ER1205731has been reported to regulate a subset of genes distinct fromthose regulated by ER1205731 when bound to E

2[41] Conversely

the human splice variants do not bind ligand with greataffinity [85] and they might therefore only regulate the classof genes that unliganded ER120573 targets

Thedownstream target genes of ER120573 splice variantsmightbe an important consideration at the time of menopauseas ER expression profiles and alternative splicing tend tochange with age [76] One recent report demonstrated anincrease in ER1205732 expression in the hippocampus of 9-month old middle-aged rats following short-term (6 days)E2deprivation that was significantly decreased compared to

the Sham group after E2administration [86] Importantly

E2replacement no longer affected ER1205732 expression in the

hippocampus after LTED (180 days)That study also reporteda decrease in hippocampal neurogenesis and increased float-ing behavior in a forced swim test thus functionally corre-lating increased ER1205732 with mood regulation and potentiallycognition Thus the expression and functions of ER120573 splicevariants are absolutely critical to understand the effects ofestrogen particularly at times of sustainedE

2deprivationwith

regard to cognition and affect While ER1205732 expression hasbeen assessed in the young male rat brain [87] and othervariants have been described in some brain regions [80 88]there is a general lack of data on most ER120573 splice variantsespecially in aged female brains

Some of the splice variants identified to date have beencharacterized as dominant negative receptors serving toinhibit activation of the full-length receptor [89] howevermost identified variants do not bind ligand with the sameaffinity and have the potential to differentially regulate targetgenes While several splice variants for ER120573 have been iden-tified in many model systems including mouse [90] rat [4546] and monkey [91] there is a general lack of comparativestudies on expression and functionality of human ER120573 vari-ants especially in neuronal systems Furthermore changingexpression levels of one or more alternatively spliced variantsduring a period of E

2deprivation may drastically change

general receptivity and downstream functions of E2

7 Novel ProteinProtein Interactions forE2-Mediated Nuclear Processes

Proteinprotein interactions are an essential relay in the reg-ulation of dynamic cellular processes Immediately followingtranslation ERs typically associate with a chaperone proteinto ensure proper folding protect from degradation and assistthe ER in becoming poised to accept ligand Once bound toligand ERs can dimerize and act as transcription factors tomediate gene regulation or associate withmembrane proteinsto initiate a signaling cascade When acting as transcriptionfactors ERs associate with a number of coregulatory proteinsthat assist in activating or repressing E

2-regulated genes

Coregulatory interactions are more characterized for ER120572

6 ISRN Endocrinology

than ER120573 and importantly less clear is how ER120573 mediatesligand-independent transcription In addition to the well-established ER interaction partners many novel interactingproteins have not yet been characterized and could be criticalfor nuclear processes not limited to gene transcription

8 HSPs and Chaperone Proteins

According to the classical two-step hypothesis inactivenuclear receptors are constantly accompanied and protectedfrom degradation by a number of chaperone proteins typi-cally members of the heat-shock protein (HSP) family Thisreceptorchaperone complex has been studied extensivelyand while the idea of a protective role for chaperones is wellsupported this complex can also perform other functionsFor instance HSPER complexes can serve to preactivatea hormone receptor by forcing a conformational changein ER such that it is able to bind its cognate hormoneThe initial HSP complex consists of the ER HSP70 andHSP70-interacting protein (HiP) as well as other accessoryand scaffolding proteins [92] HSP90 is recruited to thecomplex andHSP70 dissociates creating thematureHSPERcomplex [93] HSP90 induces a conformational change in thenuclear receptor and the ER is released from the complexready to dimerize and bind DNA or other transcriptionfactors to regulate gene transcription However some studiessuggest that HSPs could have a broader role than originallythought For example in Drosophila HSPs are required forDNA binding and in some instances they may regulateNR action [94] Interestingly aging and E

2can alter HSP70

in a cell-type specific manner [95ndash98] However recentdata from our lab (Table 1) demonstrated that HSP70 morereadily associates with ER120573 in aged female hippocampusfollowing E

2treatment compared to the young ones in which

HSP70ER120573 association decreased following E2treatment

We also observed no significant changes in HSP70 or ER120573expression suggesting that changes in the HSP70ER120573 inter-action with age in response to E

2change are a result of E

2

responsiveness andor activation of ER120573

9 Transcriptional Proteins and ERs

The process of transcribing DNA into RNA is a systematicprocess that involves multiprotein complexes binding toDNA modifying histone marks and initiating RNA synthe-sis ER120572 but not ER120573 has been shown to directly interactwith TFIIB IIE IIF and TIID proteins that initiate tran-scription [99 100] However experimental evidence from co-immunoprecipitation studies has demonstrated interactionsbetween ER120573 coregulatory proteins as well as other tran-scription factors Coregulatory proteins are transcriptionalaccessory proteins that enhance or repress transcription oftarget genes In general coactivators enhance gene tran-scription whereas corepressors block it However recentdata suggest that seemingly nontranscriptional proteins mayhave context-dependent coregulatory functions Importantly

certain coregulators can also be governed by age and E2[101ndash

103] thus recent discoveries imply that ER-mediated generegulation is not as well understood as previously thought

The best studied and well-established group of coregula-tory proteins that selectively associate with NRs is the steroidreceptor coactivator (SRCp160) family The SRC family iscomposed of three members SRC-1 SRC-2 and SRC-3all of which contain canonical LxxLL motifs known as thenuclear receptor (NR) box This motif interacts with AF-2 domains in ER120573 as well as other NR family memberssuch as glucocorticoid receptor (GR) progesterone receptor(PR) thyroid hormone receptor (TR) and ER120572 [104] SRCmembers have intrinsic histone acetyltransferase activity(HAT DNA activating) and interact with CREB-bindingprotein (CBP) [105] CBPp300 proteins are also coactivatorsthat have intrinsic HAT activity and can recruit ASC-2and other known coregulatory proteins [106] Confirmedcoregulatory interaction partners for several NRs that donot belong to the SRC family include estrogen-receptor-association protein (ERAP 140) [107] nuclear corepressor(NCoR) [108] silencing mediator of retinoic acid and thy-roid hormone receptor (SMRT) [109] and many othersAs is the case with our understanding of ER120573 interactionswith basic transcriptional machinery studies investigatingER120573coregulator interactions are sparse which may be dueto uniquely challenging issues associated with ER120573 such as alack of high-fidelity biochemical tools complicated structuralproperties and or pleiotropic physiological actions that arespecific to ER120573

In 2010 Anna Ma lovannaya and colleagues directeda high-throughput study (not including ER120573) aiming atcompiling a database for the endogenous coregulator poolldquonuclear receptor complexomerdquo [110] In this study a numberof novel protein interactions were identified and studiessuch as these are identifying proteins as ldquocoregulatorsrdquo thathad been previously thought to serve completely differentfunctionsOne group of relatively novel coregulatory proteinsare the E3 ubiquitin-protein ligases such as E6-associatedproteins (E6-AP) [111] While these proteins were thought toserve primarily as ubiquitin-conjugating enzymes they haverecently been highlighted as transcriptional enhancers ofNR-mediated activity independent of ligase function Similarlya group of E3-ligases that conjugate small ubiquitin likemodifier (SUMO) proteins to a target protein called PIASare also now considered NR coregulators and they utilize atypical LxxLLmotif In one study a decrease in ER expressionfollowing LTED or with advanced age coincided with anincrease in ER association with an E3-ubiquitin ligase CHIP[11] Together these newly described roles for HSPs and E3ligases raise novel questions about estrogen signaling such aswhen is an E3-ligaseER complex targeted for transcriptionalregulation versus degradation Also when are HSPs merelyperforming a chaperoneprotective function versus directingtranscriptional processes Future efforts aiming at elucidatingthe complexity of age-related changes in receptor structureand recruitment of coregulatory proteins could provideimportant insight into these seemingly paradoxical findings

ISRN Endocrinology 7

Table 1 Protein interactions with ER120573 were altered by age and 1198642 Selected proteins that were significantly altered (119875 lt 005) in their

association with ER120573 depending on age and 1198642treatment Experimental paradigm young (3 month) and aged (18 month) female Fischer 344

rats were ovariectomized and hormone deprived for 7 days Following deprivation animals were administered 25120583gkg 1198642(plasma levels =

7945 plusmn 225 pgmL) or vehicle (safflower oil) via subcutaneous injection onceday for 3 days Nuclear protein was isolated from the ventralhippocampus and coimmunoprecipitated for ER120573 (a beam 14C8) and associated proteins Protein interactions were identified and quantifiedusing 2D-DIGEDeCyder and ESI MSMS YV = young + vehicle YE = young + 119864

2 AV = aged + vehicle AE = aged + 119864

2

Accession noMolecularweight(Kda)

Estimatedisoelectricpoint

PEAKSscore Coverage ID

Interaction with ER120573FunctionYoung

vehicleYoung1198642

Agedvehicle

Aged1198642

gi| 149038929 80 575 494 643 Gelsolin mdash uarr mdash mdashActin-binding

coactivator

gi| 116242507 75 597 93 1458 Heat-shock protein70 mdash darr mdash uarr Chaperone

gi| 120538378 47 57 932 1072

Heterogeneousnuclear

ribonucleoproteinH12

mdash uarr mdash mdash RNA splicing

10 Nuclear Actin Setting the Stage

Coregulatory interactions may be poised upon a bed ofnuclear actin which has recently been identified as a dynamicmolecular stage for which many nuclear processes are per-formed such as transcription chromatin remodeling mRNAprocessing and nuclear importexport The general eventsthat initiate transcription are well established however theprocess by which all of the molecular components are tem-porally layered into a complex is still unclear Nuclear actin isessential in forming the preinitiation complex on a promoterelongation and RNP organization as well as remodeling ofchromatin [112ndash114] and as mentioned previously ERs arealso key factors in these processes In one study ER120572 and120573-actin were coimmunoprecipitated on the E

2responsive

pS2TFF1 promoter indicating that ER and nuclear actinmay work in concert to regulate transcriptional processesunder control of estrogens [115] The interaction betweenERs and actin is not yet fully investigated but data fromour lab (unpublished observations) and others [116] implythat both ER120572 and ER120573may utilize nuclear actin to performvarious functions Another actin-binding protein gelsolincaps actin filament ends and it has been shown to be anNR coactivator [117 118] Gelsolin may assist in actin poly-merization allowing transcriptionalmachinery to be broughtin proximity of target genes however it remains unclearhow gelsolin enhances ARER transcriptional activity Datafrom our lab indicate that gelsolinER120573 interactions increasewith E

2treatment in young but not aged animals (Table 1)

Gelsolin has been shown to increase with age [119] but alack of significant interaction with ER120573 despite increasedexpression of gelsolin could again suggest an alteration inER120573 function with age

Actin is also commonly associated with ubiquitous mul-tifunctional RNA-binding proteins such as heterologousnuclear riboproteins (hnRNPs) which also associate withERs [120] hnRNPs associate within the matrix of nuclearactin accompany transcripts out of the nucleus participatein alternative splicing and can modulate transcription [121]

Phosphorylated hnRNPK has been shown to mediate trans-lation of specific mRNAs [122] and hnRNPH is involvedin splicing and mRNA polyadenylation [123 124] In thepast the association of NRs with hnRNPs was thought to benonspecific due to the ubiquitous nature of these proteinsbut recent studies are no longer ruling out an importantinteraction between NRs and hnRNPs that may assist intranscription andor splicing [125 126] Data from our laband others demonstrate a dynamic interaction between bothER120572 and ER120573 and hnRNPs (Table 1) and furthermore datademonstrated that E

2might regulate expression of members

of the hnRNP family [127] As noted previously age-relatedincreases in splicing could lead to aberrant signaling not onlyfor E2-mediated processes but also for cellular processes in

generalNuclear ER interaction partners have historically been a

distinct class of nuclear receptor coregulators that seemedto solely assist ERs in gene transcription however thenumber of interaction partners for ERs is increasing Furtherinvestigation into ER120573-associated proteins is required as faras NRs are concerned data specific to ER120573 are inadequateto make broad conclusions Moreover post-translationalmodifications to coregulatory proteins ERs or changes intheir expression patterns due to age or sustained estrogendeprivation could all contribute to an altered microenviron-ment setting the stage for atypical estrogen signaling upontherapeutic reinstatement of hormones (Figure 3)

11 Estrogens and Cognition

Most empirical and observational data give merit to theidea that estrogens have a positive effect on cognitiveprocesses increased spine densities [128 129] enhancedsynaptic plasticity [130ndash132] and improved memory [133134] however the particular receptor(s) and the mechanismsthat regulate these processes remain unclear There are amyriad of behavioral studies suggesting that E

2enhances

prefrontal cortex (PFC) and hippocampal-dependent tasks

8 ISRN Endocrinology

Factor BER structureand function

Factor Ccoregulatory and

transcriptional interactions

120573

120573120573

120573

120572

120572

120572 120572

V

V

V

V

V

V

V

V

ESR1

ESR2

Age and E2

++

Context-dependentER-regulated

gene expression

Factor Atissue-specific

ER gene expression

Figure 3 Age and hormonalmilieu exponentially increase the potential diversity of estrogen receptor signaling leading to context-dependentgene regulation Age and E

2influence ER gene expression alternative splicing coregulatory protein expression and interaction which

ultimately direct ER-target gene transcription

For example long-term E2deprivation diminished aged

female rhesus macaquesrsquo performance in a delayed responsetask a PFC- dependent task [135] E

2also enhanced object

recognition under a number of different paradigms [136ndash138] and there are also multiple lines of evidence supportingE2-mediated neuroprotection which may be important for

cognition especially after stroke [139ndash142]Pharmacological targeting of the receptors with ER selec-

tive ligands has been a standard method for investigating thebehavioral physiological and cellular actions of E

2mediated

distinctly throughER120572 andor ER120573 however valuable insighthas also come from the ER120573-null (120573ERKO) mice 120573ERKOmice have significantly fewer neurons in the cortex hypotha-lamus amygdala and ventral tegmental area compared toWTThey also exhibit neuronal shrinkage and hyperprolifer-ation of glia by 3 months of age as well as having high levelsof apoE and apoE-dependent deposition of amyloid plaquesthroughout the CNS by 12 months of age [143] These micealso demonstrate spatial learning deficits in the Morris watermaze [144] and a decrease in hippocampal- and amygdala-dependent memory in a fear-conditioning paradigm that isaccompanied by decreased synaptic plasticity in hippocampalslice preparations [145] The critical role of ER120573 in higher-level brain functions has been deduced from these studiesand others warranting a full investigation of the wide-spreadmolecular actions of E

2known to contribute to cellular

processes on at least two levels at the synapse and on thegenome

Long-term potentiation (LTP) is an important compo-nent of learning and memory It represents an increasein synaptic transmission and plasticity that underlies cog-nitive behaviors and it is readily altered by E

2in many

circumstances In fact application of an aromatase inhibitoreliminates CA LTP generated by theta-burst stimulation inintact female neurons but not male or OVX animals posinga potentially serious concern for women using aromataseinhibitors for therapeutic treatment of breast cancer [146] E

2

can also enhance or suppress long-term depression (LTD)reducing synaptic transmission which may be dependentupon the specific receptors involved In aged male CA1cells E

2decreased LTD [147] however E

2enhanced LTP in

the cerebellum where ER120573 is the predominately expressedcognate receptor [148]

Although the majority of studies on cognitive processfocus on the rapid effects of E

2 late-phase long-term potenti-

ation (L-LTP) depends upon transcription and translation ofnewmRNA [149] to sustain an increase in synaptic transmis-sion E

2has been shown to regulate LTP in CA1 pyramidal

cells [150] over the span of 48 hours and this regulationappears to be dependent upon a higher ratio of NMDARrelative to AMPAR LTP induction requires activation ofNR2A-containing NMDARs however increased expressionof NR2B potentiates LTP magnitude [151] Notably E

2

increased expression of NR2B mRNA and NR2B expressionat the synapse [152 153] and the E

2-induced increase in

LTP can be abolished by blocking NR2B receptors [154]

ISRN Endocrinology 9

suggesting a transcriptional role for ERs in synaptic plasticityMoreover E

2application may increase CREB expression and

the amount of phosphorylated CREB in regions such as theamygdala [155] and BNST [117 155] which may be critical inthe formation of long-term memories Taken together thesedata demonstrate that E

2regulates neuronal plasticity and

memory through its original role as a transcription factor andalso by acting as a general intracellular signaling moleculethrough regulation of NMDARs and CREB However todate there are little data on the mechanisms by which ER120573regulates these processes or how the same principles ofplasticity may apply to other neurological issues

12 Estrogens and Mood Regulation

A range of behavioral experiments indicate that E2mod-

ulation of stress mood and affect is a complex storywith considerable conflicting data that may as in otherprocesses be explained in part by distinct roles for ER120572 andER120573 Anecdotally many women report mood fluctuationsas corresponding to changes in circulating estrogen levelssuch as what occurs during the menstrual cycle peripubertypostpartum and peripostmenopause Incidence of anxietyand depression are observed at perimenopause and whenhormone levels are fluctuating [156 157] However E

2can

also exhibit anxiogenic properties and often anxiety anddepression present in a comorbid fashion especially inwomen [158 159] Interestingly after the age of 55 bouts ofdepression and anxiety appear to decrease in women [160]As previously mentioned perimenopausal women receivingCEE in the KEEPs study reported an improvement in moodand the primary actions of CEE tend to be mediated throughER120573 [20] A plethora of behavioral studies has mountedin response to observational reports and at first glance itappears that ER120573 has an anxiolytic and antidepressive rolehowever there is still an immense void to be filled withrespect to biochemical and molecular mechanisms of ER120573and affective disorders Elucidating the precise molecularmechanisms that require ER120573 in plasticity and neurotrans-mitter processing in brain regions regulating these behaviorswill help clarify the role of E

2in stress- and mood-related

processesContemporary hypotheses concerning the onset of affec-

tive disorders revolve around perturbations to the cen-tral processing of environmental stress The hypothalamic-pituitary-adrenal (HPA) axis is the 3-tiered hierarchicalbiological system that mediates physical or psychologicalresponse to stressors The primary steroid regulating theHPA axis is cortisolcorticosterone (humansrats CORT) aglucocorticoid receptor (GR) ligand that is produced fromthe adrenals to exert negative feedback upon the HPAsystem to effectively modulate response to stressors Theparaventricular nucleus of hypothalamus (PVN) producestwo neuropeptides corticotropin-releasing hormone (CRH)and arginine vasopressin (AVP) to activate the HPA axisCRF and AVP synergistically stimulate release of adreno-corticotropic hormone (ACTH) from the anterior pituitarywhich acts on the adrenal cortex to produce CORT CORT

binds GR and negatively regulates CRF and AVP expressionsand releases through classical negative feedback mechanisms[161 162] ER120573 is themain ER expressed in the PVN [158 163ndash165] and regulation of AVP is an interesting example of howER action can vary AVP expression fluctuates during themenstrual cycle and is usually highest when E

2is low In fact

oral contraceptives appear to decrease AVP expression andE2is thought to inhibit AVP in the human SON [166] In

the rodent system ER120573 and its splice variants activate therodent AVP promoter independent of ligand [84] howeverthe human promoter is repressed by ER120573 and splice variantsThis discrepancy between the human and rat wasmediated byan AP-1 response element on the human AVP promoter thatis not present in the rat Importantly ER120573 acted similarly inthe two systems when the AP-1 sequence was deleted fromthe human promoter underscoring the striking alterationsthat small changes in DNA sequence can invoke in E

2

signaling pathways and the importance of understanding theexperimental context upon which such conclusions are based[77] On the contrary rat and human CRF expression wasincreased in response to E

2in rodent monkey and human

hypothalamus but it was inhibited in the placenta [167ndash170]In addition to AVP and CRF glutamatergic and GABAer-

gic projects from regions like the BNST AMY PFC andhippocampus all express ER120573 [45 46] and are likely targetsfor E2to exert effects on the HPA axis Moreover decreased

ER120573 mRNA in postmortem locus coeruleus has been foundto correlate with suicide [13] and even more recentlyER120573-mediated hippocampal nitric oxide levels have beenimplicated in affective behaviors in females but not males[171] Neurotransmitter release from these regions influencesmood affect and stress responses and E

2increases the rate

of monoamine oxidase degradation and serotonin transportwhich enhances serotonin at the synapse E

2also increases

serotonin receptor expression [172 173] Dopamine andserotonin [174] are diminished in the BNST POA and hip-pocampus and caudate putamen (dopamine) of 120573ERKOmice[174] further implicating an important role for ER120573 in theregulation of emotion and mood 120573ERKO mice also displayserious morphological and functional abnormalities in thebrain that correlate to increased depression and anxiety [12175ndash178] In addition to 120573ERKO studies administration ofER120573 selective agonists (diarylpoprionitrile DPN) decreasesboth stress markers and anxiety-related behaviors in rats[158] In fact there have been several studies implicatingER120573 and its variants in affective behaviors but the molecularmechanisms remain poorly understood

13 Summary

Estrogen-receptor-mediated signaling in the brain regulatesneurological processes many of which translate to cog-nitive and affective behavioral outputs When estrogen isdeclining and becomes replete as in menopause a num-ber of neurophysiological changes occur producing someunwanted changes The most common and logical remedyis replacement of bioidentical hormone E

2 however this

treatment can be problematic depending upon the length

10 ISRN Endocrinology

of time a woman has been in a postmenopausal estrogen-deprived state This suggests that there is a molecular switchin estrogen-mediated signaling that may allow for drasticchange in ER signaling not to mention the interaction of E

2

signaling components and the natural aging process Thesechanges are likely to include alterations to receptor profilesincluding expression of alternatively spliced variants thatrespond differently to E

2 changes in the cellular microenvi-

ronment that can alter the proteinprotein associations whichultimately leads to changes in ER-mediated gene transcrip-tion and synaptic transmission ER120573 in particular is widelyexpressed and implicated positively in the regulation ofmemory and mood fluctuations two of the most commonlyreported neurological issues in postmenopausal women Itis important to understand the actions of ER120573 in the areasregulating these processes to identify what when how andfor whom hormone therapy may be a useful treatment torectify cognitive and affective issues

Acknowledgments

This work was supported by NIA RO1 AG033605-01 andNIH T32 AG031780 The authors N N Mott and T R Pakhave nothing to disclose

References

[1] C Bengtsson O Lindquist and L Redvall ldquoIs the menopausalage rapidly changingrdquoMaturitas vol 1 no 3 pp 159ndash164 1979

[2] A Singh S Kaur and I Walia ldquoA historical perspective onmenopause andmenopausal agerdquo Bulletin of the Indian Instituteof History of Medicine (Hyderabad) vol 32 no 2 pp 121ndash1352002

[3] P Verhaeghen and J Cerella ldquoAging executive control andattention a review of meta-analysesrdquo Neuroscience and Biobe-havioral Reviews vol 26 no 7 pp 849ndash857 2002

[4] T E Wroolie H A Kenna K E Williams et al ldquoDifferencesin verbal memory performance in postmenopausal womenreceiving hormone therapy 17120573-estradiol versus conjugatedequine estrogensrdquoAmerican Journal of Geriatric Psychiatry vol19 no 9 pp 792ndash802 2011

[5] B B Sherwin ldquoEstrogenic effects on memory in womenrdquoAnnals of the New York Academy of Sciences vol 743 pp 213ndash230 1994

[6] B B Sherwin ldquoHormones mood and cognitive functioning inpostmenopausal womenrdquoObstetrics andGynecology vol 87 no2 supplement pp 20Sndash26S 1996

[7] B B Sherwin ldquoSex hormones and psychological functioning inpostmenopausalwomenrdquoExperimentalGerontology vol 29 no3-4 pp 423ndash430 1994

[8] SM Phillips and B B Sherwin ldquoEffects of estrogen onmemoryfunction in surgically menopausal womenrdquo Psychoneuroen-docrinology vol 17 no 5 pp 485ndash495 1992

[9] R Lindsay J M Aitken and J B Anderson ldquoLong term pre-vention of postmenopausal osteoporosis by oestrogen Evidencefor an increased bone mass after delayed onset of oestrogentreatmentrdquoThe Lancet vol 1 no 7968 pp 1038ndash1040 1976

[10] J E Rossouw R L Prentice J E Manson et al ldquoPost-menopausal hormone therapy and risk of cardiovascular dis-ease by age and years since menopauserdquo The Journal of the

American Medical Association vol 297 no 13 pp 1465ndash14772007

[11] Q-G Zhang D Han R-M Wang et al ldquoC terminusof Hsc70-interacting protein (CHIP)-mediated degradationof hippocampal estrogen receptor-120572 and the critical periodhypothesis of estrogen neuroprotectionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 108 no 35 pp E617ndashE624 2011

[12] W Krezel S Dupont A Krust P Chambon and P F ChapmanldquoIncreased anxiety and synaptic plasticity in estrogen receptor120573-deficient micerdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 21 pp 12278ndash12282 2001

[13] H Ostlund E Keller and Y L Hurd ldquoEstrogen receptor geneexpression in relation to neuropsychiatric disordersrdquo Annals ofthe New York Academy of Sciences vol 1007 pp 54ndash63 2003

[14] S A Shumaker C Legault S R Rapp et al ldquoEstrogen plusprogestin and the incidence of dementia and mild cognitiveimpairment in postmenopausal women the Womenrsquos HealthInitiative Memory Study a randomized controlled trialrdquo Jour-nal of the American Medical Association vol 289 no 20 pp2651ndash2662 2003

[15] S A Shumaker C Legault L Kuller et al ldquoConjugated equineestrogens and incidence of probable dementia and mild cog-nitive impairment in postmenopausal women womenrsquos HealthInitiative Memory Studyrdquo Journal of the American MedicalAssociation vol 291 no 24 pp 2947ndash2958 2004

[16] S R Rapp M A Espeland S A Shumaker et al ldquoEffect ofestrogen plus progestin on global cognitive function in post-menopausal women the Womenrsquos Health Initiative MemoryStudy a randomized controlled trialrdquo Journal of the AmericanMedical Association vol 289 no 20 pp 2663ndash2672 2003

[17] VWHenderson K S Benke R C Green L A Cupples and LA Farrer ldquoPostmenopausal hormone therapy and Alzheimerrsquosdisease risk interaction with agerdquo Journal of Neurology Neuro-surgery and Psychiatry vol 76 no 1 pp 103ndash105 2005

[18] E Garbe and S Suissa ldquoHormone replacement therapy andacute coronary syndromes methodological issues betweenrandomized and observational studiesrdquo Human Reproductionvol 19 no 1 pp 8ndash13 2004

[19] B B Braden A N Garcia S E Mennenga et al ldquoCognitive-impairing effects of medroxyprogesterone acetate in the ratindependent and interactive effects across timerdquo Psychophar-macology vol 218 no 2 pp 405ndash418 2011

[20] B R Bhavnani S-P Tam and X Lu ldquoStructure activity rela-tionships and differential interactions and functional activity ofvarious equine estrogens mediated via estrogen receptors (ERs)ER120572 and ER120573rdquo Endocrinology vol 149 no 10 pp 4857ndash48702008

[21] E Hogervorst and S Bandelow ldquoSex steroids to maintaincognitive function in women after the menopause a meta-analyses of treatment trialsrdquoMaturitas vol 66 no 1 pp 56ndash712010

[22] D J Mangelsdorf C Thummel M Beato et al ldquoThe nuclearreceptor super-family the second decaderdquo Cell vol 83 no 6pp 835ndash839 1995

[23] E V Jensen T Suzuki T Kawashima W E Stumpf P WJungblut and E R DeSombre ldquoA two-step mechanism forthe interaction of estradiol with rat uterusrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 59 no 2 pp 632ndash638 1968

ISRN Endocrinology 11

[24] F Naftolin T L Horvath R L Jakab C Leranth N Haradaand J Balthazart ldquoAromatase immunoreactivity in axon termi-nals of the vertebrate brain an immunocytochemical study onquail rat monkey and human tissuesrdquoNeuroendocrinology vol63 no 2 pp 149ndash155 1996

[25] C E Roselli S E Abdelgadir O K Roslashnnekleiv and S AKlosterman ldquoAnatomic distribution and regulation of aro-matase gene expression in the rat brainrdquo Biology of Reproduc-tion vol 58 no 1 pp 79ndash87 1998

[26] J Balthazart and G F Ball ldquoIs brain estradiol a hormone or aneurotransmitterrdquo Trends in Neurosciences vol 29 no 5 pp241ndash249 2006

[27] T R Pak Y S Rao S A Prins and N N Mott ldquoAn emergingrole for microRNAs in sexually dimorphic neurobiologicalsystemsrdquo Pflugers Archiv vol 465 no 5 pp 655ndash667 2013

[28] K Yamagata S Fujiyama S Ito et al ldquoMaturation ofmicroRNAis hormonally regulated by a nuclear receptorrdquo Molecular Cellvol 36 no 2 pp 340ndash347 2009

[29] Y Masuhiro Y Mezaki M Sakari et al ldquoSplicing potentiationby growth factor signals via estrogen receptor phosphorylationrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 23 pp 8126ndash8131 2005

[30] A Tremblay G B Tremblay F Labrie and V Giguere ldquoLigand-Independent recruitment of SRC-1 to estrogen receptor 120573through phosphorylation of activation function AF-1rdquo Molec-ular Cell vol 3 no 4 pp 513ndash519 1999

[31] S H Meijsing M A Pufall A Y So D L Bates L Chenand K R Yamamoto ldquoDNA binding site sequence directsglucocorticoid receptor structure and activityrdquo Science vol 324no 5925 pp 407ndash410 2009

[32] W Bourguet P Germain and H Gronemeyer ldquoNuclearreceptor ligand-binding domains three-dimensional struc-tures molecular interactions and pharmacological implica-tionsrdquo Trends in Pharmacological Sciences vol 21 no 10 pp381ndash388 2000

[33] A Koide C Zhao M Naganuma et al ldquoIdentification ofregions within the F domain of the human estrogen receptor 120572that are important for modulating transactivation and protein-protein interactionsrdquoMolecular Endocrinology vol 21 no 4 pp829ndash842 2007

[34] D F Skafar and S Koide ldquoUnderstanding the human estrogenreceptor-alpha using targeted mutagenesisrdquoMolecular and Cel-lular Endocrinology vol 246 no 1-2 pp 83ndash90 2006

[35] E C Chang J Frasor B Komm and B S KatzenellenbogenldquoImpact of estrogen receptor 120573 on gene networks regulated byestrogen receptor 120572 in breast cancer cellsrdquo Endocrinology vol147 no 10 pp 4831ndash4842 2006

[36] X Zhu I Leav Y-K Leung et al ldquoDynamic regulation ofestrogen receptor-120573 expression by DNA methylation duringprostate cancer development andmetastasisrdquoAmerican Journalof Pathology vol 164 no 6 pp 2003ndash2012 2004

[37] D N Petersen G T Tkalcevic P H Koza-Taylor T G Turiand T A Brown ldquoIdentification of estrogen receptor 1205732 afunctional variant of estrogen receptor 120573 expressed in normalrat tissuesrdquo Endocrinology vol 139 no 3 pp 1082ndash1092 1998

[38] L A Helguero M H Faulds J-A Gustafsson and L-AHaldosen ldquoEstrogen receptors alfa (ER120572) and beta (ER120573)differentially regulate proliferation and apoptosis of the normalmurine mammary epithelial cell line HC11rdquo Oncogene vol 24no 44 pp 6605ndash6616 2005

[39] P C Kulakosky M A McCarty S C Jernigan K E Risingerand C M Klinge ldquoResponse element sequence modulates

estrogen receptor 120572 and 120573 affinity and activityrdquo Journal ofMolecular Endocrinology vol 29 no 1 pp 137ndash152 2002

[40] OM V Grober MMutarelli G Giurato et al ldquoGlobal analysisof estrogen receptor beta binding to breast cancer cell genomereveals an extensive interplay with estrogen receptor alpha fortarget gene regulationrdquo BMC Genomics vol 12 article 36 2011

[41] O I Vivar X Zhao E F Saunier et al ldquoEstrogen receptor 120573binds to and regulates three distinct classes of target genesrdquoJournal of Biological Chemistry vol 285 no 29 pp 22059ndash22066 2010

[42] G G J M Kuiper E Enmark M Pelto-Huikko S Nilssonand J-A Gustafsson ldquoCloning of a novel estrogen receptorexpressed in rat prostate and ovaryrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 93 no12 pp 5925ndash5930 1996

[43] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and 120572 and 120573rdquo Endocrinology vol 138no 3 pp 863ndash870 1997

[44] D B Dubal H Zhu J Yu et al ldquoEstrogen receptor alpha notbeta is a critical link in estradiol-mediated protection againstbrain injuryrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 98 no 4 pp 1952ndash1957 2001

[45] P J Shughrue P J Scrimo and I Merchenthaler ldquoEvidence forthe colocalization of estrogen receptor-120573 mRNA and estrogenreceptor-120572 immunoreactivity in neurons of the rat forebrainrdquoEndocrinology vol 139 no 12 pp 5267ndash5270 1998

[46] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in therat central nervous systemrdquo Journal of Comparative Neurologyvol 388 no 4 pp 507ndash525 1997

[47] T AMilner B SMcEwen S Hayashi C J Li L P Reagan andS E Alves ldquoUltrastructural evidence that hippocampal alphaestrogen receptors are located at extranuclear sitesrdquoThe Journalof Comparative Neurology vol 429 no 3 pp 355ndash371 2001

[48] T A Milner L S Lubbers S E Alves and B S McEwenldquoNuclear and extranuclear estrogen binding sites in the ratforebrain and autonomic medullary areasrdquo Endocrinology vol149 no 7 pp 3306ndash3312 2008

[49] T A Milner K Ayoola C T Drake et al ldquoUltrastructurallocalization of estrogen receptor 120573 immunoreactivity in the rathippocampal formationrdquo Journal of ComparativeNeurology vol491 no 2 pp 81ndash95 2005

[50] A E Herbison andD TTheodosis ldquoAbsence of estrogen recep-tor immunoreactivity in somatostatin (SRIF) neurons of theperiventricular nucleus but sexually dimorphic colocalizationof estrogen receptor and SRIF immunoreactivities in neuronsof the bed nucleus of the stria terminalisrdquo Endocrinology vol132 no 4 pp 1707ndash1714 1993

[51] K Kalita S Szymczak and L Kaczmarek ldquoNon-nuclear estro-gen receptor 120573 and 120572 in the hippocampus of male and femaleratsrdquo Hippocampus vol 15 no 3 pp 404ndash412 2005

[52] T Ivanova and C Beyer ldquoOntogenetic expression and sexdifferences of aromatase and estrogen receptor-120572120573 mRNA inthe mouse hippocampusrdquo Cell and Tissue Research vol 300 no2 pp 231ndash237 2000

[53] C Y Pau K-Y F Pau and H G Spies ldquoPutative estrogenreceptor 120573 and 120572 mRNA expression in male and female rhesusmacaquesrdquo Molecular and Cellular Endocrinology vol 146 no1-2 pp 59ndash68 1998

[54] A L Wijayaratne and D P McDonnell ldquoThe human estrogenreceptor-120572 is a ubiquitinated protein whose stability is affected

12 ISRN Endocrinology

differentially by agonists antagonists and selective estrogenreceptor modulatorsrdquo Journal of Biological Chemistry vol 276no 38 pp 35684ndash35692 2001

[55] V Bartella P Rizza I Barone et al ldquoEstrogen receptor betabinds Sp1 and recruits a corepressor complex to the estrogenreceptor alpha gene promoterrdquo Breast Cancer Research andTreatment vol 134 no 2 pp 569ndash581 2012

[56] L C Li C C Yeh D Nojima and R Dahiya ldquoCloning andcharacterization of human estrogen receptor beta promoterrdquoBiochemical and Biophysical Research Communications vol 275no 2 pp 682ndash689 2000

[57] E A Vladusic A E Hornby F K Guerra-Vladusic J Lakinsand R Lupu ldquoExpression and regulation of estrogen receptor szligin human breast tumors and cell linesrdquoOncology Reports vol 7no 1 pp 157ndash167 2000

[58] T Hatsumi and Y Yamamuro ldquoDownregulation of estrogenreceptor gene expression by exogenous 17120573-estradiol in themammary glands of lactating micerdquo Experimental Biology andMedicine vol 231 no 3 pp 311ndash316 2006

[59] H B Patisaul P L Whitten and L J Young ldquoRegulation ofestrogen receptor beta mRNA in the brain opposite effectsof 17120573-estradiol and the phytoestrogen coumestrolrdquoMolecularBrain Research vol 67 no 1 pp 165ndash171 1999

[60] T J Brown N J MacLusky M Shanabrough and F NaftolinldquoComparison of age- and sex-related changes in cell nuclearestrogen-binding capacity and progestin receptor induction inthe rat brainrdquo Endocrinology vol 126 no 6 pp 2965ndash29721990

[61] B S Rubin T O Fox and R S Bridges ldquoEstrogen bindingin nuclear and cytosolic extracts from brain and pituitary ofmiddle-aged female ratsrdquo Brain Research vol 383 no 1-2 pp60ndash67 1986

[62] T Funabashi S P Kleopoulos P J Brooks et al ldquoChangesin estrogenic regulation of estrogen receptor 120572 mRNA andprogesterone receptor mRNA in the female rat hypothalamusduring aging an in situ hybridization studyrdquo NeuroscienceResearch vol 38 no 1 pp 85ndash92 2000

[63] M E Wilson K L Rosewell M L Kashon P J Shughrue IMerchenthaler and P M Wise ldquoAge differentially influencesestrogen receptor-120572 (ER120572) and estrogen receptor-120573 (ER120573) geneexpression in specific regions of the rat brainrdquo Mechanisms ofAgeing and Development vol 123 no 6 pp 593ndash601 2002

[64] W S Post P J Goldschmidt-Clermont C C Wilhide etal ldquoMethylation of the estrogen receptor gene is associatedwith aging and atherosclerosis in the cardiovascular systemrdquoCardiovascular Research vol 43 no 4 pp 985ndash991 1999

[65] J-P J Issa Y L Ottaviano P Celano S R Hamilton NE Davidson and S B Baylin ldquoMethylation of the oestrogenreceptor CpG island links ageing and neoplasia in humancolonrdquo Nature Genetics vol 7 no 4 pp 536ndash540 1994

[66] T Funabashi and F Kimura ldquoEffects of estrogen and estrogenreceptor messenger RNA levels in young and middle-agedfemale rats comparison ofmedial preoptic area andmediobasalhypothalamusrdquo Acta Biologica Hungarica vol 45 no 2ndash4 pp223ndash231 1994

[67] M AMiller P E Kolb B Planas andM A Raskind ldquoEstrogenreceptor and neurotensinneuromedin-N gene expression inthe preoptic area are unaltered with age in Fischer 344 femaleratsrdquo Endocrinology vol 135 no 5 pp 1986ndash1995 1994

[68] T R Chakraborty P R Hof L Ng and A C Gore ldquoStereologicanalysis of estrogen receptor alpha (ER alpha) expression in rat

hypothalamus and its regulation by aging and estrogenrdquo Journalof Comparative Neurology vol 466 no 3 pp 409ndash421 2003

[69] J M Westberry A L Trout and M E Wilson ldquoEpigeneticregulation of estrogen receptor beta expression in the rat cortexduring agingrdquo NeuroReport vol 22 no 9 pp 428ndash432 2011

[70] T R Chakraborty L Ng and A C Gore ldquoAge-related changesin estrogen receptor 120573 in rat hypothalamus a quantitativeanalysisrdquo Endocrinology vol 144 no 9 pp 4164ndash4171 2003

[71] I Poola S Koduri S Chatra and R Clarke ldquoIdentificationof twenty alternatively spliced estrogen receptor alpha mRNAsin breast cancer cell lines and tumors using splice targetedprimer approachrdquo Journal of Steroid Biochemistry andMolecularBiology vol 72 no 5 pp 249ndash258 2000

[72] T A Ishunina and D F Swaab ldquoHippocampal estrogenreceptor-alpha splice variant TADDI in the human brain inaging and Alzheimerrsquos diseaserdquoNeuroendocrinology vol 89 no2 pp 187ndash199 2009

[73] T A Ishunina and D F Swaab ldquoEstrogen receptor-120572 splicevariants in the human brainrdquo Gynecological Endocrinology vol24 no 2 pp 93ndash98 2008

[74] T A Ishunina F P M Kruijver R Balesar and D FSwaab ldquoDifferential expression of estrogen receptor 120572 and 120573immunoreactivity in the human supraoptic nucleus in rela-tion to sex and agingrdquo Journal of Clinical Endocrinology andMetabolism vol 85 no 9 pp 3283ndash3291 2000

[75] T A Ishunina D F Fischer andD F Swaab ldquoEstrogen receptor120572 and its splice variants in the hippocampus in aging andAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 28 no 11 pp1670ndash1681 2007

[76] J R Tollervey Z Wang T Hortobagyi et al ldquoAnalysis of alter-native splicing associated with aging and neurodegeneration inthe human brainrdquo Genome Research vol 21 no 10 pp 1572ndash1582 2011

[77] N NMott and T R Pak ldquoCharacterisation of human oestrogenreceptor beta (ER120573) splice variants in neuronal cellsrdquo Journal ofNeuroendocrinology vol 24 no 10 pp 1311ndash1321 2012

[78] S Inoue S-J Hoshino H Miyoshi et al ldquoIdentification ofa ovel isoform of estrogen receptor a potential inhibitor ofestrogen action in vascular smooth muscle cellsrdquo Biochemicaland Biophysical Research Communications vol 219 no 3 pp766ndash772 1996

[79] J K Skipper L J Young J M Bergeron M T Tetzlaff CT Osborn and D Crews ldquoIdentification of an isoform ofthe estrogen receptor messenger RNA lacking exon four andpresent in the brainrdquo Proceedings of the National Academy ofSciences of the United States of America vol 90 no 15 pp 7172ndash7175 1993

[80] R H Price Jr N Lorenzon and R J Handa ldquoDifferentialexpression of estrogen receptor beta splice variants in rat brainidentification and characterization of a novel variant missingexon 4rdquo Brain Research Molecular Brain Research vol 80 no2 pp 260ndash268 2000

[81] S Chu and P J Fuller ldquoIdentification of a splice variantof the rat estrogen receptor 120573 generdquo Molecular and CellularEndocrinology vol 132 no 1-2 pp 195ndash199 1997

[82] B Lu E Leygue H Dotzlaw L J Murphy L C Murphy andP H Watson ldquoEstrogen receptor-120573 mRNA variants in humanand murine tissuesrdquoMolecular and Cellular Endocrinology vol138 no 1-2 pp 199ndash203 1998

[83] T R Pak W C J Chung J L Roberts and R J HandaldquoLigand-independent effects of estrogen receptor 120573 on

ISRN Endocrinology 13

mouse gonadotropin-releasing hormone promoter activityrdquoEndocrinology vol 147 no 4 pp 1924ndash1931 2006

[84] T R Pak W C J Chung L R Hinds and R J HandaldquoEstrogen receptor-120573 mediates dihydrotestosterone-inducedstimulation of the arginine vasopressin promoter in neuronalcellsrdquo Endocrinology vol 148 no 7 pp 3371ndash3382 2007

[85] Y K Leung PMak S Hassan and SMHo ldquoEstrogen receptor(ER)-120573 isoforms a key to understanding ER-120573 signalingrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 103 no 35 pp 13162ndash13167 2006

[86] J M Wang X Hou S Adeosun et al ldquoA dominant negativeER120573 splice variant determines the effectiveness of early or lateestrogen therapy after ovariectomy in ratsrdquo PLoS One vol 7 no3 Article ID e33493 2012

[87] W C J Chung T R Pak S Suzuki W A Pouliot M EAndersen and R J Handa ldquoDetection and localization of anestrogen receptor beta splice variant protein (ER1205732) in theadult female rat forebrain and midbrain regionsrdquo Journal ofComparative Neurology vol 505 no 3 pp 249ndash267 2007

[88] R H Price Jr C A Butler P Webb R Uht P Kushner andR J Handa ldquoA splice variant of estrogen receptor 120573 missingexon 3 displays altered subnuclear localization and capacity fortranscriptional activationrdquo Endocrinology vol 142 no 5 pp2039ndash2049 2001

[89] Y Wang and R J Miksicek ldquoIdentification of a dominantnegative form of the human estrogen receptorrdquo MolecularEndocrinology vol 5 no 11 pp 1707ndash1715 1991

[90] E Kuppers and C Beyer ldquoExpression of estrogen receptor-120572and 120573 mRNA in the developing and adult mouse striatumrdquoNeuroscience Letters vol 276 no 2 pp 95ndash98 1999

[91] C Gundlah S G Kohama S J Mirkes V T Garyfallou H FUrbanski and C L Bethea ldquoDistribution of estrogen receptorbeta (ER120573) mRNA in hypothalamus midbrain and temporallobe of spayed macaque continued expression with hormonereplacementrdquo Brain Research Molecular Brain Research vol 76no 2 pp 191ndash204 2000

[92] Y Morishima P J M Murphy D-P Li E R Sanchez and WB Pratt ldquoStepwise assembly of a glucocorticoid receptorsdothsp90heterocomplex resolves two sequential ATP-dependent eventsinvolving first hsp70 and then hsp90 in opening of the steroidbinding pocketrdquo Journal of Biological Chemistry vol 275 no 24pp 18054ndash18060 2000

[93] K D Dittmar and W B Pratt ldquoFolding of the glucocorticoidreceptor by the reconstituted hsp90-based chaperone machin-eryThe initial hsp90sdotp60sdothsp70-dependent step is sufficient forcreating the steroid binding conformationrdquo Journal of BiologicalChemistry vol 272 no 20 pp 13047ndash13054 1997

[94] K I Kang X Meng J Devin-Leclerc et al ldquoThe molecularchaperone Hsp90 can negatively regulate the activity of aglucocorticosteroid-dependent promoterrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 4 pp 1439ndash1444 1999

[95] K Unno H Asakura Y Shibuya M Kaiho S Okada and NOku Naoto ldquoIncrease in basal level of Hsp70 consisting chieflyof constitutively expressed hsp70 (Hsc70) in aged rat brainrdquoJournals of Gerontology Series A vol 55 no 7 pp B329ndashB3352000

[96] U E Olazabal D W Pfaff and C V Mobbs ldquoSex differences inthe regulation of heat shock protein 70 kDa and 90 kDa in therat ventromedial hypothalamus by estrogenrdquo Brain Researchvol 596 no 1-2 pp 311ndash314 1992

[97] M A Pahlavani M D Harris S A Moore and A RichardsonldquoExpression of heat shock protein 70 in rat spleen lymphocytesis affected by age but not by food restrictionrdquo Journal ofNutrition vol 126 no 9 pp 2069ndash2075 1996

[98] A R Heydari B Wu R Takahashi R Strong and A Richard-son ldquoExpression of heat shock protein 70 is altered by age anddiet at the level of transcriptionrdquoMolecular andCellular Biologyvol 13 no 5 pp 2909ndash2918 1993

[99] M Sabbah K-I I Kang L Tora and G Redeuilh ldquoOestro-gen receptor facilitates the formation of preinitiation com-plex assembly involvement of the general transcription factorTFIIBrdquo Biochemical Journal vol 336 part 3 pp 639ndash646 1998

[100] S-Y Wu M C Thomas S Y Hou V Likhite and C-MChiang ldquoIsolation of mouse TFIID and functional character-ization of TBP and TFIID in mediating estrogen receptor andchromatin transcriptionrdquo Journal of Biological Chemistry vol274 no 33 pp 23480ndash23490 1999

[101] S Ghosh and M K Thakur ldquoTissue-specific expression ofreceptor-interacting protein in aging mouserdquo Age vol 30 no4 pp 237ndash243 2008

[102] J Frasor JM Danes B Komm K C N Chang C Richard Lyt-tle and B S Katzenellenbogen ldquoProfiling of estrogen up- anddown-regulated gene expression in human breast cancer cellsinsights into gene networks and pathways underlying estrogeniccontrol of proliferation and cell phenotyperdquo Endocrinology vol144 no 10 pp 4562ndash4574 2003

[103] J Frasor J M Danes C C Funk and B S Katzenellen-bogen ldquoEstrogen down-regulation of the corepressor N-CoRmechanism and implications for estrogen derepression of N-CoR-regulated genesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 102 no 37 pp13153ndash13157 2005

[104] N J McKenna and B W OrsquoMalley ldquoCombinatorial control ofgene expression by nuclear receptors and coregulatorsrdquoCell vol108 no 4 pp 465ndash474 2002

[105] T-P Yao G Ku N Zhou R Scully and D M Livingston ldquoThenuclear hormone receptor coactivator SRC-1 is a specific targetof p300rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 93 no 20 pp 10626ndash10631 1996

[106] B Hanstein R Eckner J DiRenzo et al ldquop300 is a componentof an estrogen receptor coactivator complexrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 93 no 21 pp 11540ndash11545 1996

[107] S Halachmi E Marden G Martin H MacKay C Abbon-danza and M Brown ldquoEstrogen receptor-associated proteinspossible mediators of hormone-induced transcriptionsrdquo Sci-ence vol 264 no 5164 pp 1455ndash1458 1994

[108] A J Horlein AM Naar T Heinzel et al ldquoLigand-independentrepression by the thyroid hormone receptor mediated by anuclear receptor co-repressorrdquo Nature vol 377 no 6548 pp397ndash404 1995

[109] J D Chen and R M Evans ldquoA transcriptional co-repressor thatinteracts with nuclear hormone receptorsrdquo Nature vol 377 no6548 pp 454ndash457 1995

[110] A Malovannaya R B Lanz S Y Jung et al ldquoAnalysis of thehuman endogenous coregulator complexomerdquoCell vol 145 no5 pp 787ndash799 2011

[111] Z Nawaz D M Lonard C L Smith et al ldquoThe Angelmansyndrome-associated protein E6-AP is a coactivator for thenuclear hormone receptor superfamilyrdquoMolecular and CellularBiology vol 19 no 2 pp 1182ndash1189 1999

14 ISRN Endocrinology

[112] B Zheng M Han M Bernier and J-K Wen ldquoNuclear actinand actin-binding proteins in the regulation of transcriptionand gene expressionrdquo FEBS Journal vol 276 no 10 pp 2669ndash2685 2009

[113] W A Hofmann L Stojiljkovic B Fuchsova et al ldquoActin is partof pre-initiation complexes and is necessary for transcription byRNA polymerase IIrdquoNature Cell Biology vol 6 no 11 pp 1094ndash1101 2004

[114] K Tokunaga T Shibuya Y Ishihama et al ldquoNucleocytoplasmictransport of fluorescent mRNA in living mammalian cellsnuclear mRNA export is coupled to ongoing gene transcrip-tionrdquo Genes to Cells vol 11 no 3 pp 305ndash317 2006

[115] R Metivier G Penot M R Hubner et al ldquoEstrogen receptor-120572 directs ordered cyclical and combinatorial recruitment ofcofactors on a natural target promoterrdquo Cell vol 115 no 6 pp751ndash763 2003

[116] C Ambrosino R Tarallo A Bamundo et al ldquoIdentification of ahormone-regulated dynamic nuclear actin network associatedwith estrogen receptor 120572 in human breast cancer cell nucleirdquoMolecular and Cellular Proteomics vol 9 no 6 pp 1352ndash13672010

[117] F Shao R Zhang L Dong and K Ying ldquoOverexpression ofgelsolin-like actin-capping protein is associated with progres-sion of lung adenocarcinomardquo Tohoku Journal of ExperimentalMedicine vol 225 no 2 pp 95ndash101 2011

[118] K Nishimura H-J Ting Y Harada et al ldquoModulation ofandrogen receptor transactivation by gelsolin a newly identi-fied androgen receptor coregulatorrdquo Cancer Research vol 63no 16 pp 4888ndash4894 2003

[119] J S Ahn I S Jang D I Kim et al ldquoAging-associated increaseof gelsolin for apoptosis resistancerdquoBiochemical and BiophysicalResearch Communications vol 312 no 4 pp 1335ndash1341 2003

[120] I Nalvarte T Schwend and J-A Gustafsson ldquoProteomicsanalysis of the estrogen receptor 120572 receptosomerdquoMolecular andCellular Proteomics vol 9 no 7 pp 1411ndash1422 2010

[121] L-H Miau C-J Chang B-J Shen W-H Tsai and S-C LeeldquoIdentification of heterogeneous nuclear ribonucleoprotein K(hnRNPK) as a repressor ofCEBP120573-mediated gene activationrdquoJournal of Biological Chemistry vol 273 no 17 pp 10784ndash107911998

[122] A Ostareck-Lederer D H Ostareck C Cans et al ldquoc-Src-mediated phosphorylation of hnRNP K drives translationalactivation of specifically silenced mRNAsrdquo Molecular and Cel-lular Biology vol 22 no 13 pp 4535ndash4543 2002

[123] P S Bagga G K Arhin and J Wilusz ldquoDSEF-1 is a member ofthe hnRNP H family of RNA-binding proteins and stimulatespre-mRNAcleavage and polyadenylation in vitrordquoNucleic AcidsResearch vol 26 no 23 pp 5343ndash5350 1998

[124] V Markovtsov J M Nikolic J A Goldman C W Turck M-Y Chou and D L Black ldquoCooperative assembly of an hnRNPcomplex induced by a tissue-specific homolog of polypyrimi-dine tract binding proteinrdquoMolecular and Cellular Biology vol20 no 20 pp 7463ndash7479 2000

[125] S Y Jung A Malovannaya J Wei B W OrsquoMalley and J QinldquoProteomic analysis of steady-state nuclear hormone receptorcoactivator complexesrdquoMolecular Endocrinology vol 19 no 10pp 2451ndash2465 2005

[126] W Hong R J Resnick C Rakowski D Shalloway S J Taylorand G A Blobel ldquoPhysical and functional interaction betweenthe transcriptional cofactor CBP and the KH domain proteinSam68rdquoMolecular Cancer Research vol 1 no 1 pp 48ndash55 2002

[127] R ShaoXWang BWeijdegard et al ldquoCoordinate regulation ofheterogeneous nuclear ribonucleoprotein dynamics by steroidhormones in the human fallopian tube and endometrium invivo and in vitrordquo American Journal of Physiology vol 302 no10 pp E1269ndashE1282 2012

[128] C SWoolley and B SMcEwen ldquoEstradiolmediates fluctuationin hippocampal synapse density during the estrous cycle in theadult ratrdquo Journal of Neuroscience vol 12 no 7 pp 2549ndash25541992

[129] C S Woolley H J Wenzel and P A Schwartzkroin ldquoEstradiolincreases the frequency of multiple synapse boutons in thehippocampal CA1 region of the adult female ratrdquo The Journalof Comparative Neurology vol 373 no 1 pp 108ndash117 1996

[130] C S Woolley ldquoEstrogen-mediated structural and functionalsynaptic plasticity in the female rat hippocampusrdquo Hormonesand Behavior vol 34 no 2 pp 140ndash148 1998

[131] D P Srivastava K M Woolfrey K A Jones et al ldquoRapidenhancement of two-step wiring plasticity by estrogen andNMDA receptor activityrdquo Proceedings of the National Academyof Sciences of the United States of America vol 105 no 38 pp14650ndash14655 2008

[132] M Ogiue-Ikeda N Tanabe H Mukai et al ldquoRapid modu-lation of synaptic plasticity by estrogens as well as endocrinedisrupters in hippocampal neuronsrdquo Brain Research Reviewsvol 57 no 2 pp 363ndash375 2008

[133] N J Sandstrom and C L Williams ldquoSpatial memory retentionis enhanced by acute and continuous estradiol replacementrdquoHormones and Behavior vol 45 no 2 pp 128ndash135 2004

[134] E Hogervorst J Williams M Budge W Riedel and JJolles ldquoThe nature of the effect of female gonadal hormonereplacement therapy on cognitive function in post-menopausalwomen a meta-analysisrdquo Neuroscience vol 101 no 3 pp 485ndash512 2000

[135] M E Bailey A C J Wang J Hao et al ldquoInteractive effects ofage and estrogen on cortical neurons implications for cognitiveagingrdquo Neuroscience vol 191 pp 148ndash158 2011

[136] A A Walf M E Rhodes and C A Frye ldquoOvarian steroidsenhance object recognition in naturally cycling and ovariec-tomized hormone-primed ratsrdquo Neurobiology of Learning andMemory vol 86 no 1 pp 35ndash46 2006

[137] V N Luine L F Jacome and N J Maclusky ldquoRapid enhance-ment of visual and place memory by estrogens in ratsrdquoEndocrinology vol 144 no 7 pp 2836ndash2844 2003

[138] L Fan Z Zhao P T Orr C H Chambers M C Lewis and KM Frick ldquoEstradiol-induced object memory consolidation inmiddle-aged femalemice requires dorsal hippocampal extracel-lular signal-regulated kinase and phosphatidylinositol 3-kinaseactivationrdquo Journal of Neuroscience vol 30 no 12 pp 4390ndash4400 2010

[139] D B Dubal and PMWise ldquoNeuroprotective effects of estradiolin middle-aged female ratsrdquo Endocrinology vol 142 no 1 pp43ndash48 2001

[140] S-H Yang J Shi A L Day and J W Simpkins ldquoEstradiolexerts neuroprotective effects when administered after ischemicinsultrdquo Stroke vol 31 no 3 pp 745ndash750 2000

[141] J W Simpkins G Rajakumar Y-Q Zhang et al ldquoEstrogensmay reduce mortality and ischemic damage caused by middlecerebral artery occlusion in the female ratrdquo Journal of Neuro-surgery vol 87 no 5 pp 724ndash730 1997

[142] J Shi K S Panickar S-H Yang O Rabbani A L Day and JWSimpkins ldquoEstrogen attenuates over-expression of 120573-amyloid

ISRN Endocrinology 15

precursor protein messager RNA in an animal model of focalischemiardquo Brain Research vol 810 no 1-2 pp 87ndash92 1998

[143] Q-H Zhang Y-H Huang Y-Z Hu et al ldquoDisruption ofestrogen receptor beta in mice brain results in pathologicalalterations resemblingAlzheimer diseaserdquoActa PharmacologicaSinica vol 25 no 4 pp 452ndash457 2004

[144] E F Rissman A L Heck J E Leonard M A Shupnik and J-A Gustafsson ldquoDisruption of estrogen receptor 120573 gene impairsspatial learning in female micerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no6 pp 3996ndash4001 2002

[145] M Day A Sung S Logue M Bowlby and R Arias ldquoBetaestrogen receptor knockout (BERKO) mice present attenuatedhippocampal CA1 long-term potentiation and related memorydeficits in contextual fear conditioningrdquo Behavioural BrainResearch vol 164 no 1 pp 128ndash131 2005

[146] R Vierk G Glassmeier L Zhou et al ldquoAromatase inhibitionabolishes LTP generation in female but not in male micerdquo TheJournal of Neuroscience vol 32 no 24 pp 8116ndash8126 2012

[147] R-M Vouimba M R Foy J G Foy and R FThompson ldquo17120573-estradiol suppresses expression of long-term depression in agedratsrdquo Brain Research Bulletin vol 53 no 6 pp 783ndash787 2000

[148] C E Andreescu B A Milojkovic E D Haasdijk et alldquoEstradiol improves cerebellar memory formation by activatingestrogen receptor 120573rdquo Journal of Neuroscience vol 27 no 40 pp10832ndash10839 2007

[149] Y-Y Huang P V Nguyen T Abel and E R Kandel ldquoLong-lasting forms of synaptic potentiation in the mammalian hip-pocampusrdquo Learning Memory vol 3 no 2-3 pp 74ndash85 1996

[150] H Mukai T Tsurugizawa G Murakami et al ldquoRapid mod-ulation of long-term depression and spinogenesis via synapticestrogen receptors in hippocampal principal neuronsrdquo Journalof Neurochemistry vol 100 no 4 pp 950ndash967 2007

[151] L Liu T P Wong M F Pozza et al ldquoRole of NMDA receptorsubtypes in governing the direction of hippocampal synapticplasticityrdquo Science vol 304 no 5673 pp 1021ndash1024 2004

[152] M Cyr O Ghribi C Thibault M Morissette M Landry andT di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[153] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[154] C C Smith and L L McMahon ldquoEstradiol-induced increasein the magnitude of long-term potentiation is prevented byblocking NR2B-containing receptorsrdquo Journal of Neurosciencevol 26 no 33 pp 8517ndash8522 2006

[155] Y Zhou J J Watters and D M Dorsa ldquoEstrogen rapidlyinduces the phosphorylation of the cAMP response elementbinding protein in rat brainrdquo Endocrinology vol 137 no 5 pp2163ndash2166 1996

[156] XGonda T TelekG Juhasz J Lazary AVargha andG BagdyldquoPatterns of mood changes throughout the reproductive cyclein healthy women without premenstrual dysphoric disordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 32 no 8 pp 1782ndash1788 2008

[157] E W Freeman ldquoPremenstrual syndrome and premenstrualdysphoric disorder definitions and diagnosisrdquo Psychoneuroen-docrinology vol 28 supplement 3 pp 25ndash37 2003

[158] T D Lund T Rovis W C J Chung and R J Handa ldquoNovelactions of estrogen receptor-120573 on anxiety-related behaviorsrdquoEndocrinology vol 146 no 2 pp 797ndash807 2005

[159] N Breslau L Schultz and E Peterson ldquoSex differences indepression a role for preexisting anxietyrdquo Psychiatry Researchvol 58 no 1 pp 1ndash12 1995

[160] P E Bebbington G Dunn R Jenkins et al ldquoThe influenceof age and sex on the prevalence of depressive conditionsreport from the National Survey of Psychiatric MorbidityrdquoPsychological Medicine vol 28 no 1 pp 9ndash19 1998

[161] G Aguilera J P Harwood and J X Wilson ldquoMechanisms ofaction of corticotropin-releasing factor and other regulators ofcorticotropin release in rat pituitary cellsrdquo Journal of BiologicalChemistry vol 258 no 13 pp 8039ndash8045 1983

[162] A Papadimitriou and K N Priftis ldquoRegulation of thehypothalamic-pituitary-adrenal axisrdquo NeuroImmunoModula-tion vol 16 no 5 pp 265ndash271 2009

[163] S Suzuki and R J Handa ldquoRegulation of estrogen receptor-120573expression in the female rat hypothalamus differential effectsof dexamethasone and estradiolrdquo Endocrinology vol 145 no 8pp 3658ndash3670 2004

[164] W J S Miller S Suzuki L K Miller R Handa and R M UhtldquoEstrogen receptor (ER)120573 isoforms rather than ER120572 regulatecorticotropin-releasing hormone promoter activity through analternate pathwayrdquo Journal of Neuroscience vol 24 no 47 pp10628ndash10635 2004

[165] C IsgorM CecchiM Kabbaj H Akil and S JWatson ldquoEstro-gen receptor 120573 in the paraventricular nucleus of hypothalamusregulates the neuroendocrine response to stress and is regulatedby corticosteronerdquo Neuroscience vol 121 no 4 pp 837ndash8452003

[166] M L Forsling I Kallo D E Hartley et al ldquoOestrogen receptor-120573 and neurohypophysial hormones functional interaction andneuroanatomical localisationrdquo Pharmacology Biochemistry andBehavior vol 76 no 3-4 pp 535ndash542 2003

[167] A S Lalmansingh and R M Uht ldquoEstradiol regulatescorticotropin-releasing hormone gene (crh) expression in arapid and phasic manner that parallels estrogen receptor-120572 and-120573 recruitment to a 3101584051015840-cyclic adenosine 51015840- monophosphateregulatory region of the proximal crh promoterrdquo Endocrinologyvol 149 no 1 pp 346ndash357 2008

[168] B N Roy R L Reid and D A van Vugt ldquoThe effects ofestrogen and progesterone on corticotropin-releasing hormoneand arginine vasopressin messenger ribonucleic acid levelsin the paraventricular nucleus and supraoptic nucleus of therhesus monkeyrdquo Endocrinology vol 140 no 5 pp 2191ndash21981999

[169] X Ni R C Nicholson B R King E-C Chan M A Read andR Smith ldquoEstrogen represses whereas the estrogen-antagonistICI 182780 stimulates placental CRH gene expressionrdquo Journalof Clinical Endocrinology and Metabolism vol 87 no 8 pp3774ndash3778 2002

[170] N C Vamvakopoulos and G P Chrousos ldquoEvidence of directestrogenic regulation of human corticotropin-releasing hor-mone gene expression Potential implications for the sexualdimophism of the stress response and immuneinflammatoryreactionrdquo Journal of Clinical Investigation vol 92 no 4 pp1896ndash1902 1993

[171] Y Hu D L Wu C X Luo et al ldquoHippocampal nitric oxidecontributes to sex difference in affective behaviorsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 35 pp 14224ndash14229 2012

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

EndocrinologyInternational Journal of

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Disease Markers

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BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ObesityJournal of

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

2 ISRN Endocrinology

demonstrate that (1) there is a critical window of timesurrounding menopause for which HT can be beneficialsuggesting that aging is an important factor (2) progestinsare not likely to be beneficial for cognitive and affectiveneurological issues and (3) the type of estrogen used maybe crucial Given these important conclusions this reviewwill focus on the molecular mechanisms of E

2signaling in

the brain and how variables that might contribute to thesesignaling patterns can be altered by age

2 The Menopausal Transition E2

Decline andHealth Concerns

Menopause is defined by the Mayo Clinic as ldquothe permanentend of menstruation and fertility occurring 12 months afteryour last menstrual periodrdquo Menopause is marked by areduced oocyte number attributable to progressive atresiaof ovarian follicles and by declining circulating levels of E

2

and progestinsThe perimenopausal transition is typically 4ndash8 years during which most women experience symptomsincluding hot flushes night sweats mood swings sleepdisturbances vaginal dryness and atrophy as well as urinaryincontinence most of which are alleviated by hormone (E

2)

replacement therapy (HTET) Until recently a great dealof evidence suggested that estrogens have positive effects oncognition neuroprotection memory anxiety depression aswell as bone and cardiovascular health [5 9ndash13]

The paramount studies to present negative consequencesof HT were the Womenrsquos Health Initiative (WHI) and theancillary studies including the Womenrsquos Health InitiativeStudy on Cognitive Aging (WHISCA) and the WomenrsquosHealth Initiative Memory Study (WHIMS) Data from thesestudies showed that a combination therapy of conjugatedequine estrogenmedroxyprogesterone acetate (CEEMPA)increased risk for mild cognitive impairment and decreasedglobal cognitive functioning but CEE alone did not have anysignificant effect on cognitive functioning [14ndash16] Poststudyanalyses have revealedmany confounding factors in theWHIstudies ranging from the choice of a reference group to the ageof participants and the choice of ET used (CEE) [4 17 18] aswell as the use ofMPA which has been shown to have adverseeffects onmemory after one dose in adulthood [19]While theWHI studies showed negative or neutral effects of estrogentherapy many other basic science and observational studieshave shown just the opposite The Kronos Early EstrogenPrevention Study (KEEPS) recently announced findings thatsuggested that E

2therapy had a positive effect on mood

and memory Participants receiving CEE showed significantimprovement in symptoms of depression anxiety and atrend toward reduced feelings of angerhostility ImportantlyCEE treatment or Premarin (Wyeth-Ayerst Philadelphia PAUSA) is a mixture of several estrogenic compounds butprimarily estrone sulfate and ring B unsaturated estrogenssuch as equilin and equilenin which can differentially acti-vate ER isoforms as compared to E

2alone [20] Participants

receiving CEE self-reported a trend toward better recallof printed materials as compared to placebo and womenusing transdermal E

2tended to report fewer memory-related

complaints Another study performed a meta-analysis of 36randomized HT clinical trials (RCT) focusing on cognition[21] The length of treatment type of memory variety ofhormone and age of the participant were all variables thatdrastically altered the outcomes of each trial Results fromthe meta-analysis indicated that verbal memory was mostoften affected by HT and younger women tended to have abetter outcome in this categoryThere was also a trend towardworse outcomes onmemory tests in patients treatedwithCEEtreatment alone compared to those treated with biologicallyidentical E

2 Moreover treatment with estrogens alone (ie

absent cotreatment with progestins) was overall associatedwith positive results on memory tests In conclusion datafrom these clinical trials have revealed the importance ofusing bioidentical hormones for HT and that downstreamsignaling processes for memory and mood can be affected bythe choice of estrogen andor combination of hormones usedas therapeutics

3 Estrogen Receptor Signaling

Estrogen signaling is mediated primarily through two recep-tors (ER120572 and ER120573) ERs are class I members of thenuclear hormone superfamily of receptors deemed as aligand-inducible transcription factors [22] Classically ERswere thought to be localized in the cytoplasm bound tointracellular chaperone proteins until induced by ligandto translocate to the nucleus according to the two-stephypothesis coined by Jensen et al [23] Following ligandbinding ERs undergo a conformational change that allowsfor dimerization translocation to the nucleus and DNAbinding or association with other transcription factors toregulate gene transcription however we now know that ERsignaling is much more complex

For example ERs are involved in other ldquonongenomicrdquomolecular functions including RNA processing second-messenger signaling cascades and rapid dendritic spineformation in neurons Of particular importance in the brainthe discovery of rapid signaling processes implicates E

2

as a neuromodulator however local synthesis of E2has

been the subject of fervent debate While it is likely thatthere is de novo synthesis of E

2within the parenchyma

due to technical challenges the exact levels and changeswith age and circulating hormones have yet to be identified[24 25] It is also difficult to determine how local E

2may

affect ER action Most reports suggest an implicit role forlocal E

2at the synapse and membrane [26] but whether

nucleargenomic activities of ERs are affected has yet to beestablished Recent data from our laboratory demonstratethat E

2can alter miRNA-expression [27] and from others

have shown that ER120572 can associate with miRNA processingenzymes such as Drosha [28] Data from our laboratory(unpublished observations) and others have shown that ERsare involved in alternative splicing processes and one studyhas demonstrated direct interaction of phosphorylated ER120572with splicing factor (SF) 3a p120 that potentiates alternativesplicing through EGFE

2crosstalk [29]These relatively novel

ER functions may be explained by examining well-studied

ISRN Endocrinology 3

components of classic NR signaling such as the structuralproperties of the receptors

4 Structural Contributions to ER Activity

Class I nuclear receptors (NRs) including ER120572 and ER120573have a characteristic structure comprised of five functionaldomains labeled AndashE and a sixth domain (F) unique to ERs(Figure 1) The AB domain contains an activator function-1-(AF-1-) like domain that allows for associations with coregu-latory proteins and other transcription factors Notably theAB domain is the least conserved domain between ER120572and ER120573 (17 homology) and it may be responsible forthe observed ligand-independent actions of ER120573 [30] The Cdomain is a DNA-binding domain that allows the receptorto bind a specific DNA sequence called an Estrogen ResponseElement (ERE) to regulate transcription of genes containingthis sequence within their promoter region Two zinc fingersforming a helix-loop-helix structure allow for appropriatespacing (3 nucleotides) between an inverted hexameric palin-dromic repeat that is described as the canonical ERE Theexact nucleotide sequence of hormone response elements canvary and in part dictate the affinity an NR has to regulate aparticular gene [31] The D domain is a hinge-like region thatallows the receptor to undergo a conformational change onceactivated and also contains a nuclear localization sequenceThe best-studied region of ERs is the E domain also referredto as the ligand-binding domain (LBD) Characterizationusing X-ray crystallography has shown that the LBD consistsof 12 ordered alpha-helices that are essential for conferringligand specificity [32] The orientation of helix 12 is critical tothe conformation NRs adopt once bound to a particular typeof ligand and ultimately influence the ability of the receptorto bind other proteins and activate gene transcription Helix12 contains the core residues of the activator function-2 (AF-2) domain a short amphipathic conserved alpha-helix thatinteracts with coregulatory proteins through an LxxLLmotifAdjacent to the AF-2E domain is the less characterized Fdomain that is unique to ERs ER120572 has a larger F domain thanER120573 and the two receptors only share about 18 homologywithin this region ER120572 dimerization and interactions withcoregulators are altered when the F domain is deleted ormodified demonstrating that the F domain is a relevantstructure for ER120572 transcriptional regulation but a clear rolefor this domain for ER120573 has yet to be determined [33 34]Importantly naturally occurring human ER120573 splice variantshave altered E and F domains which can affect hormoneresponsiveness in tissues that express these variants

While the overall sequence homology between ER120572 andER120573 is greater than 60 the specific gene targets of eachreceptor appear to be vastly different For example a varietyof cancer cell models have identified an antiapoptotic prolif-erative role for ER120572 whereas ER120573 tends to promote apoptosisand regulate antiproliferative genes [35ndash38] It is well knownthat ER120572 and ER120573 are readily able to form heterodimerswhen expressed in the same cell adding another layer ofcomplexity to the regulation of estrogen responsive genesER120572 andER120573 both bindEREs but the affinity for one receptor

AB

AB

AB

AB

C

C

C

C

D

D

D

D

E

E

E

E

F

FhER1205731

hER1205732

hER1205734

hER1205735

(a)

AB

AB

AB

AB

AB

AB

C

C

C

C

C

C

D

D

D

D

D

D

E

E

E

E

E

E

F

F

F

F

F

F

rER1205731

rER1205731Δ3

rER1205731Δ4

rER1205732

rER1205732Δ3

rER1205732Δ4

(b)

Figure 1 Representative image of domains within human andrat ER120573 splice variants Human ER120573 splice variants (a) containtruncations and changes in amino acid sequence in the C-terminusE and F domains Rat ER120573 splice variants (b) contain an 18-amino-acid insert in the LBDE domain andor exon 34 exclusions in theDNA-binding domain

or the other can depend highly on the specificity of the DNAsequence being regulated and the ligands present [39ndash41]Therefore it is important to consider the overlap in ER120572 andER120573 preferred transcriptional response elements when bothreceptors are expressed in the same system

5 Expression of ERs in the BrainA Complex Story

The principal determinant of E2action is the expression

of ER120572 ER120573 their alternatively spliced variants or somecombination of each which is cell-type specific even withindistinct brain nuclei ER expression has been studied exten-sively yet there are few definitive statements that can bemade about the regulation of ER120573 expression It can benoted that ER expression profiles can vary throughout thelife-span in particular when there are dramatic changes incirculating hormone levels such as puberty and menopause(Figure 2) Not only can ER expression vary dependentupon sex age and E

2treatment but these factors can also

direct subcellular localization which ultimately dictates ERfunctions Accordingly contextual studies that map the exactcellular expression patterns of each receptor and their splice

4 ISRN Endocrinology

Perimenopause(40s50s)

Postmenopause(50s+)

Peripuberty(preteens)

E2

Cyclicity

ΔER expression withhormone cyclicity ΔER expression with age

and E2 declineuarr ER splice variants

Figure 2 Timeline showing factors affecting ER gene expressionthroughout the female life-span Brain ER gene expression patternsare altered with age sex and exposure to circulating hormoneCirculating hormones fluctuate with age most dramatically at thetime of puberty andmenopause therefore contributing to changes inER gene expression Additionally alternative splicing increases withage thus potentially diversifying the ER gene expression profile

variants are a critical first step in creating a comprehensiveexamination of E

2-regulated processes in any system

The female vertebrate reproductive organs tend to bedominated by the expression of ER120572 whereas ER120573 isexpressed largely in nonreproductive tissues ER120573 was firstcloned from prostate tissue [42] and it has since been shownto have the highest levels of expression in the central nervoussystem and cardiovascular tissue as well as lung kidneycolorectal tissue mammary tissue and the immune system[43] Consequently some of the most prominent phenotypicproblems observed in mice lacking a functional ESR2 gene(120573ERKO mice) are neurological deficits By contrast ER120572knockout mice have no gross brain-related phenotypes butthey exhibit decreased E

2-mediated neuroprotection follow-

ing an ischemic event [44] Overall the phenotypes observedin ER120572- and ER120573-null mouse models suggest that ER120573 ispotentially more important for mediating nonreproductiveE2-governed processes than ER120572ER120572 and ER120573 are coexpressed in some regions of the

hypothalamus such as the medial amygdala (MeA) the bednucleus of the stria terminalis (BNST) and the periaqueduc-tal grey area However ER120572 is predominant in hypothala-mic nuclei that control reproduction sexual behavior andappetite (eg arcuate (ARC) medial preoptic (MPoA) andventromedial (VM)) but ER120573 is the predominant isoform inthe nonreproductive associated nuclei (eg paraventricular(PVN) supraoptic (SON) and suprachiasmatic (SCN)) aswell as the hippocampus dorsal raphe nuclei cortex andcerebellum [45 46] In the hippocampus mRNA and proteinfor both ERs have been detected and are well established asmediating both genomic and nongenomic processes [47ndash49]Nuclear and extranuclear ER120573mRNA and immunoreactivity(IR) have been detected in principal cells as well as inmany other nuclei of cells within the ventral CA23 [4647] Although not as prevalent as ER120573 ER120572 has also beendetected in the hippocampus primarily within GABAergicinterneurons [47 49]

ER expression is also often found to be sexually dimor-phic As onewould expectmany regions of the hypothalamusexhibit a great deal of sexual dimorphism due in part to dif-ferences in sexual behavior and regulation of gonadotrophic

hormones but regions such as the BNST also display somesex-related differences in ER expression For example ER120572 inthe BNST can be induced in somatostatin-positive neurons ofmale but not female rats [50] ERs have also been shown tobe sexually dimorphic in the developing rodent hippocam-pus but not in adults [51 52] However one report identifiedER120573mRNA in the adult female but notmale rhesusmacaquebasal ganglia and hippocampus [53] Importantly a lacksexually dimorphic regional ER expression does not precludedifferential responses to estrogens as other effectormoleculescan alter estrogen-responsive processes

Expression of ERs can vary not only with chromosomalsex but also in response to the hormonalmilieu For instanceit is well accepted that ER120572 expression is autoregulated byE2 primarily through proteasomal degradation [54] but also

perhaps on a transcriptional level by E2-bound ER120573 [55]The

ER120573 gene (ESR2) promoter region has not been extensivelycharacterized but it has been shown to contain E

2-responsive

cis sequence-binding sites for Oct-1 and Sp-1 which interactwith ERs via trans factors suggesting a molecular mechanismfor E2-mediated autoregulation of its receptor There is also

an Alu repeat sequence that may contain an ERE that couldact as an ER-dependent enhancer [56] Conversely in vitroand in vivo studies investigating the effects of E

2on ER120573

expression have yielded inconsistent conclusions dependingupon cell type animal species and age For instance in theT47D human breast cancer cell line E

2upregulated ER120573 [57]

However ER120573 expression was decreased by E2in mammary

glands of lactating mice that coexpress ER120572 [58] ER120573 wasalso decreased in the PVN of rats subjected to OVX+ E

2[59]

Thus it appears that E2may regulate ER120572 and ER120573 however

this effect is highly dependent upon cell type and possiblyupon the coexpression of other ERs

In addition to sex and E2 aging also appears to influence

ER expression Overall decreased nuclear E2binding has

been reported in the hypothalamus and anterior pituitary ofaged female rats compared to young ones but the changein E2binding was not necessarily attributed to a decrease

in total ER expression [60 61] suggesting a shift in theratio of ERs andor subcellular localization While overallnuclear E

2binding within the hypothalamus may decrease

with age changes to ER expression patterns with age remaincontentious In general it appears that age alone does noteliminate ER120572 expression in the brain but regional specificityand E

2availability may be important factors [62 63] and an

increase in ESR promoter methylation has been correlatedwith age in other systems [64 65] One study reported variedmiddle age-specific reduction in hypothalamic ER with E

2

treatment [66] yet another study showed that E2decreased

hypothalamic ER expression significantly in all ages tested(3 11 and 20 months) [67] Specific to ER120572 a work byChakraborty and colleagues determined that immunoreac-tive cell numbers did not always change following OVXand E

2replacement Rather their study revealed that with

advanced age (24ndash26 months compared to 3-4 and 10ndash12months) the number of ER120572-positive cells was increased or itstayed the same in different hypothalamic nuclei [68] In thehippocampus ER120572 was decreased after long-term estrogendeprivation (LTED 10 weeks) regardless of E

2replacement

ISRN Endocrinology 5

following LTED but E2deprivation had no effect on ER120573

[11] The same report demonstrated decreased levels of ER120573in very old rats (24-month females compared to 3-monthdiestrus females) In general most reports suggest that agingdecreases ER120573 expression but like ER120572 this effect may behighly region specific An age-related decrease in ER120573 expres-sion in the brain is underscored by a corresponding increaseinCpGmethylation of the ESR2 promoter inmiddle-aged (9ndash12months) rats [69] Other reports describe decreases in ER120573protein and message in some areas but not in others [63 70]Taken together there are a number of reports attemptingto identify the parameters that control ER expression suchas age sex and response to E

2 however with such vast

deviations in expression with cell type there is still much tobe learned about expression of these receptors especially inbrain regions controlling nonreproductive behaviors

6 Alternative Splice Variants

Based upon the highly variable reports that differ in sexand age of animals as well as exposure to hormone it maybe possible that these studies are unknowingly detectingchanges in splice variant expression which could change E

2

responsiveness as well as downstream gene regulation Notonly can ERs heterodimerize to regulate gene transcriptionbut there are a number of alternatively spliced variants of eachreceptor that are endogenously expressed and that potentiallycontribute to the diverse tissue-specific actions of E

2 Alter-

native splicing of ERs alters inherent signaling properties ofthe receptor including ligand and DNA-binding affinitiesnuclear localization and dimerization depending on wherethe alternative splice site is encoded A number of ER splicevariant transcripts and other proteins have been identifiedin demented human brains breast and prostate and insome reports an increase in alternative splicing is correlatedwith pathology [71ndash75] Also interesting age alone mayincrease alternative splicing of some gene products [76] Theidentified ER120573 human splice variants are truncated at the C-terminus of the receptor (Figure 1(a)) however we providedexperimental evidence that the C-terminus of the receptoris not required for ER120573-mediated transcription especiallywith regard to the identified human splice variants [77]Unlike the human splice variants rodent ER120573 splice variantsidentified to date have been shown to have either an exoninclusion in the ligand-binding domain creating (rER1205732)or an exon deletion in the DNA-binding domain rER1205731Δ3or rER1205731Δ4 or both rER1205732Δ3 and rER1205732Δ4 (Figure 1(b))[37 78 79] Exon inclusion (rER1205732 variants) has been shownto produce a protein that binds E

2with a 35-fold decrease

in affinity In contrast ERs with exon 3 and 4 deletions areunable to bind DNA but they can still mediate transcriptionthrough proteinprotein interactions with other transcriptionfactors such as AP-1 and it can bind E

2as well as rER1205731

[37 80] Importantly the transcriptional functions of rER1205731are significantly altered when coexpressed with other splicevariants likely due to a weaker interaction with coactivatorproteins [81 82] Despite lower E

2binding andor lack of

DNA binding the rodent and human splice variants retain a

constitutive ligand-independent transcriptional function atboth basic and complex promoters [77 83 84] suggestingthat these splice variants have an important endogenousbiological function Indeed unliganded ER1205731 or apo-ER1205731has been reported to regulate a subset of genes distinct fromthose regulated by ER1205731 when bound to E

2[41] Conversely

the human splice variants do not bind ligand with greataffinity [85] and they might therefore only regulate the classof genes that unliganded ER120573 targets

Thedownstream target genes of ER120573 splice variantsmightbe an important consideration at the time of menopauseas ER expression profiles and alternative splicing tend tochange with age [76] One recent report demonstrated anincrease in ER1205732 expression in the hippocampus of 9-month old middle-aged rats following short-term (6 days)E2deprivation that was significantly decreased compared to

the Sham group after E2administration [86] Importantly

E2replacement no longer affected ER1205732 expression in the

hippocampus after LTED (180 days)That study also reporteda decrease in hippocampal neurogenesis and increased float-ing behavior in a forced swim test thus functionally corre-lating increased ER1205732 with mood regulation and potentiallycognition Thus the expression and functions of ER120573 splicevariants are absolutely critical to understand the effects ofestrogen particularly at times of sustainedE

2deprivationwith

regard to cognition and affect While ER1205732 expression hasbeen assessed in the young male rat brain [87] and othervariants have been described in some brain regions [80 88]there is a general lack of data on most ER120573 splice variantsespecially in aged female brains

Some of the splice variants identified to date have beencharacterized as dominant negative receptors serving toinhibit activation of the full-length receptor [89] howevermost identified variants do not bind ligand with the sameaffinity and have the potential to differentially regulate targetgenes While several splice variants for ER120573 have been iden-tified in many model systems including mouse [90] rat [4546] and monkey [91] there is a general lack of comparativestudies on expression and functionality of human ER120573 vari-ants especially in neuronal systems Furthermore changingexpression levels of one or more alternatively spliced variantsduring a period of E

2deprivation may drastically change

general receptivity and downstream functions of E2

7 Novel ProteinProtein Interactions forE2-Mediated Nuclear Processes

Proteinprotein interactions are an essential relay in the reg-ulation of dynamic cellular processes Immediately followingtranslation ERs typically associate with a chaperone proteinto ensure proper folding protect from degradation and assistthe ER in becoming poised to accept ligand Once bound toligand ERs can dimerize and act as transcription factors tomediate gene regulation or associate withmembrane proteinsto initiate a signaling cascade When acting as transcriptionfactors ERs associate with a number of coregulatory proteinsthat assist in activating or repressing E

2-regulated genes

Coregulatory interactions are more characterized for ER120572

6 ISRN Endocrinology

than ER120573 and importantly less clear is how ER120573 mediatesligand-independent transcription In addition to the well-established ER interaction partners many novel interactingproteins have not yet been characterized and could be criticalfor nuclear processes not limited to gene transcription

8 HSPs and Chaperone Proteins

According to the classical two-step hypothesis inactivenuclear receptors are constantly accompanied and protectedfrom degradation by a number of chaperone proteins typi-cally members of the heat-shock protein (HSP) family Thisreceptorchaperone complex has been studied extensivelyand while the idea of a protective role for chaperones is wellsupported this complex can also perform other functionsFor instance HSPER complexes can serve to preactivatea hormone receptor by forcing a conformational changein ER such that it is able to bind its cognate hormoneThe initial HSP complex consists of the ER HSP70 andHSP70-interacting protein (HiP) as well as other accessoryand scaffolding proteins [92] HSP90 is recruited to thecomplex andHSP70 dissociates creating thematureHSPERcomplex [93] HSP90 induces a conformational change in thenuclear receptor and the ER is released from the complexready to dimerize and bind DNA or other transcriptionfactors to regulate gene transcription However some studiessuggest that HSPs could have a broader role than originallythought For example in Drosophila HSPs are required forDNA binding and in some instances they may regulateNR action [94] Interestingly aging and E

2can alter HSP70

in a cell-type specific manner [95ndash98] However recentdata from our lab (Table 1) demonstrated that HSP70 morereadily associates with ER120573 in aged female hippocampusfollowing E

2treatment compared to the young ones in which

HSP70ER120573 association decreased following E2treatment

We also observed no significant changes in HSP70 or ER120573expression suggesting that changes in the HSP70ER120573 inter-action with age in response to E

2change are a result of E

2

responsiveness andor activation of ER120573

9 Transcriptional Proteins and ERs

The process of transcribing DNA into RNA is a systematicprocess that involves multiprotein complexes binding toDNA modifying histone marks and initiating RNA synthe-sis ER120572 but not ER120573 has been shown to directly interactwith TFIIB IIE IIF and TIID proteins that initiate tran-scription [99 100] However experimental evidence from co-immunoprecipitation studies has demonstrated interactionsbetween ER120573 coregulatory proteins as well as other tran-scription factors Coregulatory proteins are transcriptionalaccessory proteins that enhance or repress transcription oftarget genes In general coactivators enhance gene tran-scription whereas corepressors block it However recentdata suggest that seemingly nontranscriptional proteins mayhave context-dependent coregulatory functions Importantly

certain coregulators can also be governed by age and E2[101ndash

103] thus recent discoveries imply that ER-mediated generegulation is not as well understood as previously thought

The best studied and well-established group of coregula-tory proteins that selectively associate with NRs is the steroidreceptor coactivator (SRCp160) family The SRC family iscomposed of three members SRC-1 SRC-2 and SRC-3all of which contain canonical LxxLL motifs known as thenuclear receptor (NR) box This motif interacts with AF-2 domains in ER120573 as well as other NR family memberssuch as glucocorticoid receptor (GR) progesterone receptor(PR) thyroid hormone receptor (TR) and ER120572 [104] SRCmembers have intrinsic histone acetyltransferase activity(HAT DNA activating) and interact with CREB-bindingprotein (CBP) [105] CBPp300 proteins are also coactivatorsthat have intrinsic HAT activity and can recruit ASC-2and other known coregulatory proteins [106] Confirmedcoregulatory interaction partners for several NRs that donot belong to the SRC family include estrogen-receptor-association protein (ERAP 140) [107] nuclear corepressor(NCoR) [108] silencing mediator of retinoic acid and thy-roid hormone receptor (SMRT) [109] and many othersAs is the case with our understanding of ER120573 interactionswith basic transcriptional machinery studies investigatingER120573coregulator interactions are sparse which may be dueto uniquely challenging issues associated with ER120573 such as alack of high-fidelity biochemical tools complicated structuralproperties and or pleiotropic physiological actions that arespecific to ER120573

In 2010 Anna Ma lovannaya and colleagues directeda high-throughput study (not including ER120573) aiming atcompiling a database for the endogenous coregulator poolldquonuclear receptor complexomerdquo [110] In this study a numberof novel protein interactions were identified and studiessuch as these are identifying proteins as ldquocoregulatorsrdquo thathad been previously thought to serve completely differentfunctionsOne group of relatively novel coregulatory proteinsare the E3 ubiquitin-protein ligases such as E6-associatedproteins (E6-AP) [111] While these proteins were thought toserve primarily as ubiquitin-conjugating enzymes they haverecently been highlighted as transcriptional enhancers ofNR-mediated activity independent of ligase function Similarlya group of E3-ligases that conjugate small ubiquitin likemodifier (SUMO) proteins to a target protein called PIASare also now considered NR coregulators and they utilize atypical LxxLLmotif In one study a decrease in ER expressionfollowing LTED or with advanced age coincided with anincrease in ER association with an E3-ubiquitin ligase CHIP[11] Together these newly described roles for HSPs and E3ligases raise novel questions about estrogen signaling such aswhen is an E3-ligaseER complex targeted for transcriptionalregulation versus degradation Also when are HSPs merelyperforming a chaperoneprotective function versus directingtranscriptional processes Future efforts aiming at elucidatingthe complexity of age-related changes in receptor structureand recruitment of coregulatory proteins could provideimportant insight into these seemingly paradoxical findings

ISRN Endocrinology 7

Table 1 Protein interactions with ER120573 were altered by age and 1198642 Selected proteins that were significantly altered (119875 lt 005) in their

association with ER120573 depending on age and 1198642treatment Experimental paradigm young (3 month) and aged (18 month) female Fischer 344

rats were ovariectomized and hormone deprived for 7 days Following deprivation animals were administered 25120583gkg 1198642(plasma levels =

7945 plusmn 225 pgmL) or vehicle (safflower oil) via subcutaneous injection onceday for 3 days Nuclear protein was isolated from the ventralhippocampus and coimmunoprecipitated for ER120573 (a beam 14C8) and associated proteins Protein interactions were identified and quantifiedusing 2D-DIGEDeCyder and ESI MSMS YV = young + vehicle YE = young + 119864

2 AV = aged + vehicle AE = aged + 119864

2

Accession noMolecularweight(Kda)

Estimatedisoelectricpoint

PEAKSscore Coverage ID

Interaction with ER120573FunctionYoung

vehicleYoung1198642

Agedvehicle

Aged1198642

gi| 149038929 80 575 494 643 Gelsolin mdash uarr mdash mdashActin-binding

coactivator

gi| 116242507 75 597 93 1458 Heat-shock protein70 mdash darr mdash uarr Chaperone

gi| 120538378 47 57 932 1072

Heterogeneousnuclear

ribonucleoproteinH12

mdash uarr mdash mdash RNA splicing

10 Nuclear Actin Setting the Stage

Coregulatory interactions may be poised upon a bed ofnuclear actin which has recently been identified as a dynamicmolecular stage for which many nuclear processes are per-formed such as transcription chromatin remodeling mRNAprocessing and nuclear importexport The general eventsthat initiate transcription are well established however theprocess by which all of the molecular components are tem-porally layered into a complex is still unclear Nuclear actin isessential in forming the preinitiation complex on a promoterelongation and RNP organization as well as remodeling ofchromatin [112ndash114] and as mentioned previously ERs arealso key factors in these processes In one study ER120572 and120573-actin were coimmunoprecipitated on the E

2responsive

pS2TFF1 promoter indicating that ER and nuclear actinmay work in concert to regulate transcriptional processesunder control of estrogens [115] The interaction betweenERs and actin is not yet fully investigated but data fromour lab (unpublished observations) and others [116] implythat both ER120572 and ER120573may utilize nuclear actin to performvarious functions Another actin-binding protein gelsolincaps actin filament ends and it has been shown to be anNR coactivator [117 118] Gelsolin may assist in actin poly-merization allowing transcriptionalmachinery to be broughtin proximity of target genes however it remains unclearhow gelsolin enhances ARER transcriptional activity Datafrom our lab indicate that gelsolinER120573 interactions increasewith E

2treatment in young but not aged animals (Table 1)

Gelsolin has been shown to increase with age [119] but alack of significant interaction with ER120573 despite increasedexpression of gelsolin could again suggest an alteration inER120573 function with age

Actin is also commonly associated with ubiquitous mul-tifunctional RNA-binding proteins such as heterologousnuclear riboproteins (hnRNPs) which also associate withERs [120] hnRNPs associate within the matrix of nuclearactin accompany transcripts out of the nucleus participatein alternative splicing and can modulate transcription [121]

Phosphorylated hnRNPK has been shown to mediate trans-lation of specific mRNAs [122] and hnRNPH is involvedin splicing and mRNA polyadenylation [123 124] In thepast the association of NRs with hnRNPs was thought to benonspecific due to the ubiquitous nature of these proteinsbut recent studies are no longer ruling out an importantinteraction between NRs and hnRNPs that may assist intranscription andor splicing [125 126] Data from our laband others demonstrate a dynamic interaction between bothER120572 and ER120573 and hnRNPs (Table 1) and furthermore datademonstrated that E

2might regulate expression of members

of the hnRNP family [127] As noted previously age-relatedincreases in splicing could lead to aberrant signaling not onlyfor E2-mediated processes but also for cellular processes in

generalNuclear ER interaction partners have historically been a

distinct class of nuclear receptor coregulators that seemedto solely assist ERs in gene transcription however thenumber of interaction partners for ERs is increasing Furtherinvestigation into ER120573-associated proteins is required as faras NRs are concerned data specific to ER120573 are inadequateto make broad conclusions Moreover post-translationalmodifications to coregulatory proteins ERs or changes intheir expression patterns due to age or sustained estrogendeprivation could all contribute to an altered microenviron-ment setting the stage for atypical estrogen signaling upontherapeutic reinstatement of hormones (Figure 3)

11 Estrogens and Cognition

Most empirical and observational data give merit to theidea that estrogens have a positive effect on cognitiveprocesses increased spine densities [128 129] enhancedsynaptic plasticity [130ndash132] and improved memory [133134] however the particular receptor(s) and the mechanismsthat regulate these processes remain unclear There are amyriad of behavioral studies suggesting that E

2enhances

prefrontal cortex (PFC) and hippocampal-dependent tasks

8 ISRN Endocrinology

Factor BER structureand function

Factor Ccoregulatory and

transcriptional interactions

120573

120573120573

120573

120572

120572

120572 120572

V

V

V

V

V

V

V

V

ESR1

ESR2

Age and E2

++

Context-dependentER-regulated

gene expression

Factor Atissue-specific

ER gene expression

Figure 3 Age and hormonalmilieu exponentially increase the potential diversity of estrogen receptor signaling leading to context-dependentgene regulation Age and E

2influence ER gene expression alternative splicing coregulatory protein expression and interaction which

ultimately direct ER-target gene transcription

For example long-term E2deprivation diminished aged

female rhesus macaquesrsquo performance in a delayed responsetask a PFC- dependent task [135] E

2also enhanced object

recognition under a number of different paradigms [136ndash138] and there are also multiple lines of evidence supportingE2-mediated neuroprotection which may be important for

cognition especially after stroke [139ndash142]Pharmacological targeting of the receptors with ER selec-

tive ligands has been a standard method for investigating thebehavioral physiological and cellular actions of E

2mediated

distinctly throughER120572 andor ER120573 however valuable insighthas also come from the ER120573-null (120573ERKO) mice 120573ERKOmice have significantly fewer neurons in the cortex hypotha-lamus amygdala and ventral tegmental area compared toWTThey also exhibit neuronal shrinkage and hyperprolifer-ation of glia by 3 months of age as well as having high levelsof apoE and apoE-dependent deposition of amyloid plaquesthroughout the CNS by 12 months of age [143] These micealso demonstrate spatial learning deficits in the Morris watermaze [144] and a decrease in hippocampal- and amygdala-dependent memory in a fear-conditioning paradigm that isaccompanied by decreased synaptic plasticity in hippocampalslice preparations [145] The critical role of ER120573 in higher-level brain functions has been deduced from these studiesand others warranting a full investigation of the wide-spreadmolecular actions of E

2known to contribute to cellular

processes on at least two levels at the synapse and on thegenome

Long-term potentiation (LTP) is an important compo-nent of learning and memory It represents an increasein synaptic transmission and plasticity that underlies cog-nitive behaviors and it is readily altered by E

2in many

circumstances In fact application of an aromatase inhibitoreliminates CA LTP generated by theta-burst stimulation inintact female neurons but not male or OVX animals posinga potentially serious concern for women using aromataseinhibitors for therapeutic treatment of breast cancer [146] E

2

can also enhance or suppress long-term depression (LTD)reducing synaptic transmission which may be dependentupon the specific receptors involved In aged male CA1cells E

2decreased LTD [147] however E

2enhanced LTP in

the cerebellum where ER120573 is the predominately expressedcognate receptor [148]

Although the majority of studies on cognitive processfocus on the rapid effects of E

2 late-phase long-term potenti-

ation (L-LTP) depends upon transcription and translation ofnewmRNA [149] to sustain an increase in synaptic transmis-sion E

2has been shown to regulate LTP in CA1 pyramidal

cells [150] over the span of 48 hours and this regulationappears to be dependent upon a higher ratio of NMDARrelative to AMPAR LTP induction requires activation ofNR2A-containing NMDARs however increased expressionof NR2B potentiates LTP magnitude [151] Notably E

2

increased expression of NR2B mRNA and NR2B expressionat the synapse [152 153] and the E

2-induced increase in

LTP can be abolished by blocking NR2B receptors [154]

ISRN Endocrinology 9

suggesting a transcriptional role for ERs in synaptic plasticityMoreover E

2application may increase CREB expression and

the amount of phosphorylated CREB in regions such as theamygdala [155] and BNST [117 155] which may be critical inthe formation of long-term memories Taken together thesedata demonstrate that E

2regulates neuronal plasticity and

memory through its original role as a transcription factor andalso by acting as a general intracellular signaling moleculethrough regulation of NMDARs and CREB However todate there are little data on the mechanisms by which ER120573regulates these processes or how the same principles ofplasticity may apply to other neurological issues

12 Estrogens and Mood Regulation

A range of behavioral experiments indicate that E2mod-

ulation of stress mood and affect is a complex storywith considerable conflicting data that may as in otherprocesses be explained in part by distinct roles for ER120572 andER120573 Anecdotally many women report mood fluctuationsas corresponding to changes in circulating estrogen levelssuch as what occurs during the menstrual cycle peripubertypostpartum and peripostmenopause Incidence of anxietyand depression are observed at perimenopause and whenhormone levels are fluctuating [156 157] However E

2can

also exhibit anxiogenic properties and often anxiety anddepression present in a comorbid fashion especially inwomen [158 159] Interestingly after the age of 55 bouts ofdepression and anxiety appear to decrease in women [160]As previously mentioned perimenopausal women receivingCEE in the KEEPs study reported an improvement in moodand the primary actions of CEE tend to be mediated throughER120573 [20] A plethora of behavioral studies has mountedin response to observational reports and at first glance itappears that ER120573 has an anxiolytic and antidepressive rolehowever there is still an immense void to be filled withrespect to biochemical and molecular mechanisms of ER120573and affective disorders Elucidating the precise molecularmechanisms that require ER120573 in plasticity and neurotrans-mitter processing in brain regions regulating these behaviorswill help clarify the role of E

2in stress- and mood-related

processesContemporary hypotheses concerning the onset of affec-

tive disorders revolve around perturbations to the cen-tral processing of environmental stress The hypothalamic-pituitary-adrenal (HPA) axis is the 3-tiered hierarchicalbiological system that mediates physical or psychologicalresponse to stressors The primary steroid regulating theHPA axis is cortisolcorticosterone (humansrats CORT) aglucocorticoid receptor (GR) ligand that is produced fromthe adrenals to exert negative feedback upon the HPAsystem to effectively modulate response to stressors Theparaventricular nucleus of hypothalamus (PVN) producestwo neuropeptides corticotropin-releasing hormone (CRH)and arginine vasopressin (AVP) to activate the HPA axisCRF and AVP synergistically stimulate release of adreno-corticotropic hormone (ACTH) from the anterior pituitarywhich acts on the adrenal cortex to produce CORT CORT

binds GR and negatively regulates CRF and AVP expressionsand releases through classical negative feedback mechanisms[161 162] ER120573 is themain ER expressed in the PVN [158 163ndash165] and regulation of AVP is an interesting example of howER action can vary AVP expression fluctuates during themenstrual cycle and is usually highest when E

2is low In fact

oral contraceptives appear to decrease AVP expression andE2is thought to inhibit AVP in the human SON [166] In

the rodent system ER120573 and its splice variants activate therodent AVP promoter independent of ligand [84] howeverthe human promoter is repressed by ER120573 and splice variantsThis discrepancy between the human and rat wasmediated byan AP-1 response element on the human AVP promoter thatis not present in the rat Importantly ER120573 acted similarly inthe two systems when the AP-1 sequence was deleted fromthe human promoter underscoring the striking alterationsthat small changes in DNA sequence can invoke in E

2

signaling pathways and the importance of understanding theexperimental context upon which such conclusions are based[77] On the contrary rat and human CRF expression wasincreased in response to E

2in rodent monkey and human

hypothalamus but it was inhibited in the placenta [167ndash170]In addition to AVP and CRF glutamatergic and GABAer-

gic projects from regions like the BNST AMY PFC andhippocampus all express ER120573 [45 46] and are likely targetsfor E2to exert effects on the HPA axis Moreover decreased

ER120573 mRNA in postmortem locus coeruleus has been foundto correlate with suicide [13] and even more recentlyER120573-mediated hippocampal nitric oxide levels have beenimplicated in affective behaviors in females but not males[171] Neurotransmitter release from these regions influencesmood affect and stress responses and E

2increases the rate

of monoamine oxidase degradation and serotonin transportwhich enhances serotonin at the synapse E

2also increases

serotonin receptor expression [172 173] Dopamine andserotonin [174] are diminished in the BNST POA and hip-pocampus and caudate putamen (dopamine) of 120573ERKOmice[174] further implicating an important role for ER120573 in theregulation of emotion and mood 120573ERKO mice also displayserious morphological and functional abnormalities in thebrain that correlate to increased depression and anxiety [12175ndash178] In addition to 120573ERKO studies administration ofER120573 selective agonists (diarylpoprionitrile DPN) decreasesboth stress markers and anxiety-related behaviors in rats[158] In fact there have been several studies implicatingER120573 and its variants in affective behaviors but the molecularmechanisms remain poorly understood

13 Summary

Estrogen-receptor-mediated signaling in the brain regulatesneurological processes many of which translate to cog-nitive and affective behavioral outputs When estrogen isdeclining and becomes replete as in menopause a num-ber of neurophysiological changes occur producing someunwanted changes The most common and logical remedyis replacement of bioidentical hormone E

2 however this

treatment can be problematic depending upon the length

10 ISRN Endocrinology

of time a woman has been in a postmenopausal estrogen-deprived state This suggests that there is a molecular switchin estrogen-mediated signaling that may allow for drasticchange in ER signaling not to mention the interaction of E

2

signaling components and the natural aging process Thesechanges are likely to include alterations to receptor profilesincluding expression of alternatively spliced variants thatrespond differently to E

2 changes in the cellular microenvi-

ronment that can alter the proteinprotein associations whichultimately leads to changes in ER-mediated gene transcrip-tion and synaptic transmission ER120573 in particular is widelyexpressed and implicated positively in the regulation ofmemory and mood fluctuations two of the most commonlyreported neurological issues in postmenopausal women Itis important to understand the actions of ER120573 in the areasregulating these processes to identify what when how andfor whom hormone therapy may be a useful treatment torectify cognitive and affective issues

Acknowledgments

This work was supported by NIA RO1 AG033605-01 andNIH T32 AG031780 The authors N N Mott and T R Pakhave nothing to disclose

References

[1] C Bengtsson O Lindquist and L Redvall ldquoIs the menopausalage rapidly changingrdquoMaturitas vol 1 no 3 pp 159ndash164 1979

[2] A Singh S Kaur and I Walia ldquoA historical perspective onmenopause andmenopausal agerdquo Bulletin of the Indian Instituteof History of Medicine (Hyderabad) vol 32 no 2 pp 121ndash1352002

[3] P Verhaeghen and J Cerella ldquoAging executive control andattention a review of meta-analysesrdquo Neuroscience and Biobe-havioral Reviews vol 26 no 7 pp 849ndash857 2002

[4] T E Wroolie H A Kenna K E Williams et al ldquoDifferencesin verbal memory performance in postmenopausal womenreceiving hormone therapy 17120573-estradiol versus conjugatedequine estrogensrdquoAmerican Journal of Geriatric Psychiatry vol19 no 9 pp 792ndash802 2011

[5] B B Sherwin ldquoEstrogenic effects on memory in womenrdquoAnnals of the New York Academy of Sciences vol 743 pp 213ndash230 1994

[6] B B Sherwin ldquoHormones mood and cognitive functioning inpostmenopausal womenrdquoObstetrics andGynecology vol 87 no2 supplement pp 20Sndash26S 1996

[7] B B Sherwin ldquoSex hormones and psychological functioning inpostmenopausalwomenrdquoExperimentalGerontology vol 29 no3-4 pp 423ndash430 1994

[8] SM Phillips and B B Sherwin ldquoEffects of estrogen onmemoryfunction in surgically menopausal womenrdquo Psychoneuroen-docrinology vol 17 no 5 pp 485ndash495 1992

[9] R Lindsay J M Aitken and J B Anderson ldquoLong term pre-vention of postmenopausal osteoporosis by oestrogen Evidencefor an increased bone mass after delayed onset of oestrogentreatmentrdquoThe Lancet vol 1 no 7968 pp 1038ndash1040 1976

[10] J E Rossouw R L Prentice J E Manson et al ldquoPost-menopausal hormone therapy and risk of cardiovascular dis-ease by age and years since menopauserdquo The Journal of the

American Medical Association vol 297 no 13 pp 1465ndash14772007

[11] Q-G Zhang D Han R-M Wang et al ldquoC terminusof Hsc70-interacting protein (CHIP)-mediated degradationof hippocampal estrogen receptor-120572 and the critical periodhypothesis of estrogen neuroprotectionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 108 no 35 pp E617ndashE624 2011

[12] W Krezel S Dupont A Krust P Chambon and P F ChapmanldquoIncreased anxiety and synaptic plasticity in estrogen receptor120573-deficient micerdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 21 pp 12278ndash12282 2001

[13] H Ostlund E Keller and Y L Hurd ldquoEstrogen receptor geneexpression in relation to neuropsychiatric disordersrdquo Annals ofthe New York Academy of Sciences vol 1007 pp 54ndash63 2003

[14] S A Shumaker C Legault S R Rapp et al ldquoEstrogen plusprogestin and the incidence of dementia and mild cognitiveimpairment in postmenopausal women the Womenrsquos HealthInitiative Memory Study a randomized controlled trialrdquo Jour-nal of the American Medical Association vol 289 no 20 pp2651ndash2662 2003

[15] S A Shumaker C Legault L Kuller et al ldquoConjugated equineestrogens and incidence of probable dementia and mild cog-nitive impairment in postmenopausal women womenrsquos HealthInitiative Memory Studyrdquo Journal of the American MedicalAssociation vol 291 no 24 pp 2947ndash2958 2004

[16] S R Rapp M A Espeland S A Shumaker et al ldquoEffect ofestrogen plus progestin on global cognitive function in post-menopausal women the Womenrsquos Health Initiative MemoryStudy a randomized controlled trialrdquo Journal of the AmericanMedical Association vol 289 no 20 pp 2663ndash2672 2003

[17] VWHenderson K S Benke R C Green L A Cupples and LA Farrer ldquoPostmenopausal hormone therapy and Alzheimerrsquosdisease risk interaction with agerdquo Journal of Neurology Neuro-surgery and Psychiatry vol 76 no 1 pp 103ndash105 2005

[18] E Garbe and S Suissa ldquoHormone replacement therapy andacute coronary syndromes methodological issues betweenrandomized and observational studiesrdquo Human Reproductionvol 19 no 1 pp 8ndash13 2004

[19] B B Braden A N Garcia S E Mennenga et al ldquoCognitive-impairing effects of medroxyprogesterone acetate in the ratindependent and interactive effects across timerdquo Psychophar-macology vol 218 no 2 pp 405ndash418 2011

[20] B R Bhavnani S-P Tam and X Lu ldquoStructure activity rela-tionships and differential interactions and functional activity ofvarious equine estrogens mediated via estrogen receptors (ERs)ER120572 and ER120573rdquo Endocrinology vol 149 no 10 pp 4857ndash48702008

[21] E Hogervorst and S Bandelow ldquoSex steroids to maintaincognitive function in women after the menopause a meta-analyses of treatment trialsrdquoMaturitas vol 66 no 1 pp 56ndash712010

[22] D J Mangelsdorf C Thummel M Beato et al ldquoThe nuclearreceptor super-family the second decaderdquo Cell vol 83 no 6pp 835ndash839 1995

[23] E V Jensen T Suzuki T Kawashima W E Stumpf P WJungblut and E R DeSombre ldquoA two-step mechanism forthe interaction of estradiol with rat uterusrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 59 no 2 pp 632ndash638 1968

ISRN Endocrinology 11

[24] F Naftolin T L Horvath R L Jakab C Leranth N Haradaand J Balthazart ldquoAromatase immunoreactivity in axon termi-nals of the vertebrate brain an immunocytochemical study onquail rat monkey and human tissuesrdquoNeuroendocrinology vol63 no 2 pp 149ndash155 1996

[25] C E Roselli S E Abdelgadir O K Roslashnnekleiv and S AKlosterman ldquoAnatomic distribution and regulation of aro-matase gene expression in the rat brainrdquo Biology of Reproduc-tion vol 58 no 1 pp 79ndash87 1998

[26] J Balthazart and G F Ball ldquoIs brain estradiol a hormone or aneurotransmitterrdquo Trends in Neurosciences vol 29 no 5 pp241ndash249 2006

[27] T R Pak Y S Rao S A Prins and N N Mott ldquoAn emergingrole for microRNAs in sexually dimorphic neurobiologicalsystemsrdquo Pflugers Archiv vol 465 no 5 pp 655ndash667 2013

[28] K Yamagata S Fujiyama S Ito et al ldquoMaturation ofmicroRNAis hormonally regulated by a nuclear receptorrdquo Molecular Cellvol 36 no 2 pp 340ndash347 2009

[29] Y Masuhiro Y Mezaki M Sakari et al ldquoSplicing potentiationby growth factor signals via estrogen receptor phosphorylationrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 23 pp 8126ndash8131 2005

[30] A Tremblay G B Tremblay F Labrie and V Giguere ldquoLigand-Independent recruitment of SRC-1 to estrogen receptor 120573through phosphorylation of activation function AF-1rdquo Molec-ular Cell vol 3 no 4 pp 513ndash519 1999

[31] S H Meijsing M A Pufall A Y So D L Bates L Chenand K R Yamamoto ldquoDNA binding site sequence directsglucocorticoid receptor structure and activityrdquo Science vol 324no 5925 pp 407ndash410 2009

[32] W Bourguet P Germain and H Gronemeyer ldquoNuclearreceptor ligand-binding domains three-dimensional struc-tures molecular interactions and pharmacological implica-tionsrdquo Trends in Pharmacological Sciences vol 21 no 10 pp381ndash388 2000

[33] A Koide C Zhao M Naganuma et al ldquoIdentification ofregions within the F domain of the human estrogen receptor 120572that are important for modulating transactivation and protein-protein interactionsrdquoMolecular Endocrinology vol 21 no 4 pp829ndash842 2007

[34] D F Skafar and S Koide ldquoUnderstanding the human estrogenreceptor-alpha using targeted mutagenesisrdquoMolecular and Cel-lular Endocrinology vol 246 no 1-2 pp 83ndash90 2006

[35] E C Chang J Frasor B Komm and B S KatzenellenbogenldquoImpact of estrogen receptor 120573 on gene networks regulated byestrogen receptor 120572 in breast cancer cellsrdquo Endocrinology vol147 no 10 pp 4831ndash4842 2006

[36] X Zhu I Leav Y-K Leung et al ldquoDynamic regulation ofestrogen receptor-120573 expression by DNA methylation duringprostate cancer development andmetastasisrdquoAmerican Journalof Pathology vol 164 no 6 pp 2003ndash2012 2004

[37] D N Petersen G T Tkalcevic P H Koza-Taylor T G Turiand T A Brown ldquoIdentification of estrogen receptor 1205732 afunctional variant of estrogen receptor 120573 expressed in normalrat tissuesrdquo Endocrinology vol 139 no 3 pp 1082ndash1092 1998

[38] L A Helguero M H Faulds J-A Gustafsson and L-AHaldosen ldquoEstrogen receptors alfa (ER120572) and beta (ER120573)differentially regulate proliferation and apoptosis of the normalmurine mammary epithelial cell line HC11rdquo Oncogene vol 24no 44 pp 6605ndash6616 2005

[39] P C Kulakosky M A McCarty S C Jernigan K E Risingerand C M Klinge ldquoResponse element sequence modulates

estrogen receptor 120572 and 120573 affinity and activityrdquo Journal ofMolecular Endocrinology vol 29 no 1 pp 137ndash152 2002

[40] OM V Grober MMutarelli G Giurato et al ldquoGlobal analysisof estrogen receptor beta binding to breast cancer cell genomereveals an extensive interplay with estrogen receptor alpha fortarget gene regulationrdquo BMC Genomics vol 12 article 36 2011

[41] O I Vivar X Zhao E F Saunier et al ldquoEstrogen receptor 120573binds to and regulates three distinct classes of target genesrdquoJournal of Biological Chemistry vol 285 no 29 pp 22059ndash22066 2010

[42] G G J M Kuiper E Enmark M Pelto-Huikko S Nilssonand J-A Gustafsson ldquoCloning of a novel estrogen receptorexpressed in rat prostate and ovaryrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 93 no12 pp 5925ndash5930 1996

[43] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and 120572 and 120573rdquo Endocrinology vol 138no 3 pp 863ndash870 1997

[44] D B Dubal H Zhu J Yu et al ldquoEstrogen receptor alpha notbeta is a critical link in estradiol-mediated protection againstbrain injuryrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 98 no 4 pp 1952ndash1957 2001

[45] P J Shughrue P J Scrimo and I Merchenthaler ldquoEvidence forthe colocalization of estrogen receptor-120573 mRNA and estrogenreceptor-120572 immunoreactivity in neurons of the rat forebrainrdquoEndocrinology vol 139 no 12 pp 5267ndash5270 1998

[46] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in therat central nervous systemrdquo Journal of Comparative Neurologyvol 388 no 4 pp 507ndash525 1997

[47] T AMilner B SMcEwen S Hayashi C J Li L P Reagan andS E Alves ldquoUltrastructural evidence that hippocampal alphaestrogen receptors are located at extranuclear sitesrdquoThe Journalof Comparative Neurology vol 429 no 3 pp 355ndash371 2001

[48] T A Milner L S Lubbers S E Alves and B S McEwenldquoNuclear and extranuclear estrogen binding sites in the ratforebrain and autonomic medullary areasrdquo Endocrinology vol149 no 7 pp 3306ndash3312 2008

[49] T A Milner K Ayoola C T Drake et al ldquoUltrastructurallocalization of estrogen receptor 120573 immunoreactivity in the rathippocampal formationrdquo Journal of ComparativeNeurology vol491 no 2 pp 81ndash95 2005

[50] A E Herbison andD TTheodosis ldquoAbsence of estrogen recep-tor immunoreactivity in somatostatin (SRIF) neurons of theperiventricular nucleus but sexually dimorphic colocalizationof estrogen receptor and SRIF immunoreactivities in neuronsof the bed nucleus of the stria terminalisrdquo Endocrinology vol132 no 4 pp 1707ndash1714 1993

[51] K Kalita S Szymczak and L Kaczmarek ldquoNon-nuclear estro-gen receptor 120573 and 120572 in the hippocampus of male and femaleratsrdquo Hippocampus vol 15 no 3 pp 404ndash412 2005

[52] T Ivanova and C Beyer ldquoOntogenetic expression and sexdifferences of aromatase and estrogen receptor-120572120573 mRNA inthe mouse hippocampusrdquo Cell and Tissue Research vol 300 no2 pp 231ndash237 2000

[53] C Y Pau K-Y F Pau and H G Spies ldquoPutative estrogenreceptor 120573 and 120572 mRNA expression in male and female rhesusmacaquesrdquo Molecular and Cellular Endocrinology vol 146 no1-2 pp 59ndash68 1998

[54] A L Wijayaratne and D P McDonnell ldquoThe human estrogenreceptor-120572 is a ubiquitinated protein whose stability is affected

12 ISRN Endocrinology

differentially by agonists antagonists and selective estrogenreceptor modulatorsrdquo Journal of Biological Chemistry vol 276no 38 pp 35684ndash35692 2001

[55] V Bartella P Rizza I Barone et al ldquoEstrogen receptor betabinds Sp1 and recruits a corepressor complex to the estrogenreceptor alpha gene promoterrdquo Breast Cancer Research andTreatment vol 134 no 2 pp 569ndash581 2012

[56] L C Li C C Yeh D Nojima and R Dahiya ldquoCloning andcharacterization of human estrogen receptor beta promoterrdquoBiochemical and Biophysical Research Communications vol 275no 2 pp 682ndash689 2000

[57] E A Vladusic A E Hornby F K Guerra-Vladusic J Lakinsand R Lupu ldquoExpression and regulation of estrogen receptor szligin human breast tumors and cell linesrdquoOncology Reports vol 7no 1 pp 157ndash167 2000

[58] T Hatsumi and Y Yamamuro ldquoDownregulation of estrogenreceptor gene expression by exogenous 17120573-estradiol in themammary glands of lactating micerdquo Experimental Biology andMedicine vol 231 no 3 pp 311ndash316 2006

[59] H B Patisaul P L Whitten and L J Young ldquoRegulation ofestrogen receptor beta mRNA in the brain opposite effectsof 17120573-estradiol and the phytoestrogen coumestrolrdquoMolecularBrain Research vol 67 no 1 pp 165ndash171 1999

[60] T J Brown N J MacLusky M Shanabrough and F NaftolinldquoComparison of age- and sex-related changes in cell nuclearestrogen-binding capacity and progestin receptor induction inthe rat brainrdquo Endocrinology vol 126 no 6 pp 2965ndash29721990

[61] B S Rubin T O Fox and R S Bridges ldquoEstrogen bindingin nuclear and cytosolic extracts from brain and pituitary ofmiddle-aged female ratsrdquo Brain Research vol 383 no 1-2 pp60ndash67 1986

[62] T Funabashi S P Kleopoulos P J Brooks et al ldquoChangesin estrogenic regulation of estrogen receptor 120572 mRNA andprogesterone receptor mRNA in the female rat hypothalamusduring aging an in situ hybridization studyrdquo NeuroscienceResearch vol 38 no 1 pp 85ndash92 2000

[63] M E Wilson K L Rosewell M L Kashon P J Shughrue IMerchenthaler and P M Wise ldquoAge differentially influencesestrogen receptor-120572 (ER120572) and estrogen receptor-120573 (ER120573) geneexpression in specific regions of the rat brainrdquo Mechanisms ofAgeing and Development vol 123 no 6 pp 593ndash601 2002

[64] W S Post P J Goldschmidt-Clermont C C Wilhide etal ldquoMethylation of the estrogen receptor gene is associatedwith aging and atherosclerosis in the cardiovascular systemrdquoCardiovascular Research vol 43 no 4 pp 985ndash991 1999

[65] J-P J Issa Y L Ottaviano P Celano S R Hamilton NE Davidson and S B Baylin ldquoMethylation of the oestrogenreceptor CpG island links ageing and neoplasia in humancolonrdquo Nature Genetics vol 7 no 4 pp 536ndash540 1994

[66] T Funabashi and F Kimura ldquoEffects of estrogen and estrogenreceptor messenger RNA levels in young and middle-agedfemale rats comparison ofmedial preoptic area andmediobasalhypothalamusrdquo Acta Biologica Hungarica vol 45 no 2ndash4 pp223ndash231 1994

[67] M AMiller P E Kolb B Planas andM A Raskind ldquoEstrogenreceptor and neurotensinneuromedin-N gene expression inthe preoptic area are unaltered with age in Fischer 344 femaleratsrdquo Endocrinology vol 135 no 5 pp 1986ndash1995 1994

[68] T R Chakraborty P R Hof L Ng and A C Gore ldquoStereologicanalysis of estrogen receptor alpha (ER alpha) expression in rat

hypothalamus and its regulation by aging and estrogenrdquo Journalof Comparative Neurology vol 466 no 3 pp 409ndash421 2003

[69] J M Westberry A L Trout and M E Wilson ldquoEpigeneticregulation of estrogen receptor beta expression in the rat cortexduring agingrdquo NeuroReport vol 22 no 9 pp 428ndash432 2011

[70] T R Chakraborty L Ng and A C Gore ldquoAge-related changesin estrogen receptor 120573 in rat hypothalamus a quantitativeanalysisrdquo Endocrinology vol 144 no 9 pp 4164ndash4171 2003

[71] I Poola S Koduri S Chatra and R Clarke ldquoIdentificationof twenty alternatively spliced estrogen receptor alpha mRNAsin breast cancer cell lines and tumors using splice targetedprimer approachrdquo Journal of Steroid Biochemistry andMolecularBiology vol 72 no 5 pp 249ndash258 2000

[72] T A Ishunina and D F Swaab ldquoHippocampal estrogenreceptor-alpha splice variant TADDI in the human brain inaging and Alzheimerrsquos diseaserdquoNeuroendocrinology vol 89 no2 pp 187ndash199 2009

[73] T A Ishunina and D F Swaab ldquoEstrogen receptor-120572 splicevariants in the human brainrdquo Gynecological Endocrinology vol24 no 2 pp 93ndash98 2008

[74] T A Ishunina F P M Kruijver R Balesar and D FSwaab ldquoDifferential expression of estrogen receptor 120572 and 120573immunoreactivity in the human supraoptic nucleus in rela-tion to sex and agingrdquo Journal of Clinical Endocrinology andMetabolism vol 85 no 9 pp 3283ndash3291 2000

[75] T A Ishunina D F Fischer andD F Swaab ldquoEstrogen receptor120572 and its splice variants in the hippocampus in aging andAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 28 no 11 pp1670ndash1681 2007

[76] J R Tollervey Z Wang T Hortobagyi et al ldquoAnalysis of alter-native splicing associated with aging and neurodegeneration inthe human brainrdquo Genome Research vol 21 no 10 pp 1572ndash1582 2011

[77] N NMott and T R Pak ldquoCharacterisation of human oestrogenreceptor beta (ER120573) splice variants in neuronal cellsrdquo Journal ofNeuroendocrinology vol 24 no 10 pp 1311ndash1321 2012

[78] S Inoue S-J Hoshino H Miyoshi et al ldquoIdentification ofa ovel isoform of estrogen receptor a potential inhibitor ofestrogen action in vascular smooth muscle cellsrdquo Biochemicaland Biophysical Research Communications vol 219 no 3 pp766ndash772 1996

[79] J K Skipper L J Young J M Bergeron M T Tetzlaff CT Osborn and D Crews ldquoIdentification of an isoform ofthe estrogen receptor messenger RNA lacking exon four andpresent in the brainrdquo Proceedings of the National Academy ofSciences of the United States of America vol 90 no 15 pp 7172ndash7175 1993

[80] R H Price Jr N Lorenzon and R J Handa ldquoDifferentialexpression of estrogen receptor beta splice variants in rat brainidentification and characterization of a novel variant missingexon 4rdquo Brain Research Molecular Brain Research vol 80 no2 pp 260ndash268 2000

[81] S Chu and P J Fuller ldquoIdentification of a splice variantof the rat estrogen receptor 120573 generdquo Molecular and CellularEndocrinology vol 132 no 1-2 pp 195ndash199 1997

[82] B Lu E Leygue H Dotzlaw L J Murphy L C Murphy andP H Watson ldquoEstrogen receptor-120573 mRNA variants in humanand murine tissuesrdquoMolecular and Cellular Endocrinology vol138 no 1-2 pp 199ndash203 1998

[83] T R Pak W C J Chung J L Roberts and R J HandaldquoLigand-independent effects of estrogen receptor 120573 on

ISRN Endocrinology 13

mouse gonadotropin-releasing hormone promoter activityrdquoEndocrinology vol 147 no 4 pp 1924ndash1931 2006

[84] T R Pak W C J Chung L R Hinds and R J HandaldquoEstrogen receptor-120573 mediates dihydrotestosterone-inducedstimulation of the arginine vasopressin promoter in neuronalcellsrdquo Endocrinology vol 148 no 7 pp 3371ndash3382 2007

[85] Y K Leung PMak S Hassan and SMHo ldquoEstrogen receptor(ER)-120573 isoforms a key to understanding ER-120573 signalingrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 103 no 35 pp 13162ndash13167 2006

[86] J M Wang X Hou S Adeosun et al ldquoA dominant negativeER120573 splice variant determines the effectiveness of early or lateestrogen therapy after ovariectomy in ratsrdquo PLoS One vol 7 no3 Article ID e33493 2012

[87] W C J Chung T R Pak S Suzuki W A Pouliot M EAndersen and R J Handa ldquoDetection and localization of anestrogen receptor beta splice variant protein (ER1205732) in theadult female rat forebrain and midbrain regionsrdquo Journal ofComparative Neurology vol 505 no 3 pp 249ndash267 2007

[88] R H Price Jr C A Butler P Webb R Uht P Kushner andR J Handa ldquoA splice variant of estrogen receptor 120573 missingexon 3 displays altered subnuclear localization and capacity fortranscriptional activationrdquo Endocrinology vol 142 no 5 pp2039ndash2049 2001

[89] Y Wang and R J Miksicek ldquoIdentification of a dominantnegative form of the human estrogen receptorrdquo MolecularEndocrinology vol 5 no 11 pp 1707ndash1715 1991

[90] E Kuppers and C Beyer ldquoExpression of estrogen receptor-120572and 120573 mRNA in the developing and adult mouse striatumrdquoNeuroscience Letters vol 276 no 2 pp 95ndash98 1999

[91] C Gundlah S G Kohama S J Mirkes V T Garyfallou H FUrbanski and C L Bethea ldquoDistribution of estrogen receptorbeta (ER120573) mRNA in hypothalamus midbrain and temporallobe of spayed macaque continued expression with hormonereplacementrdquo Brain Research Molecular Brain Research vol 76no 2 pp 191ndash204 2000

[92] Y Morishima P J M Murphy D-P Li E R Sanchez and WB Pratt ldquoStepwise assembly of a glucocorticoid receptorsdothsp90heterocomplex resolves two sequential ATP-dependent eventsinvolving first hsp70 and then hsp90 in opening of the steroidbinding pocketrdquo Journal of Biological Chemistry vol 275 no 24pp 18054ndash18060 2000

[93] K D Dittmar and W B Pratt ldquoFolding of the glucocorticoidreceptor by the reconstituted hsp90-based chaperone machin-eryThe initial hsp90sdotp60sdothsp70-dependent step is sufficient forcreating the steroid binding conformationrdquo Journal of BiologicalChemistry vol 272 no 20 pp 13047ndash13054 1997

[94] K I Kang X Meng J Devin-Leclerc et al ldquoThe molecularchaperone Hsp90 can negatively regulate the activity of aglucocorticosteroid-dependent promoterrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 4 pp 1439ndash1444 1999

[95] K Unno H Asakura Y Shibuya M Kaiho S Okada and NOku Naoto ldquoIncrease in basal level of Hsp70 consisting chieflyof constitutively expressed hsp70 (Hsc70) in aged rat brainrdquoJournals of Gerontology Series A vol 55 no 7 pp B329ndashB3352000

[96] U E Olazabal D W Pfaff and C V Mobbs ldquoSex differences inthe regulation of heat shock protein 70 kDa and 90 kDa in therat ventromedial hypothalamus by estrogenrdquo Brain Researchvol 596 no 1-2 pp 311ndash314 1992

[97] M A Pahlavani M D Harris S A Moore and A RichardsonldquoExpression of heat shock protein 70 in rat spleen lymphocytesis affected by age but not by food restrictionrdquo Journal ofNutrition vol 126 no 9 pp 2069ndash2075 1996

[98] A R Heydari B Wu R Takahashi R Strong and A Richard-son ldquoExpression of heat shock protein 70 is altered by age anddiet at the level of transcriptionrdquoMolecular andCellular Biologyvol 13 no 5 pp 2909ndash2918 1993

[99] M Sabbah K-I I Kang L Tora and G Redeuilh ldquoOestro-gen receptor facilitates the formation of preinitiation com-plex assembly involvement of the general transcription factorTFIIBrdquo Biochemical Journal vol 336 part 3 pp 639ndash646 1998

[100] S-Y Wu M C Thomas S Y Hou V Likhite and C-MChiang ldquoIsolation of mouse TFIID and functional character-ization of TBP and TFIID in mediating estrogen receptor andchromatin transcriptionrdquo Journal of Biological Chemistry vol274 no 33 pp 23480ndash23490 1999

[101] S Ghosh and M K Thakur ldquoTissue-specific expression ofreceptor-interacting protein in aging mouserdquo Age vol 30 no4 pp 237ndash243 2008

[102] J Frasor JM Danes B Komm K C N Chang C Richard Lyt-tle and B S Katzenellenbogen ldquoProfiling of estrogen up- anddown-regulated gene expression in human breast cancer cellsinsights into gene networks and pathways underlying estrogeniccontrol of proliferation and cell phenotyperdquo Endocrinology vol144 no 10 pp 4562ndash4574 2003

[103] J Frasor J M Danes C C Funk and B S Katzenellen-bogen ldquoEstrogen down-regulation of the corepressor N-CoRmechanism and implications for estrogen derepression of N-CoR-regulated genesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 102 no 37 pp13153ndash13157 2005

[104] N J McKenna and B W OrsquoMalley ldquoCombinatorial control ofgene expression by nuclear receptors and coregulatorsrdquoCell vol108 no 4 pp 465ndash474 2002

[105] T-P Yao G Ku N Zhou R Scully and D M Livingston ldquoThenuclear hormone receptor coactivator SRC-1 is a specific targetof p300rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 93 no 20 pp 10626ndash10631 1996

[106] B Hanstein R Eckner J DiRenzo et al ldquop300 is a componentof an estrogen receptor coactivator complexrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 93 no 21 pp 11540ndash11545 1996

[107] S Halachmi E Marden G Martin H MacKay C Abbon-danza and M Brown ldquoEstrogen receptor-associated proteinspossible mediators of hormone-induced transcriptionsrdquo Sci-ence vol 264 no 5164 pp 1455ndash1458 1994

[108] A J Horlein AM Naar T Heinzel et al ldquoLigand-independentrepression by the thyroid hormone receptor mediated by anuclear receptor co-repressorrdquo Nature vol 377 no 6548 pp397ndash404 1995

[109] J D Chen and R M Evans ldquoA transcriptional co-repressor thatinteracts with nuclear hormone receptorsrdquo Nature vol 377 no6548 pp 454ndash457 1995

[110] A Malovannaya R B Lanz S Y Jung et al ldquoAnalysis of thehuman endogenous coregulator complexomerdquoCell vol 145 no5 pp 787ndash799 2011

[111] Z Nawaz D M Lonard C L Smith et al ldquoThe Angelmansyndrome-associated protein E6-AP is a coactivator for thenuclear hormone receptor superfamilyrdquoMolecular and CellularBiology vol 19 no 2 pp 1182ndash1189 1999

14 ISRN Endocrinology

[112] B Zheng M Han M Bernier and J-K Wen ldquoNuclear actinand actin-binding proteins in the regulation of transcriptionand gene expressionrdquo FEBS Journal vol 276 no 10 pp 2669ndash2685 2009

[113] W A Hofmann L Stojiljkovic B Fuchsova et al ldquoActin is partof pre-initiation complexes and is necessary for transcription byRNA polymerase IIrdquoNature Cell Biology vol 6 no 11 pp 1094ndash1101 2004

[114] K Tokunaga T Shibuya Y Ishihama et al ldquoNucleocytoplasmictransport of fluorescent mRNA in living mammalian cellsnuclear mRNA export is coupled to ongoing gene transcrip-tionrdquo Genes to Cells vol 11 no 3 pp 305ndash317 2006

[115] R Metivier G Penot M R Hubner et al ldquoEstrogen receptor-120572 directs ordered cyclical and combinatorial recruitment ofcofactors on a natural target promoterrdquo Cell vol 115 no 6 pp751ndash763 2003

[116] C Ambrosino R Tarallo A Bamundo et al ldquoIdentification of ahormone-regulated dynamic nuclear actin network associatedwith estrogen receptor 120572 in human breast cancer cell nucleirdquoMolecular and Cellular Proteomics vol 9 no 6 pp 1352ndash13672010

[117] F Shao R Zhang L Dong and K Ying ldquoOverexpression ofgelsolin-like actin-capping protein is associated with progres-sion of lung adenocarcinomardquo Tohoku Journal of ExperimentalMedicine vol 225 no 2 pp 95ndash101 2011

[118] K Nishimura H-J Ting Y Harada et al ldquoModulation ofandrogen receptor transactivation by gelsolin a newly identi-fied androgen receptor coregulatorrdquo Cancer Research vol 63no 16 pp 4888ndash4894 2003

[119] J S Ahn I S Jang D I Kim et al ldquoAging-associated increaseof gelsolin for apoptosis resistancerdquoBiochemical and BiophysicalResearch Communications vol 312 no 4 pp 1335ndash1341 2003

[120] I Nalvarte T Schwend and J-A Gustafsson ldquoProteomicsanalysis of the estrogen receptor 120572 receptosomerdquoMolecular andCellular Proteomics vol 9 no 7 pp 1411ndash1422 2010

[121] L-H Miau C-J Chang B-J Shen W-H Tsai and S-C LeeldquoIdentification of heterogeneous nuclear ribonucleoprotein K(hnRNPK) as a repressor ofCEBP120573-mediated gene activationrdquoJournal of Biological Chemistry vol 273 no 17 pp 10784ndash107911998

[122] A Ostareck-Lederer D H Ostareck C Cans et al ldquoc-Src-mediated phosphorylation of hnRNP K drives translationalactivation of specifically silenced mRNAsrdquo Molecular and Cel-lular Biology vol 22 no 13 pp 4535ndash4543 2002

[123] P S Bagga G K Arhin and J Wilusz ldquoDSEF-1 is a member ofthe hnRNP H family of RNA-binding proteins and stimulatespre-mRNAcleavage and polyadenylation in vitrordquoNucleic AcidsResearch vol 26 no 23 pp 5343ndash5350 1998

[124] V Markovtsov J M Nikolic J A Goldman C W Turck M-Y Chou and D L Black ldquoCooperative assembly of an hnRNPcomplex induced by a tissue-specific homolog of polypyrimi-dine tract binding proteinrdquoMolecular and Cellular Biology vol20 no 20 pp 7463ndash7479 2000

[125] S Y Jung A Malovannaya J Wei B W OrsquoMalley and J QinldquoProteomic analysis of steady-state nuclear hormone receptorcoactivator complexesrdquoMolecular Endocrinology vol 19 no 10pp 2451ndash2465 2005

[126] W Hong R J Resnick C Rakowski D Shalloway S J Taylorand G A Blobel ldquoPhysical and functional interaction betweenthe transcriptional cofactor CBP and the KH domain proteinSam68rdquoMolecular Cancer Research vol 1 no 1 pp 48ndash55 2002

[127] R ShaoXWang BWeijdegard et al ldquoCoordinate regulation ofheterogeneous nuclear ribonucleoprotein dynamics by steroidhormones in the human fallopian tube and endometrium invivo and in vitrordquo American Journal of Physiology vol 302 no10 pp E1269ndashE1282 2012

[128] C SWoolley and B SMcEwen ldquoEstradiolmediates fluctuationin hippocampal synapse density during the estrous cycle in theadult ratrdquo Journal of Neuroscience vol 12 no 7 pp 2549ndash25541992

[129] C S Woolley H J Wenzel and P A Schwartzkroin ldquoEstradiolincreases the frequency of multiple synapse boutons in thehippocampal CA1 region of the adult female ratrdquo The Journalof Comparative Neurology vol 373 no 1 pp 108ndash117 1996

[130] C S Woolley ldquoEstrogen-mediated structural and functionalsynaptic plasticity in the female rat hippocampusrdquo Hormonesand Behavior vol 34 no 2 pp 140ndash148 1998

[131] D P Srivastava K M Woolfrey K A Jones et al ldquoRapidenhancement of two-step wiring plasticity by estrogen andNMDA receptor activityrdquo Proceedings of the National Academyof Sciences of the United States of America vol 105 no 38 pp14650ndash14655 2008

[132] M Ogiue-Ikeda N Tanabe H Mukai et al ldquoRapid modu-lation of synaptic plasticity by estrogens as well as endocrinedisrupters in hippocampal neuronsrdquo Brain Research Reviewsvol 57 no 2 pp 363ndash375 2008

[133] N J Sandstrom and C L Williams ldquoSpatial memory retentionis enhanced by acute and continuous estradiol replacementrdquoHormones and Behavior vol 45 no 2 pp 128ndash135 2004

[134] E Hogervorst J Williams M Budge W Riedel and JJolles ldquoThe nature of the effect of female gonadal hormonereplacement therapy on cognitive function in post-menopausalwomen a meta-analysisrdquo Neuroscience vol 101 no 3 pp 485ndash512 2000

[135] M E Bailey A C J Wang J Hao et al ldquoInteractive effects ofage and estrogen on cortical neurons implications for cognitiveagingrdquo Neuroscience vol 191 pp 148ndash158 2011

[136] A A Walf M E Rhodes and C A Frye ldquoOvarian steroidsenhance object recognition in naturally cycling and ovariec-tomized hormone-primed ratsrdquo Neurobiology of Learning andMemory vol 86 no 1 pp 35ndash46 2006

[137] V N Luine L F Jacome and N J Maclusky ldquoRapid enhance-ment of visual and place memory by estrogens in ratsrdquoEndocrinology vol 144 no 7 pp 2836ndash2844 2003

[138] L Fan Z Zhao P T Orr C H Chambers M C Lewis and KM Frick ldquoEstradiol-induced object memory consolidation inmiddle-aged femalemice requires dorsal hippocampal extracel-lular signal-regulated kinase and phosphatidylinositol 3-kinaseactivationrdquo Journal of Neuroscience vol 30 no 12 pp 4390ndash4400 2010

[139] D B Dubal and PMWise ldquoNeuroprotective effects of estradiolin middle-aged female ratsrdquo Endocrinology vol 142 no 1 pp43ndash48 2001

[140] S-H Yang J Shi A L Day and J W Simpkins ldquoEstradiolexerts neuroprotective effects when administered after ischemicinsultrdquo Stroke vol 31 no 3 pp 745ndash750 2000

[141] J W Simpkins G Rajakumar Y-Q Zhang et al ldquoEstrogensmay reduce mortality and ischemic damage caused by middlecerebral artery occlusion in the female ratrdquo Journal of Neuro-surgery vol 87 no 5 pp 724ndash730 1997

[142] J Shi K S Panickar S-H Yang O Rabbani A L Day and JWSimpkins ldquoEstrogen attenuates over-expression of 120573-amyloid

ISRN Endocrinology 15

precursor protein messager RNA in an animal model of focalischemiardquo Brain Research vol 810 no 1-2 pp 87ndash92 1998

[143] Q-H Zhang Y-H Huang Y-Z Hu et al ldquoDisruption ofestrogen receptor beta in mice brain results in pathologicalalterations resemblingAlzheimer diseaserdquoActa PharmacologicaSinica vol 25 no 4 pp 452ndash457 2004

[144] E F Rissman A L Heck J E Leonard M A Shupnik and J-A Gustafsson ldquoDisruption of estrogen receptor 120573 gene impairsspatial learning in female micerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no6 pp 3996ndash4001 2002

[145] M Day A Sung S Logue M Bowlby and R Arias ldquoBetaestrogen receptor knockout (BERKO) mice present attenuatedhippocampal CA1 long-term potentiation and related memorydeficits in contextual fear conditioningrdquo Behavioural BrainResearch vol 164 no 1 pp 128ndash131 2005

[146] R Vierk G Glassmeier L Zhou et al ldquoAromatase inhibitionabolishes LTP generation in female but not in male micerdquo TheJournal of Neuroscience vol 32 no 24 pp 8116ndash8126 2012

[147] R-M Vouimba M R Foy J G Foy and R FThompson ldquo17120573-estradiol suppresses expression of long-term depression in agedratsrdquo Brain Research Bulletin vol 53 no 6 pp 783ndash787 2000

[148] C E Andreescu B A Milojkovic E D Haasdijk et alldquoEstradiol improves cerebellar memory formation by activatingestrogen receptor 120573rdquo Journal of Neuroscience vol 27 no 40 pp10832ndash10839 2007

[149] Y-Y Huang P V Nguyen T Abel and E R Kandel ldquoLong-lasting forms of synaptic potentiation in the mammalian hip-pocampusrdquo Learning Memory vol 3 no 2-3 pp 74ndash85 1996

[150] H Mukai T Tsurugizawa G Murakami et al ldquoRapid mod-ulation of long-term depression and spinogenesis via synapticestrogen receptors in hippocampal principal neuronsrdquo Journalof Neurochemistry vol 100 no 4 pp 950ndash967 2007

[151] L Liu T P Wong M F Pozza et al ldquoRole of NMDA receptorsubtypes in governing the direction of hippocampal synapticplasticityrdquo Science vol 304 no 5673 pp 1021ndash1024 2004

[152] M Cyr O Ghribi C Thibault M Morissette M Landry andT di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[153] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[154] C C Smith and L L McMahon ldquoEstradiol-induced increasein the magnitude of long-term potentiation is prevented byblocking NR2B-containing receptorsrdquo Journal of Neurosciencevol 26 no 33 pp 8517ndash8522 2006

[155] Y Zhou J J Watters and D M Dorsa ldquoEstrogen rapidlyinduces the phosphorylation of the cAMP response elementbinding protein in rat brainrdquo Endocrinology vol 137 no 5 pp2163ndash2166 1996

[156] XGonda T TelekG Juhasz J Lazary AVargha andG BagdyldquoPatterns of mood changes throughout the reproductive cyclein healthy women without premenstrual dysphoric disordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 32 no 8 pp 1782ndash1788 2008

[157] E W Freeman ldquoPremenstrual syndrome and premenstrualdysphoric disorder definitions and diagnosisrdquo Psychoneuroen-docrinology vol 28 supplement 3 pp 25ndash37 2003

[158] T D Lund T Rovis W C J Chung and R J Handa ldquoNovelactions of estrogen receptor-120573 on anxiety-related behaviorsrdquoEndocrinology vol 146 no 2 pp 797ndash807 2005

[159] N Breslau L Schultz and E Peterson ldquoSex differences indepression a role for preexisting anxietyrdquo Psychiatry Researchvol 58 no 1 pp 1ndash12 1995

[160] P E Bebbington G Dunn R Jenkins et al ldquoThe influenceof age and sex on the prevalence of depressive conditionsreport from the National Survey of Psychiatric MorbidityrdquoPsychological Medicine vol 28 no 1 pp 9ndash19 1998

[161] G Aguilera J P Harwood and J X Wilson ldquoMechanisms ofaction of corticotropin-releasing factor and other regulators ofcorticotropin release in rat pituitary cellsrdquo Journal of BiologicalChemistry vol 258 no 13 pp 8039ndash8045 1983

[162] A Papadimitriou and K N Priftis ldquoRegulation of thehypothalamic-pituitary-adrenal axisrdquo NeuroImmunoModula-tion vol 16 no 5 pp 265ndash271 2009

[163] S Suzuki and R J Handa ldquoRegulation of estrogen receptor-120573expression in the female rat hypothalamus differential effectsof dexamethasone and estradiolrdquo Endocrinology vol 145 no 8pp 3658ndash3670 2004

[164] W J S Miller S Suzuki L K Miller R Handa and R M UhtldquoEstrogen receptor (ER)120573 isoforms rather than ER120572 regulatecorticotropin-releasing hormone promoter activity through analternate pathwayrdquo Journal of Neuroscience vol 24 no 47 pp10628ndash10635 2004

[165] C IsgorM CecchiM Kabbaj H Akil and S JWatson ldquoEstro-gen receptor 120573 in the paraventricular nucleus of hypothalamusregulates the neuroendocrine response to stress and is regulatedby corticosteronerdquo Neuroscience vol 121 no 4 pp 837ndash8452003

[166] M L Forsling I Kallo D E Hartley et al ldquoOestrogen receptor-120573 and neurohypophysial hormones functional interaction andneuroanatomical localisationrdquo Pharmacology Biochemistry andBehavior vol 76 no 3-4 pp 535ndash542 2003

[167] A S Lalmansingh and R M Uht ldquoEstradiol regulatescorticotropin-releasing hormone gene (crh) expression in arapid and phasic manner that parallels estrogen receptor-120572 and-120573 recruitment to a 3101584051015840-cyclic adenosine 51015840- monophosphateregulatory region of the proximal crh promoterrdquo Endocrinologyvol 149 no 1 pp 346ndash357 2008

[168] B N Roy R L Reid and D A van Vugt ldquoThe effects ofestrogen and progesterone on corticotropin-releasing hormoneand arginine vasopressin messenger ribonucleic acid levelsin the paraventricular nucleus and supraoptic nucleus of therhesus monkeyrdquo Endocrinology vol 140 no 5 pp 2191ndash21981999

[169] X Ni R C Nicholson B R King E-C Chan M A Read andR Smith ldquoEstrogen represses whereas the estrogen-antagonistICI 182780 stimulates placental CRH gene expressionrdquo Journalof Clinical Endocrinology and Metabolism vol 87 no 8 pp3774ndash3778 2002

[170] N C Vamvakopoulos and G P Chrousos ldquoEvidence of directestrogenic regulation of human corticotropin-releasing hor-mone gene expression Potential implications for the sexualdimophism of the stress response and immuneinflammatoryreactionrdquo Journal of Clinical Investigation vol 92 no 4 pp1896ndash1902 1993

[171] Y Hu D L Wu C X Luo et al ldquoHippocampal nitric oxidecontributes to sex difference in affective behaviorsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 35 pp 14224ndash14229 2012

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

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BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

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Research and TreatmentAIDS

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Endocrinology 3

components of classic NR signaling such as the structuralproperties of the receptors

4 Structural Contributions to ER Activity

Class I nuclear receptors (NRs) including ER120572 and ER120573have a characteristic structure comprised of five functionaldomains labeled AndashE and a sixth domain (F) unique to ERs(Figure 1) The AB domain contains an activator function-1-(AF-1-) like domain that allows for associations with coregu-latory proteins and other transcription factors Notably theAB domain is the least conserved domain between ER120572and ER120573 (17 homology) and it may be responsible forthe observed ligand-independent actions of ER120573 [30] The Cdomain is a DNA-binding domain that allows the receptorto bind a specific DNA sequence called an Estrogen ResponseElement (ERE) to regulate transcription of genes containingthis sequence within their promoter region Two zinc fingersforming a helix-loop-helix structure allow for appropriatespacing (3 nucleotides) between an inverted hexameric palin-dromic repeat that is described as the canonical ERE Theexact nucleotide sequence of hormone response elements canvary and in part dictate the affinity an NR has to regulate aparticular gene [31] The D domain is a hinge-like region thatallows the receptor to undergo a conformational change onceactivated and also contains a nuclear localization sequenceThe best-studied region of ERs is the E domain also referredto as the ligand-binding domain (LBD) Characterizationusing X-ray crystallography has shown that the LBD consistsof 12 ordered alpha-helices that are essential for conferringligand specificity [32] The orientation of helix 12 is critical tothe conformation NRs adopt once bound to a particular typeof ligand and ultimately influence the ability of the receptorto bind other proteins and activate gene transcription Helix12 contains the core residues of the activator function-2 (AF-2) domain a short amphipathic conserved alpha-helix thatinteracts with coregulatory proteins through an LxxLLmotifAdjacent to the AF-2E domain is the less characterized Fdomain that is unique to ERs ER120572 has a larger F domain thanER120573 and the two receptors only share about 18 homologywithin this region ER120572 dimerization and interactions withcoregulators are altered when the F domain is deleted ormodified demonstrating that the F domain is a relevantstructure for ER120572 transcriptional regulation but a clear rolefor this domain for ER120573 has yet to be determined [33 34]Importantly naturally occurring human ER120573 splice variantshave altered E and F domains which can affect hormoneresponsiveness in tissues that express these variants

While the overall sequence homology between ER120572 andER120573 is greater than 60 the specific gene targets of eachreceptor appear to be vastly different For example a varietyof cancer cell models have identified an antiapoptotic prolif-erative role for ER120572 whereas ER120573 tends to promote apoptosisand regulate antiproliferative genes [35ndash38] It is well knownthat ER120572 and ER120573 are readily able to form heterodimerswhen expressed in the same cell adding another layer ofcomplexity to the regulation of estrogen responsive genesER120572 andER120573 both bindEREs but the affinity for one receptor

AB

AB

AB

AB

C

C

C

C

D

D

D

D

E

E

E

E

F

FhER1205731

hER1205732

hER1205734

hER1205735

(a)

AB

AB

AB

AB

AB

AB

C

C

C

C

C

C

D

D

D

D

D

D

E

E

E

E

E

E

F

F

F

F

F

F

rER1205731

rER1205731Δ3

rER1205731Δ4

rER1205732

rER1205732Δ3

rER1205732Δ4

(b)

Figure 1 Representative image of domains within human andrat ER120573 splice variants Human ER120573 splice variants (a) containtruncations and changes in amino acid sequence in the C-terminusE and F domains Rat ER120573 splice variants (b) contain an 18-amino-acid insert in the LBDE domain andor exon 34 exclusions in theDNA-binding domain

or the other can depend highly on the specificity of the DNAsequence being regulated and the ligands present [39ndash41]Therefore it is important to consider the overlap in ER120572 andER120573 preferred transcriptional response elements when bothreceptors are expressed in the same system

5 Expression of ERs in the BrainA Complex Story

The principal determinant of E2action is the expression

of ER120572 ER120573 their alternatively spliced variants or somecombination of each which is cell-type specific even withindistinct brain nuclei ER expression has been studied exten-sively yet there are few definitive statements that can bemade about the regulation of ER120573 expression It can benoted that ER expression profiles can vary throughout thelife-span in particular when there are dramatic changes incirculating hormone levels such as puberty and menopause(Figure 2) Not only can ER expression vary dependentupon sex age and E

2treatment but these factors can also

direct subcellular localization which ultimately dictates ERfunctions Accordingly contextual studies that map the exactcellular expression patterns of each receptor and their splice

4 ISRN Endocrinology

Perimenopause(40s50s)

Postmenopause(50s+)

Peripuberty(preteens)

E2

Cyclicity

ΔER expression withhormone cyclicity ΔER expression with age

and E2 declineuarr ER splice variants

Figure 2 Timeline showing factors affecting ER gene expressionthroughout the female life-span Brain ER gene expression patternsare altered with age sex and exposure to circulating hormoneCirculating hormones fluctuate with age most dramatically at thetime of puberty andmenopause therefore contributing to changes inER gene expression Additionally alternative splicing increases withage thus potentially diversifying the ER gene expression profile

variants are a critical first step in creating a comprehensiveexamination of E

2-regulated processes in any system

The female vertebrate reproductive organs tend to bedominated by the expression of ER120572 whereas ER120573 isexpressed largely in nonreproductive tissues ER120573 was firstcloned from prostate tissue [42] and it has since been shownto have the highest levels of expression in the central nervoussystem and cardiovascular tissue as well as lung kidneycolorectal tissue mammary tissue and the immune system[43] Consequently some of the most prominent phenotypicproblems observed in mice lacking a functional ESR2 gene(120573ERKO mice) are neurological deficits By contrast ER120572knockout mice have no gross brain-related phenotypes butthey exhibit decreased E

2-mediated neuroprotection follow-

ing an ischemic event [44] Overall the phenotypes observedin ER120572- and ER120573-null mouse models suggest that ER120573 ispotentially more important for mediating nonreproductiveE2-governed processes than ER120572ER120572 and ER120573 are coexpressed in some regions of the

hypothalamus such as the medial amygdala (MeA) the bednucleus of the stria terminalis (BNST) and the periaqueduc-tal grey area However ER120572 is predominant in hypothala-mic nuclei that control reproduction sexual behavior andappetite (eg arcuate (ARC) medial preoptic (MPoA) andventromedial (VM)) but ER120573 is the predominant isoform inthe nonreproductive associated nuclei (eg paraventricular(PVN) supraoptic (SON) and suprachiasmatic (SCN)) aswell as the hippocampus dorsal raphe nuclei cortex andcerebellum [45 46] In the hippocampus mRNA and proteinfor both ERs have been detected and are well established asmediating both genomic and nongenomic processes [47ndash49]Nuclear and extranuclear ER120573mRNA and immunoreactivity(IR) have been detected in principal cells as well as inmany other nuclei of cells within the ventral CA23 [4647] Although not as prevalent as ER120573 ER120572 has also beendetected in the hippocampus primarily within GABAergicinterneurons [47 49]

ER expression is also often found to be sexually dimor-phic As onewould expectmany regions of the hypothalamusexhibit a great deal of sexual dimorphism due in part to dif-ferences in sexual behavior and regulation of gonadotrophic

hormones but regions such as the BNST also display somesex-related differences in ER expression For example ER120572 inthe BNST can be induced in somatostatin-positive neurons ofmale but not female rats [50] ERs have also been shown tobe sexually dimorphic in the developing rodent hippocam-pus but not in adults [51 52] However one report identifiedER120573mRNA in the adult female but notmale rhesusmacaquebasal ganglia and hippocampus [53] Importantly a lacksexually dimorphic regional ER expression does not precludedifferential responses to estrogens as other effectormoleculescan alter estrogen-responsive processes

Expression of ERs can vary not only with chromosomalsex but also in response to the hormonalmilieu For instanceit is well accepted that ER120572 expression is autoregulated byE2 primarily through proteasomal degradation [54] but also

perhaps on a transcriptional level by E2-bound ER120573 [55]The

ER120573 gene (ESR2) promoter region has not been extensivelycharacterized but it has been shown to contain E

2-responsive

cis sequence-binding sites for Oct-1 and Sp-1 which interactwith ERs via trans factors suggesting a molecular mechanismfor E2-mediated autoregulation of its receptor There is also

an Alu repeat sequence that may contain an ERE that couldact as an ER-dependent enhancer [56] Conversely in vitroand in vivo studies investigating the effects of E

2on ER120573

expression have yielded inconsistent conclusions dependingupon cell type animal species and age For instance in theT47D human breast cancer cell line E

2upregulated ER120573 [57]

However ER120573 expression was decreased by E2in mammary

glands of lactating mice that coexpress ER120572 [58] ER120573 wasalso decreased in the PVN of rats subjected to OVX+ E

2[59]

Thus it appears that E2may regulate ER120572 and ER120573 however

this effect is highly dependent upon cell type and possiblyupon the coexpression of other ERs

In addition to sex and E2 aging also appears to influence

ER expression Overall decreased nuclear E2binding has

been reported in the hypothalamus and anterior pituitary ofaged female rats compared to young ones but the changein E2binding was not necessarily attributed to a decrease

in total ER expression [60 61] suggesting a shift in theratio of ERs andor subcellular localization While overallnuclear E

2binding within the hypothalamus may decrease

with age changes to ER expression patterns with age remaincontentious In general it appears that age alone does noteliminate ER120572 expression in the brain but regional specificityand E

2availability may be important factors [62 63] and an

increase in ESR promoter methylation has been correlatedwith age in other systems [64 65] One study reported variedmiddle age-specific reduction in hypothalamic ER with E

2

treatment [66] yet another study showed that E2decreased

hypothalamic ER expression significantly in all ages tested(3 11 and 20 months) [67] Specific to ER120572 a work byChakraborty and colleagues determined that immunoreac-tive cell numbers did not always change following OVXand E

2replacement Rather their study revealed that with

advanced age (24ndash26 months compared to 3-4 and 10ndash12months) the number of ER120572-positive cells was increased or itstayed the same in different hypothalamic nuclei [68] In thehippocampus ER120572 was decreased after long-term estrogendeprivation (LTED 10 weeks) regardless of E

2replacement

ISRN Endocrinology 5

following LTED but E2deprivation had no effect on ER120573

[11] The same report demonstrated decreased levels of ER120573in very old rats (24-month females compared to 3-monthdiestrus females) In general most reports suggest that agingdecreases ER120573 expression but like ER120572 this effect may behighly region specific An age-related decrease in ER120573 expres-sion in the brain is underscored by a corresponding increaseinCpGmethylation of the ESR2 promoter inmiddle-aged (9ndash12months) rats [69] Other reports describe decreases in ER120573protein and message in some areas but not in others [63 70]Taken together there are a number of reports attemptingto identify the parameters that control ER expression suchas age sex and response to E

2 however with such vast

deviations in expression with cell type there is still much tobe learned about expression of these receptors especially inbrain regions controlling nonreproductive behaviors

6 Alternative Splice Variants

Based upon the highly variable reports that differ in sexand age of animals as well as exposure to hormone it maybe possible that these studies are unknowingly detectingchanges in splice variant expression which could change E

2

responsiveness as well as downstream gene regulation Notonly can ERs heterodimerize to regulate gene transcriptionbut there are a number of alternatively spliced variants of eachreceptor that are endogenously expressed and that potentiallycontribute to the diverse tissue-specific actions of E

2 Alter-

native splicing of ERs alters inherent signaling properties ofthe receptor including ligand and DNA-binding affinitiesnuclear localization and dimerization depending on wherethe alternative splice site is encoded A number of ER splicevariant transcripts and other proteins have been identifiedin demented human brains breast and prostate and insome reports an increase in alternative splicing is correlatedwith pathology [71ndash75] Also interesting age alone mayincrease alternative splicing of some gene products [76] Theidentified ER120573 human splice variants are truncated at the C-terminus of the receptor (Figure 1(a)) however we providedexperimental evidence that the C-terminus of the receptoris not required for ER120573-mediated transcription especiallywith regard to the identified human splice variants [77]Unlike the human splice variants rodent ER120573 splice variantsidentified to date have been shown to have either an exoninclusion in the ligand-binding domain creating (rER1205732)or an exon deletion in the DNA-binding domain rER1205731Δ3or rER1205731Δ4 or both rER1205732Δ3 and rER1205732Δ4 (Figure 1(b))[37 78 79] Exon inclusion (rER1205732 variants) has been shownto produce a protein that binds E

2with a 35-fold decrease

in affinity In contrast ERs with exon 3 and 4 deletions areunable to bind DNA but they can still mediate transcriptionthrough proteinprotein interactions with other transcriptionfactors such as AP-1 and it can bind E

2as well as rER1205731

[37 80] Importantly the transcriptional functions of rER1205731are significantly altered when coexpressed with other splicevariants likely due to a weaker interaction with coactivatorproteins [81 82] Despite lower E

2binding andor lack of

DNA binding the rodent and human splice variants retain a

constitutive ligand-independent transcriptional function atboth basic and complex promoters [77 83 84] suggestingthat these splice variants have an important endogenousbiological function Indeed unliganded ER1205731 or apo-ER1205731has been reported to regulate a subset of genes distinct fromthose regulated by ER1205731 when bound to E

2[41] Conversely

the human splice variants do not bind ligand with greataffinity [85] and they might therefore only regulate the classof genes that unliganded ER120573 targets

Thedownstream target genes of ER120573 splice variantsmightbe an important consideration at the time of menopauseas ER expression profiles and alternative splicing tend tochange with age [76] One recent report demonstrated anincrease in ER1205732 expression in the hippocampus of 9-month old middle-aged rats following short-term (6 days)E2deprivation that was significantly decreased compared to

the Sham group after E2administration [86] Importantly

E2replacement no longer affected ER1205732 expression in the

hippocampus after LTED (180 days)That study also reporteda decrease in hippocampal neurogenesis and increased float-ing behavior in a forced swim test thus functionally corre-lating increased ER1205732 with mood regulation and potentiallycognition Thus the expression and functions of ER120573 splicevariants are absolutely critical to understand the effects ofestrogen particularly at times of sustainedE

2deprivationwith

regard to cognition and affect While ER1205732 expression hasbeen assessed in the young male rat brain [87] and othervariants have been described in some brain regions [80 88]there is a general lack of data on most ER120573 splice variantsespecially in aged female brains

Some of the splice variants identified to date have beencharacterized as dominant negative receptors serving toinhibit activation of the full-length receptor [89] howevermost identified variants do not bind ligand with the sameaffinity and have the potential to differentially regulate targetgenes While several splice variants for ER120573 have been iden-tified in many model systems including mouse [90] rat [4546] and monkey [91] there is a general lack of comparativestudies on expression and functionality of human ER120573 vari-ants especially in neuronal systems Furthermore changingexpression levels of one or more alternatively spliced variantsduring a period of E

2deprivation may drastically change

general receptivity and downstream functions of E2

7 Novel ProteinProtein Interactions forE2-Mediated Nuclear Processes

Proteinprotein interactions are an essential relay in the reg-ulation of dynamic cellular processes Immediately followingtranslation ERs typically associate with a chaperone proteinto ensure proper folding protect from degradation and assistthe ER in becoming poised to accept ligand Once bound toligand ERs can dimerize and act as transcription factors tomediate gene regulation or associate withmembrane proteinsto initiate a signaling cascade When acting as transcriptionfactors ERs associate with a number of coregulatory proteinsthat assist in activating or repressing E

2-regulated genes

Coregulatory interactions are more characterized for ER120572

6 ISRN Endocrinology

than ER120573 and importantly less clear is how ER120573 mediatesligand-independent transcription In addition to the well-established ER interaction partners many novel interactingproteins have not yet been characterized and could be criticalfor nuclear processes not limited to gene transcription

8 HSPs and Chaperone Proteins

According to the classical two-step hypothesis inactivenuclear receptors are constantly accompanied and protectedfrom degradation by a number of chaperone proteins typi-cally members of the heat-shock protein (HSP) family Thisreceptorchaperone complex has been studied extensivelyand while the idea of a protective role for chaperones is wellsupported this complex can also perform other functionsFor instance HSPER complexes can serve to preactivatea hormone receptor by forcing a conformational changein ER such that it is able to bind its cognate hormoneThe initial HSP complex consists of the ER HSP70 andHSP70-interacting protein (HiP) as well as other accessoryand scaffolding proteins [92] HSP90 is recruited to thecomplex andHSP70 dissociates creating thematureHSPERcomplex [93] HSP90 induces a conformational change in thenuclear receptor and the ER is released from the complexready to dimerize and bind DNA or other transcriptionfactors to regulate gene transcription However some studiessuggest that HSPs could have a broader role than originallythought For example in Drosophila HSPs are required forDNA binding and in some instances they may regulateNR action [94] Interestingly aging and E

2can alter HSP70

in a cell-type specific manner [95ndash98] However recentdata from our lab (Table 1) demonstrated that HSP70 morereadily associates with ER120573 in aged female hippocampusfollowing E

2treatment compared to the young ones in which

HSP70ER120573 association decreased following E2treatment

We also observed no significant changes in HSP70 or ER120573expression suggesting that changes in the HSP70ER120573 inter-action with age in response to E

2change are a result of E

2

responsiveness andor activation of ER120573

9 Transcriptional Proteins and ERs

The process of transcribing DNA into RNA is a systematicprocess that involves multiprotein complexes binding toDNA modifying histone marks and initiating RNA synthe-sis ER120572 but not ER120573 has been shown to directly interactwith TFIIB IIE IIF and TIID proteins that initiate tran-scription [99 100] However experimental evidence from co-immunoprecipitation studies has demonstrated interactionsbetween ER120573 coregulatory proteins as well as other tran-scription factors Coregulatory proteins are transcriptionalaccessory proteins that enhance or repress transcription oftarget genes In general coactivators enhance gene tran-scription whereas corepressors block it However recentdata suggest that seemingly nontranscriptional proteins mayhave context-dependent coregulatory functions Importantly

certain coregulators can also be governed by age and E2[101ndash

103] thus recent discoveries imply that ER-mediated generegulation is not as well understood as previously thought

The best studied and well-established group of coregula-tory proteins that selectively associate with NRs is the steroidreceptor coactivator (SRCp160) family The SRC family iscomposed of three members SRC-1 SRC-2 and SRC-3all of which contain canonical LxxLL motifs known as thenuclear receptor (NR) box This motif interacts with AF-2 domains in ER120573 as well as other NR family memberssuch as glucocorticoid receptor (GR) progesterone receptor(PR) thyroid hormone receptor (TR) and ER120572 [104] SRCmembers have intrinsic histone acetyltransferase activity(HAT DNA activating) and interact with CREB-bindingprotein (CBP) [105] CBPp300 proteins are also coactivatorsthat have intrinsic HAT activity and can recruit ASC-2and other known coregulatory proteins [106] Confirmedcoregulatory interaction partners for several NRs that donot belong to the SRC family include estrogen-receptor-association protein (ERAP 140) [107] nuclear corepressor(NCoR) [108] silencing mediator of retinoic acid and thy-roid hormone receptor (SMRT) [109] and many othersAs is the case with our understanding of ER120573 interactionswith basic transcriptional machinery studies investigatingER120573coregulator interactions are sparse which may be dueto uniquely challenging issues associated with ER120573 such as alack of high-fidelity biochemical tools complicated structuralproperties and or pleiotropic physiological actions that arespecific to ER120573

In 2010 Anna Ma lovannaya and colleagues directeda high-throughput study (not including ER120573) aiming atcompiling a database for the endogenous coregulator poolldquonuclear receptor complexomerdquo [110] In this study a numberof novel protein interactions were identified and studiessuch as these are identifying proteins as ldquocoregulatorsrdquo thathad been previously thought to serve completely differentfunctionsOne group of relatively novel coregulatory proteinsare the E3 ubiquitin-protein ligases such as E6-associatedproteins (E6-AP) [111] While these proteins were thought toserve primarily as ubiquitin-conjugating enzymes they haverecently been highlighted as transcriptional enhancers ofNR-mediated activity independent of ligase function Similarlya group of E3-ligases that conjugate small ubiquitin likemodifier (SUMO) proteins to a target protein called PIASare also now considered NR coregulators and they utilize atypical LxxLLmotif In one study a decrease in ER expressionfollowing LTED or with advanced age coincided with anincrease in ER association with an E3-ubiquitin ligase CHIP[11] Together these newly described roles for HSPs and E3ligases raise novel questions about estrogen signaling such aswhen is an E3-ligaseER complex targeted for transcriptionalregulation versus degradation Also when are HSPs merelyperforming a chaperoneprotective function versus directingtranscriptional processes Future efforts aiming at elucidatingthe complexity of age-related changes in receptor structureand recruitment of coregulatory proteins could provideimportant insight into these seemingly paradoxical findings

ISRN Endocrinology 7

Table 1 Protein interactions with ER120573 were altered by age and 1198642 Selected proteins that were significantly altered (119875 lt 005) in their

association with ER120573 depending on age and 1198642treatment Experimental paradigm young (3 month) and aged (18 month) female Fischer 344

rats were ovariectomized and hormone deprived for 7 days Following deprivation animals were administered 25120583gkg 1198642(plasma levels =

7945 plusmn 225 pgmL) or vehicle (safflower oil) via subcutaneous injection onceday for 3 days Nuclear protein was isolated from the ventralhippocampus and coimmunoprecipitated for ER120573 (a beam 14C8) and associated proteins Protein interactions were identified and quantifiedusing 2D-DIGEDeCyder and ESI MSMS YV = young + vehicle YE = young + 119864

2 AV = aged + vehicle AE = aged + 119864

2

Accession noMolecularweight(Kda)

Estimatedisoelectricpoint

PEAKSscore Coverage ID

Interaction with ER120573FunctionYoung

vehicleYoung1198642

Agedvehicle

Aged1198642

gi| 149038929 80 575 494 643 Gelsolin mdash uarr mdash mdashActin-binding

coactivator

gi| 116242507 75 597 93 1458 Heat-shock protein70 mdash darr mdash uarr Chaperone

gi| 120538378 47 57 932 1072

Heterogeneousnuclear

ribonucleoproteinH12

mdash uarr mdash mdash RNA splicing

10 Nuclear Actin Setting the Stage

Coregulatory interactions may be poised upon a bed ofnuclear actin which has recently been identified as a dynamicmolecular stage for which many nuclear processes are per-formed such as transcription chromatin remodeling mRNAprocessing and nuclear importexport The general eventsthat initiate transcription are well established however theprocess by which all of the molecular components are tem-porally layered into a complex is still unclear Nuclear actin isessential in forming the preinitiation complex on a promoterelongation and RNP organization as well as remodeling ofchromatin [112ndash114] and as mentioned previously ERs arealso key factors in these processes In one study ER120572 and120573-actin were coimmunoprecipitated on the E

2responsive

pS2TFF1 promoter indicating that ER and nuclear actinmay work in concert to regulate transcriptional processesunder control of estrogens [115] The interaction betweenERs and actin is not yet fully investigated but data fromour lab (unpublished observations) and others [116] implythat both ER120572 and ER120573may utilize nuclear actin to performvarious functions Another actin-binding protein gelsolincaps actin filament ends and it has been shown to be anNR coactivator [117 118] Gelsolin may assist in actin poly-merization allowing transcriptionalmachinery to be broughtin proximity of target genes however it remains unclearhow gelsolin enhances ARER transcriptional activity Datafrom our lab indicate that gelsolinER120573 interactions increasewith E

2treatment in young but not aged animals (Table 1)

Gelsolin has been shown to increase with age [119] but alack of significant interaction with ER120573 despite increasedexpression of gelsolin could again suggest an alteration inER120573 function with age

Actin is also commonly associated with ubiquitous mul-tifunctional RNA-binding proteins such as heterologousnuclear riboproteins (hnRNPs) which also associate withERs [120] hnRNPs associate within the matrix of nuclearactin accompany transcripts out of the nucleus participatein alternative splicing and can modulate transcription [121]

Phosphorylated hnRNPK has been shown to mediate trans-lation of specific mRNAs [122] and hnRNPH is involvedin splicing and mRNA polyadenylation [123 124] In thepast the association of NRs with hnRNPs was thought to benonspecific due to the ubiquitous nature of these proteinsbut recent studies are no longer ruling out an importantinteraction between NRs and hnRNPs that may assist intranscription andor splicing [125 126] Data from our laband others demonstrate a dynamic interaction between bothER120572 and ER120573 and hnRNPs (Table 1) and furthermore datademonstrated that E

2might regulate expression of members

of the hnRNP family [127] As noted previously age-relatedincreases in splicing could lead to aberrant signaling not onlyfor E2-mediated processes but also for cellular processes in

generalNuclear ER interaction partners have historically been a

distinct class of nuclear receptor coregulators that seemedto solely assist ERs in gene transcription however thenumber of interaction partners for ERs is increasing Furtherinvestigation into ER120573-associated proteins is required as faras NRs are concerned data specific to ER120573 are inadequateto make broad conclusions Moreover post-translationalmodifications to coregulatory proteins ERs or changes intheir expression patterns due to age or sustained estrogendeprivation could all contribute to an altered microenviron-ment setting the stage for atypical estrogen signaling upontherapeutic reinstatement of hormones (Figure 3)

11 Estrogens and Cognition

Most empirical and observational data give merit to theidea that estrogens have a positive effect on cognitiveprocesses increased spine densities [128 129] enhancedsynaptic plasticity [130ndash132] and improved memory [133134] however the particular receptor(s) and the mechanismsthat regulate these processes remain unclear There are amyriad of behavioral studies suggesting that E

2enhances

prefrontal cortex (PFC) and hippocampal-dependent tasks

8 ISRN Endocrinology

Factor BER structureand function

Factor Ccoregulatory and

transcriptional interactions

120573

120573120573

120573

120572

120572

120572 120572

V

V

V

V

V

V

V

V

ESR1

ESR2

Age and E2

++

Context-dependentER-regulated

gene expression

Factor Atissue-specific

ER gene expression

Figure 3 Age and hormonalmilieu exponentially increase the potential diversity of estrogen receptor signaling leading to context-dependentgene regulation Age and E

2influence ER gene expression alternative splicing coregulatory protein expression and interaction which

ultimately direct ER-target gene transcription

For example long-term E2deprivation diminished aged

female rhesus macaquesrsquo performance in a delayed responsetask a PFC- dependent task [135] E

2also enhanced object

recognition under a number of different paradigms [136ndash138] and there are also multiple lines of evidence supportingE2-mediated neuroprotection which may be important for

cognition especially after stroke [139ndash142]Pharmacological targeting of the receptors with ER selec-

tive ligands has been a standard method for investigating thebehavioral physiological and cellular actions of E

2mediated

distinctly throughER120572 andor ER120573 however valuable insighthas also come from the ER120573-null (120573ERKO) mice 120573ERKOmice have significantly fewer neurons in the cortex hypotha-lamus amygdala and ventral tegmental area compared toWTThey also exhibit neuronal shrinkage and hyperprolifer-ation of glia by 3 months of age as well as having high levelsof apoE and apoE-dependent deposition of amyloid plaquesthroughout the CNS by 12 months of age [143] These micealso demonstrate spatial learning deficits in the Morris watermaze [144] and a decrease in hippocampal- and amygdala-dependent memory in a fear-conditioning paradigm that isaccompanied by decreased synaptic plasticity in hippocampalslice preparations [145] The critical role of ER120573 in higher-level brain functions has been deduced from these studiesand others warranting a full investigation of the wide-spreadmolecular actions of E

2known to contribute to cellular

processes on at least two levels at the synapse and on thegenome

Long-term potentiation (LTP) is an important compo-nent of learning and memory It represents an increasein synaptic transmission and plasticity that underlies cog-nitive behaviors and it is readily altered by E

2in many

circumstances In fact application of an aromatase inhibitoreliminates CA LTP generated by theta-burst stimulation inintact female neurons but not male or OVX animals posinga potentially serious concern for women using aromataseinhibitors for therapeutic treatment of breast cancer [146] E

2

can also enhance or suppress long-term depression (LTD)reducing synaptic transmission which may be dependentupon the specific receptors involved In aged male CA1cells E

2decreased LTD [147] however E

2enhanced LTP in

the cerebellum where ER120573 is the predominately expressedcognate receptor [148]

Although the majority of studies on cognitive processfocus on the rapid effects of E

2 late-phase long-term potenti-

ation (L-LTP) depends upon transcription and translation ofnewmRNA [149] to sustain an increase in synaptic transmis-sion E

2has been shown to regulate LTP in CA1 pyramidal

cells [150] over the span of 48 hours and this regulationappears to be dependent upon a higher ratio of NMDARrelative to AMPAR LTP induction requires activation ofNR2A-containing NMDARs however increased expressionof NR2B potentiates LTP magnitude [151] Notably E

2

increased expression of NR2B mRNA and NR2B expressionat the synapse [152 153] and the E

2-induced increase in

LTP can be abolished by blocking NR2B receptors [154]

ISRN Endocrinology 9

suggesting a transcriptional role for ERs in synaptic plasticityMoreover E

2application may increase CREB expression and

the amount of phosphorylated CREB in regions such as theamygdala [155] and BNST [117 155] which may be critical inthe formation of long-term memories Taken together thesedata demonstrate that E

2regulates neuronal plasticity and

memory through its original role as a transcription factor andalso by acting as a general intracellular signaling moleculethrough regulation of NMDARs and CREB However todate there are little data on the mechanisms by which ER120573regulates these processes or how the same principles ofplasticity may apply to other neurological issues

12 Estrogens and Mood Regulation

A range of behavioral experiments indicate that E2mod-

ulation of stress mood and affect is a complex storywith considerable conflicting data that may as in otherprocesses be explained in part by distinct roles for ER120572 andER120573 Anecdotally many women report mood fluctuationsas corresponding to changes in circulating estrogen levelssuch as what occurs during the menstrual cycle peripubertypostpartum and peripostmenopause Incidence of anxietyand depression are observed at perimenopause and whenhormone levels are fluctuating [156 157] However E

2can

also exhibit anxiogenic properties and often anxiety anddepression present in a comorbid fashion especially inwomen [158 159] Interestingly after the age of 55 bouts ofdepression and anxiety appear to decrease in women [160]As previously mentioned perimenopausal women receivingCEE in the KEEPs study reported an improvement in moodand the primary actions of CEE tend to be mediated throughER120573 [20] A plethora of behavioral studies has mountedin response to observational reports and at first glance itappears that ER120573 has an anxiolytic and antidepressive rolehowever there is still an immense void to be filled withrespect to biochemical and molecular mechanisms of ER120573and affective disorders Elucidating the precise molecularmechanisms that require ER120573 in plasticity and neurotrans-mitter processing in brain regions regulating these behaviorswill help clarify the role of E

2in stress- and mood-related

processesContemporary hypotheses concerning the onset of affec-

tive disorders revolve around perturbations to the cen-tral processing of environmental stress The hypothalamic-pituitary-adrenal (HPA) axis is the 3-tiered hierarchicalbiological system that mediates physical or psychologicalresponse to stressors The primary steroid regulating theHPA axis is cortisolcorticosterone (humansrats CORT) aglucocorticoid receptor (GR) ligand that is produced fromthe adrenals to exert negative feedback upon the HPAsystem to effectively modulate response to stressors Theparaventricular nucleus of hypothalamus (PVN) producestwo neuropeptides corticotropin-releasing hormone (CRH)and arginine vasopressin (AVP) to activate the HPA axisCRF and AVP synergistically stimulate release of adreno-corticotropic hormone (ACTH) from the anterior pituitarywhich acts on the adrenal cortex to produce CORT CORT

binds GR and negatively regulates CRF and AVP expressionsand releases through classical negative feedback mechanisms[161 162] ER120573 is themain ER expressed in the PVN [158 163ndash165] and regulation of AVP is an interesting example of howER action can vary AVP expression fluctuates during themenstrual cycle and is usually highest when E

2is low In fact

oral contraceptives appear to decrease AVP expression andE2is thought to inhibit AVP in the human SON [166] In

the rodent system ER120573 and its splice variants activate therodent AVP promoter independent of ligand [84] howeverthe human promoter is repressed by ER120573 and splice variantsThis discrepancy between the human and rat wasmediated byan AP-1 response element on the human AVP promoter thatis not present in the rat Importantly ER120573 acted similarly inthe two systems when the AP-1 sequence was deleted fromthe human promoter underscoring the striking alterationsthat small changes in DNA sequence can invoke in E

2

signaling pathways and the importance of understanding theexperimental context upon which such conclusions are based[77] On the contrary rat and human CRF expression wasincreased in response to E

2in rodent monkey and human

hypothalamus but it was inhibited in the placenta [167ndash170]In addition to AVP and CRF glutamatergic and GABAer-

gic projects from regions like the BNST AMY PFC andhippocampus all express ER120573 [45 46] and are likely targetsfor E2to exert effects on the HPA axis Moreover decreased

ER120573 mRNA in postmortem locus coeruleus has been foundto correlate with suicide [13] and even more recentlyER120573-mediated hippocampal nitric oxide levels have beenimplicated in affective behaviors in females but not males[171] Neurotransmitter release from these regions influencesmood affect and stress responses and E

2increases the rate

of monoamine oxidase degradation and serotonin transportwhich enhances serotonin at the synapse E

2also increases

serotonin receptor expression [172 173] Dopamine andserotonin [174] are diminished in the BNST POA and hip-pocampus and caudate putamen (dopamine) of 120573ERKOmice[174] further implicating an important role for ER120573 in theregulation of emotion and mood 120573ERKO mice also displayserious morphological and functional abnormalities in thebrain that correlate to increased depression and anxiety [12175ndash178] In addition to 120573ERKO studies administration ofER120573 selective agonists (diarylpoprionitrile DPN) decreasesboth stress markers and anxiety-related behaviors in rats[158] In fact there have been several studies implicatingER120573 and its variants in affective behaviors but the molecularmechanisms remain poorly understood

13 Summary

Estrogen-receptor-mediated signaling in the brain regulatesneurological processes many of which translate to cog-nitive and affective behavioral outputs When estrogen isdeclining and becomes replete as in menopause a num-ber of neurophysiological changes occur producing someunwanted changes The most common and logical remedyis replacement of bioidentical hormone E

2 however this

treatment can be problematic depending upon the length

10 ISRN Endocrinology

of time a woman has been in a postmenopausal estrogen-deprived state This suggests that there is a molecular switchin estrogen-mediated signaling that may allow for drasticchange in ER signaling not to mention the interaction of E

2

signaling components and the natural aging process Thesechanges are likely to include alterations to receptor profilesincluding expression of alternatively spliced variants thatrespond differently to E

2 changes in the cellular microenvi-

ronment that can alter the proteinprotein associations whichultimately leads to changes in ER-mediated gene transcrip-tion and synaptic transmission ER120573 in particular is widelyexpressed and implicated positively in the regulation ofmemory and mood fluctuations two of the most commonlyreported neurological issues in postmenopausal women Itis important to understand the actions of ER120573 in the areasregulating these processes to identify what when how andfor whom hormone therapy may be a useful treatment torectify cognitive and affective issues

Acknowledgments

This work was supported by NIA RO1 AG033605-01 andNIH T32 AG031780 The authors N N Mott and T R Pakhave nothing to disclose

References

[1] C Bengtsson O Lindquist and L Redvall ldquoIs the menopausalage rapidly changingrdquoMaturitas vol 1 no 3 pp 159ndash164 1979

[2] A Singh S Kaur and I Walia ldquoA historical perspective onmenopause andmenopausal agerdquo Bulletin of the Indian Instituteof History of Medicine (Hyderabad) vol 32 no 2 pp 121ndash1352002

[3] P Verhaeghen and J Cerella ldquoAging executive control andattention a review of meta-analysesrdquo Neuroscience and Biobe-havioral Reviews vol 26 no 7 pp 849ndash857 2002

[4] T E Wroolie H A Kenna K E Williams et al ldquoDifferencesin verbal memory performance in postmenopausal womenreceiving hormone therapy 17120573-estradiol versus conjugatedequine estrogensrdquoAmerican Journal of Geriatric Psychiatry vol19 no 9 pp 792ndash802 2011

[5] B B Sherwin ldquoEstrogenic effects on memory in womenrdquoAnnals of the New York Academy of Sciences vol 743 pp 213ndash230 1994

[6] B B Sherwin ldquoHormones mood and cognitive functioning inpostmenopausal womenrdquoObstetrics andGynecology vol 87 no2 supplement pp 20Sndash26S 1996

[7] B B Sherwin ldquoSex hormones and psychological functioning inpostmenopausalwomenrdquoExperimentalGerontology vol 29 no3-4 pp 423ndash430 1994

[8] SM Phillips and B B Sherwin ldquoEffects of estrogen onmemoryfunction in surgically menopausal womenrdquo Psychoneuroen-docrinology vol 17 no 5 pp 485ndash495 1992

[9] R Lindsay J M Aitken and J B Anderson ldquoLong term pre-vention of postmenopausal osteoporosis by oestrogen Evidencefor an increased bone mass after delayed onset of oestrogentreatmentrdquoThe Lancet vol 1 no 7968 pp 1038ndash1040 1976

[10] J E Rossouw R L Prentice J E Manson et al ldquoPost-menopausal hormone therapy and risk of cardiovascular dis-ease by age and years since menopauserdquo The Journal of the

American Medical Association vol 297 no 13 pp 1465ndash14772007

[11] Q-G Zhang D Han R-M Wang et al ldquoC terminusof Hsc70-interacting protein (CHIP)-mediated degradationof hippocampal estrogen receptor-120572 and the critical periodhypothesis of estrogen neuroprotectionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 108 no 35 pp E617ndashE624 2011

[12] W Krezel S Dupont A Krust P Chambon and P F ChapmanldquoIncreased anxiety and synaptic plasticity in estrogen receptor120573-deficient micerdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 21 pp 12278ndash12282 2001

[13] H Ostlund E Keller and Y L Hurd ldquoEstrogen receptor geneexpression in relation to neuropsychiatric disordersrdquo Annals ofthe New York Academy of Sciences vol 1007 pp 54ndash63 2003

[14] S A Shumaker C Legault S R Rapp et al ldquoEstrogen plusprogestin and the incidence of dementia and mild cognitiveimpairment in postmenopausal women the Womenrsquos HealthInitiative Memory Study a randomized controlled trialrdquo Jour-nal of the American Medical Association vol 289 no 20 pp2651ndash2662 2003

[15] S A Shumaker C Legault L Kuller et al ldquoConjugated equineestrogens and incidence of probable dementia and mild cog-nitive impairment in postmenopausal women womenrsquos HealthInitiative Memory Studyrdquo Journal of the American MedicalAssociation vol 291 no 24 pp 2947ndash2958 2004

[16] S R Rapp M A Espeland S A Shumaker et al ldquoEffect ofestrogen plus progestin on global cognitive function in post-menopausal women the Womenrsquos Health Initiative MemoryStudy a randomized controlled trialrdquo Journal of the AmericanMedical Association vol 289 no 20 pp 2663ndash2672 2003

[17] VWHenderson K S Benke R C Green L A Cupples and LA Farrer ldquoPostmenopausal hormone therapy and Alzheimerrsquosdisease risk interaction with agerdquo Journal of Neurology Neuro-surgery and Psychiatry vol 76 no 1 pp 103ndash105 2005

[18] E Garbe and S Suissa ldquoHormone replacement therapy andacute coronary syndromes methodological issues betweenrandomized and observational studiesrdquo Human Reproductionvol 19 no 1 pp 8ndash13 2004

[19] B B Braden A N Garcia S E Mennenga et al ldquoCognitive-impairing effects of medroxyprogesterone acetate in the ratindependent and interactive effects across timerdquo Psychophar-macology vol 218 no 2 pp 405ndash418 2011

[20] B R Bhavnani S-P Tam and X Lu ldquoStructure activity rela-tionships and differential interactions and functional activity ofvarious equine estrogens mediated via estrogen receptors (ERs)ER120572 and ER120573rdquo Endocrinology vol 149 no 10 pp 4857ndash48702008

[21] E Hogervorst and S Bandelow ldquoSex steroids to maintaincognitive function in women after the menopause a meta-analyses of treatment trialsrdquoMaturitas vol 66 no 1 pp 56ndash712010

[22] D J Mangelsdorf C Thummel M Beato et al ldquoThe nuclearreceptor super-family the second decaderdquo Cell vol 83 no 6pp 835ndash839 1995

[23] E V Jensen T Suzuki T Kawashima W E Stumpf P WJungblut and E R DeSombre ldquoA two-step mechanism forthe interaction of estradiol with rat uterusrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 59 no 2 pp 632ndash638 1968

ISRN Endocrinology 11

[24] F Naftolin T L Horvath R L Jakab C Leranth N Haradaand J Balthazart ldquoAromatase immunoreactivity in axon termi-nals of the vertebrate brain an immunocytochemical study onquail rat monkey and human tissuesrdquoNeuroendocrinology vol63 no 2 pp 149ndash155 1996

[25] C E Roselli S E Abdelgadir O K Roslashnnekleiv and S AKlosterman ldquoAnatomic distribution and regulation of aro-matase gene expression in the rat brainrdquo Biology of Reproduc-tion vol 58 no 1 pp 79ndash87 1998

[26] J Balthazart and G F Ball ldquoIs brain estradiol a hormone or aneurotransmitterrdquo Trends in Neurosciences vol 29 no 5 pp241ndash249 2006

[27] T R Pak Y S Rao S A Prins and N N Mott ldquoAn emergingrole for microRNAs in sexually dimorphic neurobiologicalsystemsrdquo Pflugers Archiv vol 465 no 5 pp 655ndash667 2013

[28] K Yamagata S Fujiyama S Ito et al ldquoMaturation ofmicroRNAis hormonally regulated by a nuclear receptorrdquo Molecular Cellvol 36 no 2 pp 340ndash347 2009

[29] Y Masuhiro Y Mezaki M Sakari et al ldquoSplicing potentiationby growth factor signals via estrogen receptor phosphorylationrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 23 pp 8126ndash8131 2005

[30] A Tremblay G B Tremblay F Labrie and V Giguere ldquoLigand-Independent recruitment of SRC-1 to estrogen receptor 120573through phosphorylation of activation function AF-1rdquo Molec-ular Cell vol 3 no 4 pp 513ndash519 1999

[31] S H Meijsing M A Pufall A Y So D L Bates L Chenand K R Yamamoto ldquoDNA binding site sequence directsglucocorticoid receptor structure and activityrdquo Science vol 324no 5925 pp 407ndash410 2009

[32] W Bourguet P Germain and H Gronemeyer ldquoNuclearreceptor ligand-binding domains three-dimensional struc-tures molecular interactions and pharmacological implica-tionsrdquo Trends in Pharmacological Sciences vol 21 no 10 pp381ndash388 2000

[33] A Koide C Zhao M Naganuma et al ldquoIdentification ofregions within the F domain of the human estrogen receptor 120572that are important for modulating transactivation and protein-protein interactionsrdquoMolecular Endocrinology vol 21 no 4 pp829ndash842 2007

[34] D F Skafar and S Koide ldquoUnderstanding the human estrogenreceptor-alpha using targeted mutagenesisrdquoMolecular and Cel-lular Endocrinology vol 246 no 1-2 pp 83ndash90 2006

[35] E C Chang J Frasor B Komm and B S KatzenellenbogenldquoImpact of estrogen receptor 120573 on gene networks regulated byestrogen receptor 120572 in breast cancer cellsrdquo Endocrinology vol147 no 10 pp 4831ndash4842 2006

[36] X Zhu I Leav Y-K Leung et al ldquoDynamic regulation ofestrogen receptor-120573 expression by DNA methylation duringprostate cancer development andmetastasisrdquoAmerican Journalof Pathology vol 164 no 6 pp 2003ndash2012 2004

[37] D N Petersen G T Tkalcevic P H Koza-Taylor T G Turiand T A Brown ldquoIdentification of estrogen receptor 1205732 afunctional variant of estrogen receptor 120573 expressed in normalrat tissuesrdquo Endocrinology vol 139 no 3 pp 1082ndash1092 1998

[38] L A Helguero M H Faulds J-A Gustafsson and L-AHaldosen ldquoEstrogen receptors alfa (ER120572) and beta (ER120573)differentially regulate proliferation and apoptosis of the normalmurine mammary epithelial cell line HC11rdquo Oncogene vol 24no 44 pp 6605ndash6616 2005

[39] P C Kulakosky M A McCarty S C Jernigan K E Risingerand C M Klinge ldquoResponse element sequence modulates

estrogen receptor 120572 and 120573 affinity and activityrdquo Journal ofMolecular Endocrinology vol 29 no 1 pp 137ndash152 2002

[40] OM V Grober MMutarelli G Giurato et al ldquoGlobal analysisof estrogen receptor beta binding to breast cancer cell genomereveals an extensive interplay with estrogen receptor alpha fortarget gene regulationrdquo BMC Genomics vol 12 article 36 2011

[41] O I Vivar X Zhao E F Saunier et al ldquoEstrogen receptor 120573binds to and regulates three distinct classes of target genesrdquoJournal of Biological Chemistry vol 285 no 29 pp 22059ndash22066 2010

[42] G G J M Kuiper E Enmark M Pelto-Huikko S Nilssonand J-A Gustafsson ldquoCloning of a novel estrogen receptorexpressed in rat prostate and ovaryrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 93 no12 pp 5925ndash5930 1996

[43] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and 120572 and 120573rdquo Endocrinology vol 138no 3 pp 863ndash870 1997

[44] D B Dubal H Zhu J Yu et al ldquoEstrogen receptor alpha notbeta is a critical link in estradiol-mediated protection againstbrain injuryrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 98 no 4 pp 1952ndash1957 2001

[45] P J Shughrue P J Scrimo and I Merchenthaler ldquoEvidence forthe colocalization of estrogen receptor-120573 mRNA and estrogenreceptor-120572 immunoreactivity in neurons of the rat forebrainrdquoEndocrinology vol 139 no 12 pp 5267ndash5270 1998

[46] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in therat central nervous systemrdquo Journal of Comparative Neurologyvol 388 no 4 pp 507ndash525 1997

[47] T AMilner B SMcEwen S Hayashi C J Li L P Reagan andS E Alves ldquoUltrastructural evidence that hippocampal alphaestrogen receptors are located at extranuclear sitesrdquoThe Journalof Comparative Neurology vol 429 no 3 pp 355ndash371 2001

[48] T A Milner L S Lubbers S E Alves and B S McEwenldquoNuclear and extranuclear estrogen binding sites in the ratforebrain and autonomic medullary areasrdquo Endocrinology vol149 no 7 pp 3306ndash3312 2008

[49] T A Milner K Ayoola C T Drake et al ldquoUltrastructurallocalization of estrogen receptor 120573 immunoreactivity in the rathippocampal formationrdquo Journal of ComparativeNeurology vol491 no 2 pp 81ndash95 2005

[50] A E Herbison andD TTheodosis ldquoAbsence of estrogen recep-tor immunoreactivity in somatostatin (SRIF) neurons of theperiventricular nucleus but sexually dimorphic colocalizationof estrogen receptor and SRIF immunoreactivities in neuronsof the bed nucleus of the stria terminalisrdquo Endocrinology vol132 no 4 pp 1707ndash1714 1993

[51] K Kalita S Szymczak and L Kaczmarek ldquoNon-nuclear estro-gen receptor 120573 and 120572 in the hippocampus of male and femaleratsrdquo Hippocampus vol 15 no 3 pp 404ndash412 2005

[52] T Ivanova and C Beyer ldquoOntogenetic expression and sexdifferences of aromatase and estrogen receptor-120572120573 mRNA inthe mouse hippocampusrdquo Cell and Tissue Research vol 300 no2 pp 231ndash237 2000

[53] C Y Pau K-Y F Pau and H G Spies ldquoPutative estrogenreceptor 120573 and 120572 mRNA expression in male and female rhesusmacaquesrdquo Molecular and Cellular Endocrinology vol 146 no1-2 pp 59ndash68 1998

[54] A L Wijayaratne and D P McDonnell ldquoThe human estrogenreceptor-120572 is a ubiquitinated protein whose stability is affected

12 ISRN Endocrinology

differentially by agonists antagonists and selective estrogenreceptor modulatorsrdquo Journal of Biological Chemistry vol 276no 38 pp 35684ndash35692 2001

[55] V Bartella P Rizza I Barone et al ldquoEstrogen receptor betabinds Sp1 and recruits a corepressor complex to the estrogenreceptor alpha gene promoterrdquo Breast Cancer Research andTreatment vol 134 no 2 pp 569ndash581 2012

[56] L C Li C C Yeh D Nojima and R Dahiya ldquoCloning andcharacterization of human estrogen receptor beta promoterrdquoBiochemical and Biophysical Research Communications vol 275no 2 pp 682ndash689 2000

[57] E A Vladusic A E Hornby F K Guerra-Vladusic J Lakinsand R Lupu ldquoExpression and regulation of estrogen receptor szligin human breast tumors and cell linesrdquoOncology Reports vol 7no 1 pp 157ndash167 2000

[58] T Hatsumi and Y Yamamuro ldquoDownregulation of estrogenreceptor gene expression by exogenous 17120573-estradiol in themammary glands of lactating micerdquo Experimental Biology andMedicine vol 231 no 3 pp 311ndash316 2006

[59] H B Patisaul P L Whitten and L J Young ldquoRegulation ofestrogen receptor beta mRNA in the brain opposite effectsof 17120573-estradiol and the phytoestrogen coumestrolrdquoMolecularBrain Research vol 67 no 1 pp 165ndash171 1999

[60] T J Brown N J MacLusky M Shanabrough and F NaftolinldquoComparison of age- and sex-related changes in cell nuclearestrogen-binding capacity and progestin receptor induction inthe rat brainrdquo Endocrinology vol 126 no 6 pp 2965ndash29721990

[61] B S Rubin T O Fox and R S Bridges ldquoEstrogen bindingin nuclear and cytosolic extracts from brain and pituitary ofmiddle-aged female ratsrdquo Brain Research vol 383 no 1-2 pp60ndash67 1986

[62] T Funabashi S P Kleopoulos P J Brooks et al ldquoChangesin estrogenic regulation of estrogen receptor 120572 mRNA andprogesterone receptor mRNA in the female rat hypothalamusduring aging an in situ hybridization studyrdquo NeuroscienceResearch vol 38 no 1 pp 85ndash92 2000

[63] M E Wilson K L Rosewell M L Kashon P J Shughrue IMerchenthaler and P M Wise ldquoAge differentially influencesestrogen receptor-120572 (ER120572) and estrogen receptor-120573 (ER120573) geneexpression in specific regions of the rat brainrdquo Mechanisms ofAgeing and Development vol 123 no 6 pp 593ndash601 2002

[64] W S Post P J Goldschmidt-Clermont C C Wilhide etal ldquoMethylation of the estrogen receptor gene is associatedwith aging and atherosclerosis in the cardiovascular systemrdquoCardiovascular Research vol 43 no 4 pp 985ndash991 1999

[65] J-P J Issa Y L Ottaviano P Celano S R Hamilton NE Davidson and S B Baylin ldquoMethylation of the oestrogenreceptor CpG island links ageing and neoplasia in humancolonrdquo Nature Genetics vol 7 no 4 pp 536ndash540 1994

[66] T Funabashi and F Kimura ldquoEffects of estrogen and estrogenreceptor messenger RNA levels in young and middle-agedfemale rats comparison ofmedial preoptic area andmediobasalhypothalamusrdquo Acta Biologica Hungarica vol 45 no 2ndash4 pp223ndash231 1994

[67] M AMiller P E Kolb B Planas andM A Raskind ldquoEstrogenreceptor and neurotensinneuromedin-N gene expression inthe preoptic area are unaltered with age in Fischer 344 femaleratsrdquo Endocrinology vol 135 no 5 pp 1986ndash1995 1994

[68] T R Chakraborty P R Hof L Ng and A C Gore ldquoStereologicanalysis of estrogen receptor alpha (ER alpha) expression in rat

hypothalamus and its regulation by aging and estrogenrdquo Journalof Comparative Neurology vol 466 no 3 pp 409ndash421 2003

[69] J M Westberry A L Trout and M E Wilson ldquoEpigeneticregulation of estrogen receptor beta expression in the rat cortexduring agingrdquo NeuroReport vol 22 no 9 pp 428ndash432 2011

[70] T R Chakraborty L Ng and A C Gore ldquoAge-related changesin estrogen receptor 120573 in rat hypothalamus a quantitativeanalysisrdquo Endocrinology vol 144 no 9 pp 4164ndash4171 2003

[71] I Poola S Koduri S Chatra and R Clarke ldquoIdentificationof twenty alternatively spliced estrogen receptor alpha mRNAsin breast cancer cell lines and tumors using splice targetedprimer approachrdquo Journal of Steroid Biochemistry andMolecularBiology vol 72 no 5 pp 249ndash258 2000

[72] T A Ishunina and D F Swaab ldquoHippocampal estrogenreceptor-alpha splice variant TADDI in the human brain inaging and Alzheimerrsquos diseaserdquoNeuroendocrinology vol 89 no2 pp 187ndash199 2009

[73] T A Ishunina and D F Swaab ldquoEstrogen receptor-120572 splicevariants in the human brainrdquo Gynecological Endocrinology vol24 no 2 pp 93ndash98 2008

[74] T A Ishunina F P M Kruijver R Balesar and D FSwaab ldquoDifferential expression of estrogen receptor 120572 and 120573immunoreactivity in the human supraoptic nucleus in rela-tion to sex and agingrdquo Journal of Clinical Endocrinology andMetabolism vol 85 no 9 pp 3283ndash3291 2000

[75] T A Ishunina D F Fischer andD F Swaab ldquoEstrogen receptor120572 and its splice variants in the hippocampus in aging andAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 28 no 11 pp1670ndash1681 2007

[76] J R Tollervey Z Wang T Hortobagyi et al ldquoAnalysis of alter-native splicing associated with aging and neurodegeneration inthe human brainrdquo Genome Research vol 21 no 10 pp 1572ndash1582 2011

[77] N NMott and T R Pak ldquoCharacterisation of human oestrogenreceptor beta (ER120573) splice variants in neuronal cellsrdquo Journal ofNeuroendocrinology vol 24 no 10 pp 1311ndash1321 2012

[78] S Inoue S-J Hoshino H Miyoshi et al ldquoIdentification ofa ovel isoform of estrogen receptor a potential inhibitor ofestrogen action in vascular smooth muscle cellsrdquo Biochemicaland Biophysical Research Communications vol 219 no 3 pp766ndash772 1996

[79] J K Skipper L J Young J M Bergeron M T Tetzlaff CT Osborn and D Crews ldquoIdentification of an isoform ofthe estrogen receptor messenger RNA lacking exon four andpresent in the brainrdquo Proceedings of the National Academy ofSciences of the United States of America vol 90 no 15 pp 7172ndash7175 1993

[80] R H Price Jr N Lorenzon and R J Handa ldquoDifferentialexpression of estrogen receptor beta splice variants in rat brainidentification and characterization of a novel variant missingexon 4rdquo Brain Research Molecular Brain Research vol 80 no2 pp 260ndash268 2000

[81] S Chu and P J Fuller ldquoIdentification of a splice variantof the rat estrogen receptor 120573 generdquo Molecular and CellularEndocrinology vol 132 no 1-2 pp 195ndash199 1997

[82] B Lu E Leygue H Dotzlaw L J Murphy L C Murphy andP H Watson ldquoEstrogen receptor-120573 mRNA variants in humanand murine tissuesrdquoMolecular and Cellular Endocrinology vol138 no 1-2 pp 199ndash203 1998

[83] T R Pak W C J Chung J L Roberts and R J HandaldquoLigand-independent effects of estrogen receptor 120573 on

ISRN Endocrinology 13

mouse gonadotropin-releasing hormone promoter activityrdquoEndocrinology vol 147 no 4 pp 1924ndash1931 2006

[84] T R Pak W C J Chung L R Hinds and R J HandaldquoEstrogen receptor-120573 mediates dihydrotestosterone-inducedstimulation of the arginine vasopressin promoter in neuronalcellsrdquo Endocrinology vol 148 no 7 pp 3371ndash3382 2007

[85] Y K Leung PMak S Hassan and SMHo ldquoEstrogen receptor(ER)-120573 isoforms a key to understanding ER-120573 signalingrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 103 no 35 pp 13162ndash13167 2006

[86] J M Wang X Hou S Adeosun et al ldquoA dominant negativeER120573 splice variant determines the effectiveness of early or lateestrogen therapy after ovariectomy in ratsrdquo PLoS One vol 7 no3 Article ID e33493 2012

[87] W C J Chung T R Pak S Suzuki W A Pouliot M EAndersen and R J Handa ldquoDetection and localization of anestrogen receptor beta splice variant protein (ER1205732) in theadult female rat forebrain and midbrain regionsrdquo Journal ofComparative Neurology vol 505 no 3 pp 249ndash267 2007

[88] R H Price Jr C A Butler P Webb R Uht P Kushner andR J Handa ldquoA splice variant of estrogen receptor 120573 missingexon 3 displays altered subnuclear localization and capacity fortranscriptional activationrdquo Endocrinology vol 142 no 5 pp2039ndash2049 2001

[89] Y Wang and R J Miksicek ldquoIdentification of a dominantnegative form of the human estrogen receptorrdquo MolecularEndocrinology vol 5 no 11 pp 1707ndash1715 1991

[90] E Kuppers and C Beyer ldquoExpression of estrogen receptor-120572and 120573 mRNA in the developing and adult mouse striatumrdquoNeuroscience Letters vol 276 no 2 pp 95ndash98 1999

[91] C Gundlah S G Kohama S J Mirkes V T Garyfallou H FUrbanski and C L Bethea ldquoDistribution of estrogen receptorbeta (ER120573) mRNA in hypothalamus midbrain and temporallobe of spayed macaque continued expression with hormonereplacementrdquo Brain Research Molecular Brain Research vol 76no 2 pp 191ndash204 2000

[92] Y Morishima P J M Murphy D-P Li E R Sanchez and WB Pratt ldquoStepwise assembly of a glucocorticoid receptorsdothsp90heterocomplex resolves two sequential ATP-dependent eventsinvolving first hsp70 and then hsp90 in opening of the steroidbinding pocketrdquo Journal of Biological Chemistry vol 275 no 24pp 18054ndash18060 2000

[93] K D Dittmar and W B Pratt ldquoFolding of the glucocorticoidreceptor by the reconstituted hsp90-based chaperone machin-eryThe initial hsp90sdotp60sdothsp70-dependent step is sufficient forcreating the steroid binding conformationrdquo Journal of BiologicalChemistry vol 272 no 20 pp 13047ndash13054 1997

[94] K I Kang X Meng J Devin-Leclerc et al ldquoThe molecularchaperone Hsp90 can negatively regulate the activity of aglucocorticosteroid-dependent promoterrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 4 pp 1439ndash1444 1999

[95] K Unno H Asakura Y Shibuya M Kaiho S Okada and NOku Naoto ldquoIncrease in basal level of Hsp70 consisting chieflyof constitutively expressed hsp70 (Hsc70) in aged rat brainrdquoJournals of Gerontology Series A vol 55 no 7 pp B329ndashB3352000

[96] U E Olazabal D W Pfaff and C V Mobbs ldquoSex differences inthe regulation of heat shock protein 70 kDa and 90 kDa in therat ventromedial hypothalamus by estrogenrdquo Brain Researchvol 596 no 1-2 pp 311ndash314 1992

[97] M A Pahlavani M D Harris S A Moore and A RichardsonldquoExpression of heat shock protein 70 in rat spleen lymphocytesis affected by age but not by food restrictionrdquo Journal ofNutrition vol 126 no 9 pp 2069ndash2075 1996

[98] A R Heydari B Wu R Takahashi R Strong and A Richard-son ldquoExpression of heat shock protein 70 is altered by age anddiet at the level of transcriptionrdquoMolecular andCellular Biologyvol 13 no 5 pp 2909ndash2918 1993

[99] M Sabbah K-I I Kang L Tora and G Redeuilh ldquoOestro-gen receptor facilitates the formation of preinitiation com-plex assembly involvement of the general transcription factorTFIIBrdquo Biochemical Journal vol 336 part 3 pp 639ndash646 1998

[100] S-Y Wu M C Thomas S Y Hou V Likhite and C-MChiang ldquoIsolation of mouse TFIID and functional character-ization of TBP and TFIID in mediating estrogen receptor andchromatin transcriptionrdquo Journal of Biological Chemistry vol274 no 33 pp 23480ndash23490 1999

[101] S Ghosh and M K Thakur ldquoTissue-specific expression ofreceptor-interacting protein in aging mouserdquo Age vol 30 no4 pp 237ndash243 2008

[102] J Frasor JM Danes B Komm K C N Chang C Richard Lyt-tle and B S Katzenellenbogen ldquoProfiling of estrogen up- anddown-regulated gene expression in human breast cancer cellsinsights into gene networks and pathways underlying estrogeniccontrol of proliferation and cell phenotyperdquo Endocrinology vol144 no 10 pp 4562ndash4574 2003

[103] J Frasor J M Danes C C Funk and B S Katzenellen-bogen ldquoEstrogen down-regulation of the corepressor N-CoRmechanism and implications for estrogen derepression of N-CoR-regulated genesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 102 no 37 pp13153ndash13157 2005

[104] N J McKenna and B W OrsquoMalley ldquoCombinatorial control ofgene expression by nuclear receptors and coregulatorsrdquoCell vol108 no 4 pp 465ndash474 2002

[105] T-P Yao G Ku N Zhou R Scully and D M Livingston ldquoThenuclear hormone receptor coactivator SRC-1 is a specific targetof p300rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 93 no 20 pp 10626ndash10631 1996

[106] B Hanstein R Eckner J DiRenzo et al ldquop300 is a componentof an estrogen receptor coactivator complexrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 93 no 21 pp 11540ndash11545 1996

[107] S Halachmi E Marden G Martin H MacKay C Abbon-danza and M Brown ldquoEstrogen receptor-associated proteinspossible mediators of hormone-induced transcriptionsrdquo Sci-ence vol 264 no 5164 pp 1455ndash1458 1994

[108] A J Horlein AM Naar T Heinzel et al ldquoLigand-independentrepression by the thyroid hormone receptor mediated by anuclear receptor co-repressorrdquo Nature vol 377 no 6548 pp397ndash404 1995

[109] J D Chen and R M Evans ldquoA transcriptional co-repressor thatinteracts with nuclear hormone receptorsrdquo Nature vol 377 no6548 pp 454ndash457 1995

[110] A Malovannaya R B Lanz S Y Jung et al ldquoAnalysis of thehuman endogenous coregulator complexomerdquoCell vol 145 no5 pp 787ndash799 2011

[111] Z Nawaz D M Lonard C L Smith et al ldquoThe Angelmansyndrome-associated protein E6-AP is a coactivator for thenuclear hormone receptor superfamilyrdquoMolecular and CellularBiology vol 19 no 2 pp 1182ndash1189 1999

14 ISRN Endocrinology

[112] B Zheng M Han M Bernier and J-K Wen ldquoNuclear actinand actin-binding proteins in the regulation of transcriptionand gene expressionrdquo FEBS Journal vol 276 no 10 pp 2669ndash2685 2009

[113] W A Hofmann L Stojiljkovic B Fuchsova et al ldquoActin is partof pre-initiation complexes and is necessary for transcription byRNA polymerase IIrdquoNature Cell Biology vol 6 no 11 pp 1094ndash1101 2004

[114] K Tokunaga T Shibuya Y Ishihama et al ldquoNucleocytoplasmictransport of fluorescent mRNA in living mammalian cellsnuclear mRNA export is coupled to ongoing gene transcrip-tionrdquo Genes to Cells vol 11 no 3 pp 305ndash317 2006

[115] R Metivier G Penot M R Hubner et al ldquoEstrogen receptor-120572 directs ordered cyclical and combinatorial recruitment ofcofactors on a natural target promoterrdquo Cell vol 115 no 6 pp751ndash763 2003

[116] C Ambrosino R Tarallo A Bamundo et al ldquoIdentification of ahormone-regulated dynamic nuclear actin network associatedwith estrogen receptor 120572 in human breast cancer cell nucleirdquoMolecular and Cellular Proteomics vol 9 no 6 pp 1352ndash13672010

[117] F Shao R Zhang L Dong and K Ying ldquoOverexpression ofgelsolin-like actin-capping protein is associated with progres-sion of lung adenocarcinomardquo Tohoku Journal of ExperimentalMedicine vol 225 no 2 pp 95ndash101 2011

[118] K Nishimura H-J Ting Y Harada et al ldquoModulation ofandrogen receptor transactivation by gelsolin a newly identi-fied androgen receptor coregulatorrdquo Cancer Research vol 63no 16 pp 4888ndash4894 2003

[119] J S Ahn I S Jang D I Kim et al ldquoAging-associated increaseof gelsolin for apoptosis resistancerdquoBiochemical and BiophysicalResearch Communications vol 312 no 4 pp 1335ndash1341 2003

[120] I Nalvarte T Schwend and J-A Gustafsson ldquoProteomicsanalysis of the estrogen receptor 120572 receptosomerdquoMolecular andCellular Proteomics vol 9 no 7 pp 1411ndash1422 2010

[121] L-H Miau C-J Chang B-J Shen W-H Tsai and S-C LeeldquoIdentification of heterogeneous nuclear ribonucleoprotein K(hnRNPK) as a repressor ofCEBP120573-mediated gene activationrdquoJournal of Biological Chemistry vol 273 no 17 pp 10784ndash107911998

[122] A Ostareck-Lederer D H Ostareck C Cans et al ldquoc-Src-mediated phosphorylation of hnRNP K drives translationalactivation of specifically silenced mRNAsrdquo Molecular and Cel-lular Biology vol 22 no 13 pp 4535ndash4543 2002

[123] P S Bagga G K Arhin and J Wilusz ldquoDSEF-1 is a member ofthe hnRNP H family of RNA-binding proteins and stimulatespre-mRNAcleavage and polyadenylation in vitrordquoNucleic AcidsResearch vol 26 no 23 pp 5343ndash5350 1998

[124] V Markovtsov J M Nikolic J A Goldman C W Turck M-Y Chou and D L Black ldquoCooperative assembly of an hnRNPcomplex induced by a tissue-specific homolog of polypyrimi-dine tract binding proteinrdquoMolecular and Cellular Biology vol20 no 20 pp 7463ndash7479 2000

[125] S Y Jung A Malovannaya J Wei B W OrsquoMalley and J QinldquoProteomic analysis of steady-state nuclear hormone receptorcoactivator complexesrdquoMolecular Endocrinology vol 19 no 10pp 2451ndash2465 2005

[126] W Hong R J Resnick C Rakowski D Shalloway S J Taylorand G A Blobel ldquoPhysical and functional interaction betweenthe transcriptional cofactor CBP and the KH domain proteinSam68rdquoMolecular Cancer Research vol 1 no 1 pp 48ndash55 2002

[127] R ShaoXWang BWeijdegard et al ldquoCoordinate regulation ofheterogeneous nuclear ribonucleoprotein dynamics by steroidhormones in the human fallopian tube and endometrium invivo and in vitrordquo American Journal of Physiology vol 302 no10 pp E1269ndashE1282 2012

[128] C SWoolley and B SMcEwen ldquoEstradiolmediates fluctuationin hippocampal synapse density during the estrous cycle in theadult ratrdquo Journal of Neuroscience vol 12 no 7 pp 2549ndash25541992

[129] C S Woolley H J Wenzel and P A Schwartzkroin ldquoEstradiolincreases the frequency of multiple synapse boutons in thehippocampal CA1 region of the adult female ratrdquo The Journalof Comparative Neurology vol 373 no 1 pp 108ndash117 1996

[130] C S Woolley ldquoEstrogen-mediated structural and functionalsynaptic plasticity in the female rat hippocampusrdquo Hormonesand Behavior vol 34 no 2 pp 140ndash148 1998

[131] D P Srivastava K M Woolfrey K A Jones et al ldquoRapidenhancement of two-step wiring plasticity by estrogen andNMDA receptor activityrdquo Proceedings of the National Academyof Sciences of the United States of America vol 105 no 38 pp14650ndash14655 2008

[132] M Ogiue-Ikeda N Tanabe H Mukai et al ldquoRapid modu-lation of synaptic plasticity by estrogens as well as endocrinedisrupters in hippocampal neuronsrdquo Brain Research Reviewsvol 57 no 2 pp 363ndash375 2008

[133] N J Sandstrom and C L Williams ldquoSpatial memory retentionis enhanced by acute and continuous estradiol replacementrdquoHormones and Behavior vol 45 no 2 pp 128ndash135 2004

[134] E Hogervorst J Williams M Budge W Riedel and JJolles ldquoThe nature of the effect of female gonadal hormonereplacement therapy on cognitive function in post-menopausalwomen a meta-analysisrdquo Neuroscience vol 101 no 3 pp 485ndash512 2000

[135] M E Bailey A C J Wang J Hao et al ldquoInteractive effects ofage and estrogen on cortical neurons implications for cognitiveagingrdquo Neuroscience vol 191 pp 148ndash158 2011

[136] A A Walf M E Rhodes and C A Frye ldquoOvarian steroidsenhance object recognition in naturally cycling and ovariec-tomized hormone-primed ratsrdquo Neurobiology of Learning andMemory vol 86 no 1 pp 35ndash46 2006

[137] V N Luine L F Jacome and N J Maclusky ldquoRapid enhance-ment of visual and place memory by estrogens in ratsrdquoEndocrinology vol 144 no 7 pp 2836ndash2844 2003

[138] L Fan Z Zhao P T Orr C H Chambers M C Lewis and KM Frick ldquoEstradiol-induced object memory consolidation inmiddle-aged femalemice requires dorsal hippocampal extracel-lular signal-regulated kinase and phosphatidylinositol 3-kinaseactivationrdquo Journal of Neuroscience vol 30 no 12 pp 4390ndash4400 2010

[139] D B Dubal and PMWise ldquoNeuroprotective effects of estradiolin middle-aged female ratsrdquo Endocrinology vol 142 no 1 pp43ndash48 2001

[140] S-H Yang J Shi A L Day and J W Simpkins ldquoEstradiolexerts neuroprotective effects when administered after ischemicinsultrdquo Stroke vol 31 no 3 pp 745ndash750 2000

[141] J W Simpkins G Rajakumar Y-Q Zhang et al ldquoEstrogensmay reduce mortality and ischemic damage caused by middlecerebral artery occlusion in the female ratrdquo Journal of Neuro-surgery vol 87 no 5 pp 724ndash730 1997

[142] J Shi K S Panickar S-H Yang O Rabbani A L Day and JWSimpkins ldquoEstrogen attenuates over-expression of 120573-amyloid

ISRN Endocrinology 15

precursor protein messager RNA in an animal model of focalischemiardquo Brain Research vol 810 no 1-2 pp 87ndash92 1998

[143] Q-H Zhang Y-H Huang Y-Z Hu et al ldquoDisruption ofestrogen receptor beta in mice brain results in pathologicalalterations resemblingAlzheimer diseaserdquoActa PharmacologicaSinica vol 25 no 4 pp 452ndash457 2004

[144] E F Rissman A L Heck J E Leonard M A Shupnik and J-A Gustafsson ldquoDisruption of estrogen receptor 120573 gene impairsspatial learning in female micerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no6 pp 3996ndash4001 2002

[145] M Day A Sung S Logue M Bowlby and R Arias ldquoBetaestrogen receptor knockout (BERKO) mice present attenuatedhippocampal CA1 long-term potentiation and related memorydeficits in contextual fear conditioningrdquo Behavioural BrainResearch vol 164 no 1 pp 128ndash131 2005

[146] R Vierk G Glassmeier L Zhou et al ldquoAromatase inhibitionabolishes LTP generation in female but not in male micerdquo TheJournal of Neuroscience vol 32 no 24 pp 8116ndash8126 2012

[147] R-M Vouimba M R Foy J G Foy and R FThompson ldquo17120573-estradiol suppresses expression of long-term depression in agedratsrdquo Brain Research Bulletin vol 53 no 6 pp 783ndash787 2000

[148] C E Andreescu B A Milojkovic E D Haasdijk et alldquoEstradiol improves cerebellar memory formation by activatingestrogen receptor 120573rdquo Journal of Neuroscience vol 27 no 40 pp10832ndash10839 2007

[149] Y-Y Huang P V Nguyen T Abel and E R Kandel ldquoLong-lasting forms of synaptic potentiation in the mammalian hip-pocampusrdquo Learning Memory vol 3 no 2-3 pp 74ndash85 1996

[150] H Mukai T Tsurugizawa G Murakami et al ldquoRapid mod-ulation of long-term depression and spinogenesis via synapticestrogen receptors in hippocampal principal neuronsrdquo Journalof Neurochemistry vol 100 no 4 pp 950ndash967 2007

[151] L Liu T P Wong M F Pozza et al ldquoRole of NMDA receptorsubtypes in governing the direction of hippocampal synapticplasticityrdquo Science vol 304 no 5673 pp 1021ndash1024 2004

[152] M Cyr O Ghribi C Thibault M Morissette M Landry andT di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[153] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[154] C C Smith and L L McMahon ldquoEstradiol-induced increasein the magnitude of long-term potentiation is prevented byblocking NR2B-containing receptorsrdquo Journal of Neurosciencevol 26 no 33 pp 8517ndash8522 2006

[155] Y Zhou J J Watters and D M Dorsa ldquoEstrogen rapidlyinduces the phosphorylation of the cAMP response elementbinding protein in rat brainrdquo Endocrinology vol 137 no 5 pp2163ndash2166 1996

[156] XGonda T TelekG Juhasz J Lazary AVargha andG BagdyldquoPatterns of mood changes throughout the reproductive cyclein healthy women without premenstrual dysphoric disordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 32 no 8 pp 1782ndash1788 2008

[157] E W Freeman ldquoPremenstrual syndrome and premenstrualdysphoric disorder definitions and diagnosisrdquo Psychoneuroen-docrinology vol 28 supplement 3 pp 25ndash37 2003

[158] T D Lund T Rovis W C J Chung and R J Handa ldquoNovelactions of estrogen receptor-120573 on anxiety-related behaviorsrdquoEndocrinology vol 146 no 2 pp 797ndash807 2005

[159] N Breslau L Schultz and E Peterson ldquoSex differences indepression a role for preexisting anxietyrdquo Psychiatry Researchvol 58 no 1 pp 1ndash12 1995

[160] P E Bebbington G Dunn R Jenkins et al ldquoThe influenceof age and sex on the prevalence of depressive conditionsreport from the National Survey of Psychiatric MorbidityrdquoPsychological Medicine vol 28 no 1 pp 9ndash19 1998

[161] G Aguilera J P Harwood and J X Wilson ldquoMechanisms ofaction of corticotropin-releasing factor and other regulators ofcorticotropin release in rat pituitary cellsrdquo Journal of BiologicalChemistry vol 258 no 13 pp 8039ndash8045 1983

[162] A Papadimitriou and K N Priftis ldquoRegulation of thehypothalamic-pituitary-adrenal axisrdquo NeuroImmunoModula-tion vol 16 no 5 pp 265ndash271 2009

[163] S Suzuki and R J Handa ldquoRegulation of estrogen receptor-120573expression in the female rat hypothalamus differential effectsof dexamethasone and estradiolrdquo Endocrinology vol 145 no 8pp 3658ndash3670 2004

[164] W J S Miller S Suzuki L K Miller R Handa and R M UhtldquoEstrogen receptor (ER)120573 isoforms rather than ER120572 regulatecorticotropin-releasing hormone promoter activity through analternate pathwayrdquo Journal of Neuroscience vol 24 no 47 pp10628ndash10635 2004

[165] C IsgorM CecchiM Kabbaj H Akil and S JWatson ldquoEstro-gen receptor 120573 in the paraventricular nucleus of hypothalamusregulates the neuroendocrine response to stress and is regulatedby corticosteronerdquo Neuroscience vol 121 no 4 pp 837ndash8452003

[166] M L Forsling I Kallo D E Hartley et al ldquoOestrogen receptor-120573 and neurohypophysial hormones functional interaction andneuroanatomical localisationrdquo Pharmacology Biochemistry andBehavior vol 76 no 3-4 pp 535ndash542 2003

[167] A S Lalmansingh and R M Uht ldquoEstradiol regulatescorticotropin-releasing hormone gene (crh) expression in arapid and phasic manner that parallels estrogen receptor-120572 and-120573 recruitment to a 3101584051015840-cyclic adenosine 51015840- monophosphateregulatory region of the proximal crh promoterrdquo Endocrinologyvol 149 no 1 pp 346ndash357 2008

[168] B N Roy R L Reid and D A van Vugt ldquoThe effects ofestrogen and progesterone on corticotropin-releasing hormoneand arginine vasopressin messenger ribonucleic acid levelsin the paraventricular nucleus and supraoptic nucleus of therhesus monkeyrdquo Endocrinology vol 140 no 5 pp 2191ndash21981999

[169] X Ni R C Nicholson B R King E-C Chan M A Read andR Smith ldquoEstrogen represses whereas the estrogen-antagonistICI 182780 stimulates placental CRH gene expressionrdquo Journalof Clinical Endocrinology and Metabolism vol 87 no 8 pp3774ndash3778 2002

[170] N C Vamvakopoulos and G P Chrousos ldquoEvidence of directestrogenic regulation of human corticotropin-releasing hor-mone gene expression Potential implications for the sexualdimophism of the stress response and immuneinflammatoryreactionrdquo Journal of Clinical Investigation vol 92 no 4 pp1896ndash1902 1993

[171] Y Hu D L Wu C X Luo et al ldquoHippocampal nitric oxidecontributes to sex difference in affective behaviorsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 35 pp 14224ndash14229 2012

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

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Behavioural Neurology

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Disease Markers

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Oxidative Medicine and Cellular Longevity

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

4 ISRN Endocrinology

Perimenopause(40s50s)

Postmenopause(50s+)

Peripuberty(preteens)

E2

Cyclicity

ΔER expression withhormone cyclicity ΔER expression with age

and E2 declineuarr ER splice variants

Figure 2 Timeline showing factors affecting ER gene expressionthroughout the female life-span Brain ER gene expression patternsare altered with age sex and exposure to circulating hormoneCirculating hormones fluctuate with age most dramatically at thetime of puberty andmenopause therefore contributing to changes inER gene expression Additionally alternative splicing increases withage thus potentially diversifying the ER gene expression profile

variants are a critical first step in creating a comprehensiveexamination of E

2-regulated processes in any system

The female vertebrate reproductive organs tend to bedominated by the expression of ER120572 whereas ER120573 isexpressed largely in nonreproductive tissues ER120573 was firstcloned from prostate tissue [42] and it has since been shownto have the highest levels of expression in the central nervoussystem and cardiovascular tissue as well as lung kidneycolorectal tissue mammary tissue and the immune system[43] Consequently some of the most prominent phenotypicproblems observed in mice lacking a functional ESR2 gene(120573ERKO mice) are neurological deficits By contrast ER120572knockout mice have no gross brain-related phenotypes butthey exhibit decreased E

2-mediated neuroprotection follow-

ing an ischemic event [44] Overall the phenotypes observedin ER120572- and ER120573-null mouse models suggest that ER120573 ispotentially more important for mediating nonreproductiveE2-governed processes than ER120572ER120572 and ER120573 are coexpressed in some regions of the

hypothalamus such as the medial amygdala (MeA) the bednucleus of the stria terminalis (BNST) and the periaqueduc-tal grey area However ER120572 is predominant in hypothala-mic nuclei that control reproduction sexual behavior andappetite (eg arcuate (ARC) medial preoptic (MPoA) andventromedial (VM)) but ER120573 is the predominant isoform inthe nonreproductive associated nuclei (eg paraventricular(PVN) supraoptic (SON) and suprachiasmatic (SCN)) aswell as the hippocampus dorsal raphe nuclei cortex andcerebellum [45 46] In the hippocampus mRNA and proteinfor both ERs have been detected and are well established asmediating both genomic and nongenomic processes [47ndash49]Nuclear and extranuclear ER120573mRNA and immunoreactivity(IR) have been detected in principal cells as well as inmany other nuclei of cells within the ventral CA23 [4647] Although not as prevalent as ER120573 ER120572 has also beendetected in the hippocampus primarily within GABAergicinterneurons [47 49]

ER expression is also often found to be sexually dimor-phic As onewould expectmany regions of the hypothalamusexhibit a great deal of sexual dimorphism due in part to dif-ferences in sexual behavior and regulation of gonadotrophic

hormones but regions such as the BNST also display somesex-related differences in ER expression For example ER120572 inthe BNST can be induced in somatostatin-positive neurons ofmale but not female rats [50] ERs have also been shown tobe sexually dimorphic in the developing rodent hippocam-pus but not in adults [51 52] However one report identifiedER120573mRNA in the adult female but notmale rhesusmacaquebasal ganglia and hippocampus [53] Importantly a lacksexually dimorphic regional ER expression does not precludedifferential responses to estrogens as other effectormoleculescan alter estrogen-responsive processes

Expression of ERs can vary not only with chromosomalsex but also in response to the hormonalmilieu For instanceit is well accepted that ER120572 expression is autoregulated byE2 primarily through proteasomal degradation [54] but also

perhaps on a transcriptional level by E2-bound ER120573 [55]The

ER120573 gene (ESR2) promoter region has not been extensivelycharacterized but it has been shown to contain E

2-responsive

cis sequence-binding sites for Oct-1 and Sp-1 which interactwith ERs via trans factors suggesting a molecular mechanismfor E2-mediated autoregulation of its receptor There is also

an Alu repeat sequence that may contain an ERE that couldact as an ER-dependent enhancer [56] Conversely in vitroand in vivo studies investigating the effects of E

2on ER120573

expression have yielded inconsistent conclusions dependingupon cell type animal species and age For instance in theT47D human breast cancer cell line E

2upregulated ER120573 [57]

However ER120573 expression was decreased by E2in mammary

glands of lactating mice that coexpress ER120572 [58] ER120573 wasalso decreased in the PVN of rats subjected to OVX+ E

2[59]

Thus it appears that E2may regulate ER120572 and ER120573 however

this effect is highly dependent upon cell type and possiblyupon the coexpression of other ERs

In addition to sex and E2 aging also appears to influence

ER expression Overall decreased nuclear E2binding has

been reported in the hypothalamus and anterior pituitary ofaged female rats compared to young ones but the changein E2binding was not necessarily attributed to a decrease

in total ER expression [60 61] suggesting a shift in theratio of ERs andor subcellular localization While overallnuclear E

2binding within the hypothalamus may decrease

with age changes to ER expression patterns with age remaincontentious In general it appears that age alone does noteliminate ER120572 expression in the brain but regional specificityand E

2availability may be important factors [62 63] and an

increase in ESR promoter methylation has been correlatedwith age in other systems [64 65] One study reported variedmiddle age-specific reduction in hypothalamic ER with E

2

treatment [66] yet another study showed that E2decreased

hypothalamic ER expression significantly in all ages tested(3 11 and 20 months) [67] Specific to ER120572 a work byChakraborty and colleagues determined that immunoreac-tive cell numbers did not always change following OVXand E

2replacement Rather their study revealed that with

advanced age (24ndash26 months compared to 3-4 and 10ndash12months) the number of ER120572-positive cells was increased or itstayed the same in different hypothalamic nuclei [68] In thehippocampus ER120572 was decreased after long-term estrogendeprivation (LTED 10 weeks) regardless of E

2replacement

ISRN Endocrinology 5

following LTED but E2deprivation had no effect on ER120573

[11] The same report demonstrated decreased levels of ER120573in very old rats (24-month females compared to 3-monthdiestrus females) In general most reports suggest that agingdecreases ER120573 expression but like ER120572 this effect may behighly region specific An age-related decrease in ER120573 expres-sion in the brain is underscored by a corresponding increaseinCpGmethylation of the ESR2 promoter inmiddle-aged (9ndash12months) rats [69] Other reports describe decreases in ER120573protein and message in some areas but not in others [63 70]Taken together there are a number of reports attemptingto identify the parameters that control ER expression suchas age sex and response to E

2 however with such vast

deviations in expression with cell type there is still much tobe learned about expression of these receptors especially inbrain regions controlling nonreproductive behaviors

6 Alternative Splice Variants

Based upon the highly variable reports that differ in sexand age of animals as well as exposure to hormone it maybe possible that these studies are unknowingly detectingchanges in splice variant expression which could change E

2

responsiveness as well as downstream gene regulation Notonly can ERs heterodimerize to regulate gene transcriptionbut there are a number of alternatively spliced variants of eachreceptor that are endogenously expressed and that potentiallycontribute to the diverse tissue-specific actions of E

2 Alter-

native splicing of ERs alters inherent signaling properties ofthe receptor including ligand and DNA-binding affinitiesnuclear localization and dimerization depending on wherethe alternative splice site is encoded A number of ER splicevariant transcripts and other proteins have been identifiedin demented human brains breast and prostate and insome reports an increase in alternative splicing is correlatedwith pathology [71ndash75] Also interesting age alone mayincrease alternative splicing of some gene products [76] Theidentified ER120573 human splice variants are truncated at the C-terminus of the receptor (Figure 1(a)) however we providedexperimental evidence that the C-terminus of the receptoris not required for ER120573-mediated transcription especiallywith regard to the identified human splice variants [77]Unlike the human splice variants rodent ER120573 splice variantsidentified to date have been shown to have either an exoninclusion in the ligand-binding domain creating (rER1205732)or an exon deletion in the DNA-binding domain rER1205731Δ3or rER1205731Δ4 or both rER1205732Δ3 and rER1205732Δ4 (Figure 1(b))[37 78 79] Exon inclusion (rER1205732 variants) has been shownto produce a protein that binds E

2with a 35-fold decrease

in affinity In contrast ERs with exon 3 and 4 deletions areunable to bind DNA but they can still mediate transcriptionthrough proteinprotein interactions with other transcriptionfactors such as AP-1 and it can bind E

2as well as rER1205731

[37 80] Importantly the transcriptional functions of rER1205731are significantly altered when coexpressed with other splicevariants likely due to a weaker interaction with coactivatorproteins [81 82] Despite lower E

2binding andor lack of

DNA binding the rodent and human splice variants retain a

constitutive ligand-independent transcriptional function atboth basic and complex promoters [77 83 84] suggestingthat these splice variants have an important endogenousbiological function Indeed unliganded ER1205731 or apo-ER1205731has been reported to regulate a subset of genes distinct fromthose regulated by ER1205731 when bound to E

2[41] Conversely

the human splice variants do not bind ligand with greataffinity [85] and they might therefore only regulate the classof genes that unliganded ER120573 targets

Thedownstream target genes of ER120573 splice variantsmightbe an important consideration at the time of menopauseas ER expression profiles and alternative splicing tend tochange with age [76] One recent report demonstrated anincrease in ER1205732 expression in the hippocampus of 9-month old middle-aged rats following short-term (6 days)E2deprivation that was significantly decreased compared to

the Sham group after E2administration [86] Importantly

E2replacement no longer affected ER1205732 expression in the

hippocampus after LTED (180 days)That study also reporteda decrease in hippocampal neurogenesis and increased float-ing behavior in a forced swim test thus functionally corre-lating increased ER1205732 with mood regulation and potentiallycognition Thus the expression and functions of ER120573 splicevariants are absolutely critical to understand the effects ofestrogen particularly at times of sustainedE

2deprivationwith

regard to cognition and affect While ER1205732 expression hasbeen assessed in the young male rat brain [87] and othervariants have been described in some brain regions [80 88]there is a general lack of data on most ER120573 splice variantsespecially in aged female brains

Some of the splice variants identified to date have beencharacterized as dominant negative receptors serving toinhibit activation of the full-length receptor [89] howevermost identified variants do not bind ligand with the sameaffinity and have the potential to differentially regulate targetgenes While several splice variants for ER120573 have been iden-tified in many model systems including mouse [90] rat [4546] and monkey [91] there is a general lack of comparativestudies on expression and functionality of human ER120573 vari-ants especially in neuronal systems Furthermore changingexpression levels of one or more alternatively spliced variantsduring a period of E

2deprivation may drastically change

general receptivity and downstream functions of E2

7 Novel ProteinProtein Interactions forE2-Mediated Nuclear Processes

Proteinprotein interactions are an essential relay in the reg-ulation of dynamic cellular processes Immediately followingtranslation ERs typically associate with a chaperone proteinto ensure proper folding protect from degradation and assistthe ER in becoming poised to accept ligand Once bound toligand ERs can dimerize and act as transcription factors tomediate gene regulation or associate withmembrane proteinsto initiate a signaling cascade When acting as transcriptionfactors ERs associate with a number of coregulatory proteinsthat assist in activating or repressing E

2-regulated genes

Coregulatory interactions are more characterized for ER120572

6 ISRN Endocrinology

than ER120573 and importantly less clear is how ER120573 mediatesligand-independent transcription In addition to the well-established ER interaction partners many novel interactingproteins have not yet been characterized and could be criticalfor nuclear processes not limited to gene transcription

8 HSPs and Chaperone Proteins

According to the classical two-step hypothesis inactivenuclear receptors are constantly accompanied and protectedfrom degradation by a number of chaperone proteins typi-cally members of the heat-shock protein (HSP) family Thisreceptorchaperone complex has been studied extensivelyand while the idea of a protective role for chaperones is wellsupported this complex can also perform other functionsFor instance HSPER complexes can serve to preactivatea hormone receptor by forcing a conformational changein ER such that it is able to bind its cognate hormoneThe initial HSP complex consists of the ER HSP70 andHSP70-interacting protein (HiP) as well as other accessoryand scaffolding proteins [92] HSP90 is recruited to thecomplex andHSP70 dissociates creating thematureHSPERcomplex [93] HSP90 induces a conformational change in thenuclear receptor and the ER is released from the complexready to dimerize and bind DNA or other transcriptionfactors to regulate gene transcription However some studiessuggest that HSPs could have a broader role than originallythought For example in Drosophila HSPs are required forDNA binding and in some instances they may regulateNR action [94] Interestingly aging and E

2can alter HSP70

in a cell-type specific manner [95ndash98] However recentdata from our lab (Table 1) demonstrated that HSP70 morereadily associates with ER120573 in aged female hippocampusfollowing E

2treatment compared to the young ones in which

HSP70ER120573 association decreased following E2treatment

We also observed no significant changes in HSP70 or ER120573expression suggesting that changes in the HSP70ER120573 inter-action with age in response to E

2change are a result of E

2

responsiveness andor activation of ER120573

9 Transcriptional Proteins and ERs

The process of transcribing DNA into RNA is a systematicprocess that involves multiprotein complexes binding toDNA modifying histone marks and initiating RNA synthe-sis ER120572 but not ER120573 has been shown to directly interactwith TFIIB IIE IIF and TIID proteins that initiate tran-scription [99 100] However experimental evidence from co-immunoprecipitation studies has demonstrated interactionsbetween ER120573 coregulatory proteins as well as other tran-scription factors Coregulatory proteins are transcriptionalaccessory proteins that enhance or repress transcription oftarget genes In general coactivators enhance gene tran-scription whereas corepressors block it However recentdata suggest that seemingly nontranscriptional proteins mayhave context-dependent coregulatory functions Importantly

certain coregulators can also be governed by age and E2[101ndash

103] thus recent discoveries imply that ER-mediated generegulation is not as well understood as previously thought

The best studied and well-established group of coregula-tory proteins that selectively associate with NRs is the steroidreceptor coactivator (SRCp160) family The SRC family iscomposed of three members SRC-1 SRC-2 and SRC-3all of which contain canonical LxxLL motifs known as thenuclear receptor (NR) box This motif interacts with AF-2 domains in ER120573 as well as other NR family memberssuch as glucocorticoid receptor (GR) progesterone receptor(PR) thyroid hormone receptor (TR) and ER120572 [104] SRCmembers have intrinsic histone acetyltransferase activity(HAT DNA activating) and interact with CREB-bindingprotein (CBP) [105] CBPp300 proteins are also coactivatorsthat have intrinsic HAT activity and can recruit ASC-2and other known coregulatory proteins [106] Confirmedcoregulatory interaction partners for several NRs that donot belong to the SRC family include estrogen-receptor-association protein (ERAP 140) [107] nuclear corepressor(NCoR) [108] silencing mediator of retinoic acid and thy-roid hormone receptor (SMRT) [109] and many othersAs is the case with our understanding of ER120573 interactionswith basic transcriptional machinery studies investigatingER120573coregulator interactions are sparse which may be dueto uniquely challenging issues associated with ER120573 such as alack of high-fidelity biochemical tools complicated structuralproperties and or pleiotropic physiological actions that arespecific to ER120573

In 2010 Anna Ma lovannaya and colleagues directeda high-throughput study (not including ER120573) aiming atcompiling a database for the endogenous coregulator poolldquonuclear receptor complexomerdquo [110] In this study a numberof novel protein interactions were identified and studiessuch as these are identifying proteins as ldquocoregulatorsrdquo thathad been previously thought to serve completely differentfunctionsOne group of relatively novel coregulatory proteinsare the E3 ubiquitin-protein ligases such as E6-associatedproteins (E6-AP) [111] While these proteins were thought toserve primarily as ubiquitin-conjugating enzymes they haverecently been highlighted as transcriptional enhancers ofNR-mediated activity independent of ligase function Similarlya group of E3-ligases that conjugate small ubiquitin likemodifier (SUMO) proteins to a target protein called PIASare also now considered NR coregulators and they utilize atypical LxxLLmotif In one study a decrease in ER expressionfollowing LTED or with advanced age coincided with anincrease in ER association with an E3-ubiquitin ligase CHIP[11] Together these newly described roles for HSPs and E3ligases raise novel questions about estrogen signaling such aswhen is an E3-ligaseER complex targeted for transcriptionalregulation versus degradation Also when are HSPs merelyperforming a chaperoneprotective function versus directingtranscriptional processes Future efforts aiming at elucidatingthe complexity of age-related changes in receptor structureand recruitment of coregulatory proteins could provideimportant insight into these seemingly paradoxical findings

ISRN Endocrinology 7

Table 1 Protein interactions with ER120573 were altered by age and 1198642 Selected proteins that were significantly altered (119875 lt 005) in their

association with ER120573 depending on age and 1198642treatment Experimental paradigm young (3 month) and aged (18 month) female Fischer 344

rats were ovariectomized and hormone deprived for 7 days Following deprivation animals were administered 25120583gkg 1198642(plasma levels =

7945 plusmn 225 pgmL) or vehicle (safflower oil) via subcutaneous injection onceday for 3 days Nuclear protein was isolated from the ventralhippocampus and coimmunoprecipitated for ER120573 (a beam 14C8) and associated proteins Protein interactions were identified and quantifiedusing 2D-DIGEDeCyder and ESI MSMS YV = young + vehicle YE = young + 119864

2 AV = aged + vehicle AE = aged + 119864

2

Accession noMolecularweight(Kda)

Estimatedisoelectricpoint

PEAKSscore Coverage ID

Interaction with ER120573FunctionYoung

vehicleYoung1198642

Agedvehicle

Aged1198642

gi| 149038929 80 575 494 643 Gelsolin mdash uarr mdash mdashActin-binding

coactivator

gi| 116242507 75 597 93 1458 Heat-shock protein70 mdash darr mdash uarr Chaperone

gi| 120538378 47 57 932 1072

Heterogeneousnuclear

ribonucleoproteinH12

mdash uarr mdash mdash RNA splicing

10 Nuclear Actin Setting the Stage

Coregulatory interactions may be poised upon a bed ofnuclear actin which has recently been identified as a dynamicmolecular stage for which many nuclear processes are per-formed such as transcription chromatin remodeling mRNAprocessing and nuclear importexport The general eventsthat initiate transcription are well established however theprocess by which all of the molecular components are tem-porally layered into a complex is still unclear Nuclear actin isessential in forming the preinitiation complex on a promoterelongation and RNP organization as well as remodeling ofchromatin [112ndash114] and as mentioned previously ERs arealso key factors in these processes In one study ER120572 and120573-actin were coimmunoprecipitated on the E

2responsive

pS2TFF1 promoter indicating that ER and nuclear actinmay work in concert to regulate transcriptional processesunder control of estrogens [115] The interaction betweenERs and actin is not yet fully investigated but data fromour lab (unpublished observations) and others [116] implythat both ER120572 and ER120573may utilize nuclear actin to performvarious functions Another actin-binding protein gelsolincaps actin filament ends and it has been shown to be anNR coactivator [117 118] Gelsolin may assist in actin poly-merization allowing transcriptionalmachinery to be broughtin proximity of target genes however it remains unclearhow gelsolin enhances ARER transcriptional activity Datafrom our lab indicate that gelsolinER120573 interactions increasewith E

2treatment in young but not aged animals (Table 1)

Gelsolin has been shown to increase with age [119] but alack of significant interaction with ER120573 despite increasedexpression of gelsolin could again suggest an alteration inER120573 function with age

Actin is also commonly associated with ubiquitous mul-tifunctional RNA-binding proteins such as heterologousnuclear riboproteins (hnRNPs) which also associate withERs [120] hnRNPs associate within the matrix of nuclearactin accompany transcripts out of the nucleus participatein alternative splicing and can modulate transcription [121]

Phosphorylated hnRNPK has been shown to mediate trans-lation of specific mRNAs [122] and hnRNPH is involvedin splicing and mRNA polyadenylation [123 124] In thepast the association of NRs with hnRNPs was thought to benonspecific due to the ubiquitous nature of these proteinsbut recent studies are no longer ruling out an importantinteraction between NRs and hnRNPs that may assist intranscription andor splicing [125 126] Data from our laband others demonstrate a dynamic interaction between bothER120572 and ER120573 and hnRNPs (Table 1) and furthermore datademonstrated that E

2might regulate expression of members

of the hnRNP family [127] As noted previously age-relatedincreases in splicing could lead to aberrant signaling not onlyfor E2-mediated processes but also for cellular processes in

generalNuclear ER interaction partners have historically been a

distinct class of nuclear receptor coregulators that seemedto solely assist ERs in gene transcription however thenumber of interaction partners for ERs is increasing Furtherinvestigation into ER120573-associated proteins is required as faras NRs are concerned data specific to ER120573 are inadequateto make broad conclusions Moreover post-translationalmodifications to coregulatory proteins ERs or changes intheir expression patterns due to age or sustained estrogendeprivation could all contribute to an altered microenviron-ment setting the stage for atypical estrogen signaling upontherapeutic reinstatement of hormones (Figure 3)

11 Estrogens and Cognition

Most empirical and observational data give merit to theidea that estrogens have a positive effect on cognitiveprocesses increased spine densities [128 129] enhancedsynaptic plasticity [130ndash132] and improved memory [133134] however the particular receptor(s) and the mechanismsthat regulate these processes remain unclear There are amyriad of behavioral studies suggesting that E

2enhances

prefrontal cortex (PFC) and hippocampal-dependent tasks

8 ISRN Endocrinology

Factor BER structureand function

Factor Ccoregulatory and

transcriptional interactions

120573

120573120573

120573

120572

120572

120572 120572

V

V

V

V

V

V

V

V

ESR1

ESR2

Age and E2

++

Context-dependentER-regulated

gene expression

Factor Atissue-specific

ER gene expression

Figure 3 Age and hormonalmilieu exponentially increase the potential diversity of estrogen receptor signaling leading to context-dependentgene regulation Age and E

2influence ER gene expression alternative splicing coregulatory protein expression and interaction which

ultimately direct ER-target gene transcription

For example long-term E2deprivation diminished aged

female rhesus macaquesrsquo performance in a delayed responsetask a PFC- dependent task [135] E

2also enhanced object

recognition under a number of different paradigms [136ndash138] and there are also multiple lines of evidence supportingE2-mediated neuroprotection which may be important for

cognition especially after stroke [139ndash142]Pharmacological targeting of the receptors with ER selec-

tive ligands has been a standard method for investigating thebehavioral physiological and cellular actions of E

2mediated

distinctly throughER120572 andor ER120573 however valuable insighthas also come from the ER120573-null (120573ERKO) mice 120573ERKOmice have significantly fewer neurons in the cortex hypotha-lamus amygdala and ventral tegmental area compared toWTThey also exhibit neuronal shrinkage and hyperprolifer-ation of glia by 3 months of age as well as having high levelsof apoE and apoE-dependent deposition of amyloid plaquesthroughout the CNS by 12 months of age [143] These micealso demonstrate spatial learning deficits in the Morris watermaze [144] and a decrease in hippocampal- and amygdala-dependent memory in a fear-conditioning paradigm that isaccompanied by decreased synaptic plasticity in hippocampalslice preparations [145] The critical role of ER120573 in higher-level brain functions has been deduced from these studiesand others warranting a full investigation of the wide-spreadmolecular actions of E

2known to contribute to cellular

processes on at least two levels at the synapse and on thegenome

Long-term potentiation (LTP) is an important compo-nent of learning and memory It represents an increasein synaptic transmission and plasticity that underlies cog-nitive behaviors and it is readily altered by E

2in many

circumstances In fact application of an aromatase inhibitoreliminates CA LTP generated by theta-burst stimulation inintact female neurons but not male or OVX animals posinga potentially serious concern for women using aromataseinhibitors for therapeutic treatment of breast cancer [146] E

2

can also enhance or suppress long-term depression (LTD)reducing synaptic transmission which may be dependentupon the specific receptors involved In aged male CA1cells E

2decreased LTD [147] however E

2enhanced LTP in

the cerebellum where ER120573 is the predominately expressedcognate receptor [148]

Although the majority of studies on cognitive processfocus on the rapid effects of E

2 late-phase long-term potenti-

ation (L-LTP) depends upon transcription and translation ofnewmRNA [149] to sustain an increase in synaptic transmis-sion E

2has been shown to regulate LTP in CA1 pyramidal

cells [150] over the span of 48 hours and this regulationappears to be dependent upon a higher ratio of NMDARrelative to AMPAR LTP induction requires activation ofNR2A-containing NMDARs however increased expressionof NR2B potentiates LTP magnitude [151] Notably E

2

increased expression of NR2B mRNA and NR2B expressionat the synapse [152 153] and the E

2-induced increase in

LTP can be abolished by blocking NR2B receptors [154]

ISRN Endocrinology 9

suggesting a transcriptional role for ERs in synaptic plasticityMoreover E

2application may increase CREB expression and

the amount of phosphorylated CREB in regions such as theamygdala [155] and BNST [117 155] which may be critical inthe formation of long-term memories Taken together thesedata demonstrate that E

2regulates neuronal plasticity and

memory through its original role as a transcription factor andalso by acting as a general intracellular signaling moleculethrough regulation of NMDARs and CREB However todate there are little data on the mechanisms by which ER120573regulates these processes or how the same principles ofplasticity may apply to other neurological issues

12 Estrogens and Mood Regulation

A range of behavioral experiments indicate that E2mod-

ulation of stress mood and affect is a complex storywith considerable conflicting data that may as in otherprocesses be explained in part by distinct roles for ER120572 andER120573 Anecdotally many women report mood fluctuationsas corresponding to changes in circulating estrogen levelssuch as what occurs during the menstrual cycle peripubertypostpartum and peripostmenopause Incidence of anxietyand depression are observed at perimenopause and whenhormone levels are fluctuating [156 157] However E

2can

also exhibit anxiogenic properties and often anxiety anddepression present in a comorbid fashion especially inwomen [158 159] Interestingly after the age of 55 bouts ofdepression and anxiety appear to decrease in women [160]As previously mentioned perimenopausal women receivingCEE in the KEEPs study reported an improvement in moodand the primary actions of CEE tend to be mediated throughER120573 [20] A plethora of behavioral studies has mountedin response to observational reports and at first glance itappears that ER120573 has an anxiolytic and antidepressive rolehowever there is still an immense void to be filled withrespect to biochemical and molecular mechanisms of ER120573and affective disorders Elucidating the precise molecularmechanisms that require ER120573 in plasticity and neurotrans-mitter processing in brain regions regulating these behaviorswill help clarify the role of E

2in stress- and mood-related

processesContemporary hypotheses concerning the onset of affec-

tive disorders revolve around perturbations to the cen-tral processing of environmental stress The hypothalamic-pituitary-adrenal (HPA) axis is the 3-tiered hierarchicalbiological system that mediates physical or psychologicalresponse to stressors The primary steroid regulating theHPA axis is cortisolcorticosterone (humansrats CORT) aglucocorticoid receptor (GR) ligand that is produced fromthe adrenals to exert negative feedback upon the HPAsystem to effectively modulate response to stressors Theparaventricular nucleus of hypothalamus (PVN) producestwo neuropeptides corticotropin-releasing hormone (CRH)and arginine vasopressin (AVP) to activate the HPA axisCRF and AVP synergistically stimulate release of adreno-corticotropic hormone (ACTH) from the anterior pituitarywhich acts on the adrenal cortex to produce CORT CORT

binds GR and negatively regulates CRF and AVP expressionsand releases through classical negative feedback mechanisms[161 162] ER120573 is themain ER expressed in the PVN [158 163ndash165] and regulation of AVP is an interesting example of howER action can vary AVP expression fluctuates during themenstrual cycle and is usually highest when E

2is low In fact

oral contraceptives appear to decrease AVP expression andE2is thought to inhibit AVP in the human SON [166] In

the rodent system ER120573 and its splice variants activate therodent AVP promoter independent of ligand [84] howeverthe human promoter is repressed by ER120573 and splice variantsThis discrepancy between the human and rat wasmediated byan AP-1 response element on the human AVP promoter thatis not present in the rat Importantly ER120573 acted similarly inthe two systems when the AP-1 sequence was deleted fromthe human promoter underscoring the striking alterationsthat small changes in DNA sequence can invoke in E

2

signaling pathways and the importance of understanding theexperimental context upon which such conclusions are based[77] On the contrary rat and human CRF expression wasincreased in response to E

2in rodent monkey and human

hypothalamus but it was inhibited in the placenta [167ndash170]In addition to AVP and CRF glutamatergic and GABAer-

gic projects from regions like the BNST AMY PFC andhippocampus all express ER120573 [45 46] and are likely targetsfor E2to exert effects on the HPA axis Moreover decreased

ER120573 mRNA in postmortem locus coeruleus has been foundto correlate with suicide [13] and even more recentlyER120573-mediated hippocampal nitric oxide levels have beenimplicated in affective behaviors in females but not males[171] Neurotransmitter release from these regions influencesmood affect and stress responses and E

2increases the rate

of monoamine oxidase degradation and serotonin transportwhich enhances serotonin at the synapse E

2also increases

serotonin receptor expression [172 173] Dopamine andserotonin [174] are diminished in the BNST POA and hip-pocampus and caudate putamen (dopamine) of 120573ERKOmice[174] further implicating an important role for ER120573 in theregulation of emotion and mood 120573ERKO mice also displayserious morphological and functional abnormalities in thebrain that correlate to increased depression and anxiety [12175ndash178] In addition to 120573ERKO studies administration ofER120573 selective agonists (diarylpoprionitrile DPN) decreasesboth stress markers and anxiety-related behaviors in rats[158] In fact there have been several studies implicatingER120573 and its variants in affective behaviors but the molecularmechanisms remain poorly understood

13 Summary

Estrogen-receptor-mediated signaling in the brain regulatesneurological processes many of which translate to cog-nitive and affective behavioral outputs When estrogen isdeclining and becomes replete as in menopause a num-ber of neurophysiological changes occur producing someunwanted changes The most common and logical remedyis replacement of bioidentical hormone E

2 however this

treatment can be problematic depending upon the length

10 ISRN Endocrinology

of time a woman has been in a postmenopausal estrogen-deprived state This suggests that there is a molecular switchin estrogen-mediated signaling that may allow for drasticchange in ER signaling not to mention the interaction of E

2

signaling components and the natural aging process Thesechanges are likely to include alterations to receptor profilesincluding expression of alternatively spliced variants thatrespond differently to E

2 changes in the cellular microenvi-

ronment that can alter the proteinprotein associations whichultimately leads to changes in ER-mediated gene transcrip-tion and synaptic transmission ER120573 in particular is widelyexpressed and implicated positively in the regulation ofmemory and mood fluctuations two of the most commonlyreported neurological issues in postmenopausal women Itis important to understand the actions of ER120573 in the areasregulating these processes to identify what when how andfor whom hormone therapy may be a useful treatment torectify cognitive and affective issues

Acknowledgments

This work was supported by NIA RO1 AG033605-01 andNIH T32 AG031780 The authors N N Mott and T R Pakhave nothing to disclose

References

[1] C Bengtsson O Lindquist and L Redvall ldquoIs the menopausalage rapidly changingrdquoMaturitas vol 1 no 3 pp 159ndash164 1979

[2] A Singh S Kaur and I Walia ldquoA historical perspective onmenopause andmenopausal agerdquo Bulletin of the Indian Instituteof History of Medicine (Hyderabad) vol 32 no 2 pp 121ndash1352002

[3] P Verhaeghen and J Cerella ldquoAging executive control andattention a review of meta-analysesrdquo Neuroscience and Biobe-havioral Reviews vol 26 no 7 pp 849ndash857 2002

[4] T E Wroolie H A Kenna K E Williams et al ldquoDifferencesin verbal memory performance in postmenopausal womenreceiving hormone therapy 17120573-estradiol versus conjugatedequine estrogensrdquoAmerican Journal of Geriatric Psychiatry vol19 no 9 pp 792ndash802 2011

[5] B B Sherwin ldquoEstrogenic effects on memory in womenrdquoAnnals of the New York Academy of Sciences vol 743 pp 213ndash230 1994

[6] B B Sherwin ldquoHormones mood and cognitive functioning inpostmenopausal womenrdquoObstetrics andGynecology vol 87 no2 supplement pp 20Sndash26S 1996

[7] B B Sherwin ldquoSex hormones and psychological functioning inpostmenopausalwomenrdquoExperimentalGerontology vol 29 no3-4 pp 423ndash430 1994

[8] SM Phillips and B B Sherwin ldquoEffects of estrogen onmemoryfunction in surgically menopausal womenrdquo Psychoneuroen-docrinology vol 17 no 5 pp 485ndash495 1992

[9] R Lindsay J M Aitken and J B Anderson ldquoLong term pre-vention of postmenopausal osteoporosis by oestrogen Evidencefor an increased bone mass after delayed onset of oestrogentreatmentrdquoThe Lancet vol 1 no 7968 pp 1038ndash1040 1976

[10] J E Rossouw R L Prentice J E Manson et al ldquoPost-menopausal hormone therapy and risk of cardiovascular dis-ease by age and years since menopauserdquo The Journal of the

American Medical Association vol 297 no 13 pp 1465ndash14772007

[11] Q-G Zhang D Han R-M Wang et al ldquoC terminusof Hsc70-interacting protein (CHIP)-mediated degradationof hippocampal estrogen receptor-120572 and the critical periodhypothesis of estrogen neuroprotectionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 108 no 35 pp E617ndashE624 2011

[12] W Krezel S Dupont A Krust P Chambon and P F ChapmanldquoIncreased anxiety and synaptic plasticity in estrogen receptor120573-deficient micerdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 21 pp 12278ndash12282 2001

[13] H Ostlund E Keller and Y L Hurd ldquoEstrogen receptor geneexpression in relation to neuropsychiatric disordersrdquo Annals ofthe New York Academy of Sciences vol 1007 pp 54ndash63 2003

[14] S A Shumaker C Legault S R Rapp et al ldquoEstrogen plusprogestin and the incidence of dementia and mild cognitiveimpairment in postmenopausal women the Womenrsquos HealthInitiative Memory Study a randomized controlled trialrdquo Jour-nal of the American Medical Association vol 289 no 20 pp2651ndash2662 2003

[15] S A Shumaker C Legault L Kuller et al ldquoConjugated equineestrogens and incidence of probable dementia and mild cog-nitive impairment in postmenopausal women womenrsquos HealthInitiative Memory Studyrdquo Journal of the American MedicalAssociation vol 291 no 24 pp 2947ndash2958 2004

[16] S R Rapp M A Espeland S A Shumaker et al ldquoEffect ofestrogen plus progestin on global cognitive function in post-menopausal women the Womenrsquos Health Initiative MemoryStudy a randomized controlled trialrdquo Journal of the AmericanMedical Association vol 289 no 20 pp 2663ndash2672 2003

[17] VWHenderson K S Benke R C Green L A Cupples and LA Farrer ldquoPostmenopausal hormone therapy and Alzheimerrsquosdisease risk interaction with agerdquo Journal of Neurology Neuro-surgery and Psychiatry vol 76 no 1 pp 103ndash105 2005

[18] E Garbe and S Suissa ldquoHormone replacement therapy andacute coronary syndromes methodological issues betweenrandomized and observational studiesrdquo Human Reproductionvol 19 no 1 pp 8ndash13 2004

[19] B B Braden A N Garcia S E Mennenga et al ldquoCognitive-impairing effects of medroxyprogesterone acetate in the ratindependent and interactive effects across timerdquo Psychophar-macology vol 218 no 2 pp 405ndash418 2011

[20] B R Bhavnani S-P Tam and X Lu ldquoStructure activity rela-tionships and differential interactions and functional activity ofvarious equine estrogens mediated via estrogen receptors (ERs)ER120572 and ER120573rdquo Endocrinology vol 149 no 10 pp 4857ndash48702008

[21] E Hogervorst and S Bandelow ldquoSex steroids to maintaincognitive function in women after the menopause a meta-analyses of treatment trialsrdquoMaturitas vol 66 no 1 pp 56ndash712010

[22] D J Mangelsdorf C Thummel M Beato et al ldquoThe nuclearreceptor super-family the second decaderdquo Cell vol 83 no 6pp 835ndash839 1995

[23] E V Jensen T Suzuki T Kawashima W E Stumpf P WJungblut and E R DeSombre ldquoA two-step mechanism forthe interaction of estradiol with rat uterusrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 59 no 2 pp 632ndash638 1968

ISRN Endocrinology 11

[24] F Naftolin T L Horvath R L Jakab C Leranth N Haradaand J Balthazart ldquoAromatase immunoreactivity in axon termi-nals of the vertebrate brain an immunocytochemical study onquail rat monkey and human tissuesrdquoNeuroendocrinology vol63 no 2 pp 149ndash155 1996

[25] C E Roselli S E Abdelgadir O K Roslashnnekleiv and S AKlosterman ldquoAnatomic distribution and regulation of aro-matase gene expression in the rat brainrdquo Biology of Reproduc-tion vol 58 no 1 pp 79ndash87 1998

[26] J Balthazart and G F Ball ldquoIs brain estradiol a hormone or aneurotransmitterrdquo Trends in Neurosciences vol 29 no 5 pp241ndash249 2006

[27] T R Pak Y S Rao S A Prins and N N Mott ldquoAn emergingrole for microRNAs in sexually dimorphic neurobiologicalsystemsrdquo Pflugers Archiv vol 465 no 5 pp 655ndash667 2013

[28] K Yamagata S Fujiyama S Ito et al ldquoMaturation ofmicroRNAis hormonally regulated by a nuclear receptorrdquo Molecular Cellvol 36 no 2 pp 340ndash347 2009

[29] Y Masuhiro Y Mezaki M Sakari et al ldquoSplicing potentiationby growth factor signals via estrogen receptor phosphorylationrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 23 pp 8126ndash8131 2005

[30] A Tremblay G B Tremblay F Labrie and V Giguere ldquoLigand-Independent recruitment of SRC-1 to estrogen receptor 120573through phosphorylation of activation function AF-1rdquo Molec-ular Cell vol 3 no 4 pp 513ndash519 1999

[31] S H Meijsing M A Pufall A Y So D L Bates L Chenand K R Yamamoto ldquoDNA binding site sequence directsglucocorticoid receptor structure and activityrdquo Science vol 324no 5925 pp 407ndash410 2009

[32] W Bourguet P Germain and H Gronemeyer ldquoNuclearreceptor ligand-binding domains three-dimensional struc-tures molecular interactions and pharmacological implica-tionsrdquo Trends in Pharmacological Sciences vol 21 no 10 pp381ndash388 2000

[33] A Koide C Zhao M Naganuma et al ldquoIdentification ofregions within the F domain of the human estrogen receptor 120572that are important for modulating transactivation and protein-protein interactionsrdquoMolecular Endocrinology vol 21 no 4 pp829ndash842 2007

[34] D F Skafar and S Koide ldquoUnderstanding the human estrogenreceptor-alpha using targeted mutagenesisrdquoMolecular and Cel-lular Endocrinology vol 246 no 1-2 pp 83ndash90 2006

[35] E C Chang J Frasor B Komm and B S KatzenellenbogenldquoImpact of estrogen receptor 120573 on gene networks regulated byestrogen receptor 120572 in breast cancer cellsrdquo Endocrinology vol147 no 10 pp 4831ndash4842 2006

[36] X Zhu I Leav Y-K Leung et al ldquoDynamic regulation ofestrogen receptor-120573 expression by DNA methylation duringprostate cancer development andmetastasisrdquoAmerican Journalof Pathology vol 164 no 6 pp 2003ndash2012 2004

[37] D N Petersen G T Tkalcevic P H Koza-Taylor T G Turiand T A Brown ldquoIdentification of estrogen receptor 1205732 afunctional variant of estrogen receptor 120573 expressed in normalrat tissuesrdquo Endocrinology vol 139 no 3 pp 1082ndash1092 1998

[38] L A Helguero M H Faulds J-A Gustafsson and L-AHaldosen ldquoEstrogen receptors alfa (ER120572) and beta (ER120573)differentially regulate proliferation and apoptosis of the normalmurine mammary epithelial cell line HC11rdquo Oncogene vol 24no 44 pp 6605ndash6616 2005

[39] P C Kulakosky M A McCarty S C Jernigan K E Risingerand C M Klinge ldquoResponse element sequence modulates

estrogen receptor 120572 and 120573 affinity and activityrdquo Journal ofMolecular Endocrinology vol 29 no 1 pp 137ndash152 2002

[40] OM V Grober MMutarelli G Giurato et al ldquoGlobal analysisof estrogen receptor beta binding to breast cancer cell genomereveals an extensive interplay with estrogen receptor alpha fortarget gene regulationrdquo BMC Genomics vol 12 article 36 2011

[41] O I Vivar X Zhao E F Saunier et al ldquoEstrogen receptor 120573binds to and regulates three distinct classes of target genesrdquoJournal of Biological Chemistry vol 285 no 29 pp 22059ndash22066 2010

[42] G G J M Kuiper E Enmark M Pelto-Huikko S Nilssonand J-A Gustafsson ldquoCloning of a novel estrogen receptorexpressed in rat prostate and ovaryrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 93 no12 pp 5925ndash5930 1996

[43] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and 120572 and 120573rdquo Endocrinology vol 138no 3 pp 863ndash870 1997

[44] D B Dubal H Zhu J Yu et al ldquoEstrogen receptor alpha notbeta is a critical link in estradiol-mediated protection againstbrain injuryrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 98 no 4 pp 1952ndash1957 2001

[45] P J Shughrue P J Scrimo and I Merchenthaler ldquoEvidence forthe colocalization of estrogen receptor-120573 mRNA and estrogenreceptor-120572 immunoreactivity in neurons of the rat forebrainrdquoEndocrinology vol 139 no 12 pp 5267ndash5270 1998

[46] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in therat central nervous systemrdquo Journal of Comparative Neurologyvol 388 no 4 pp 507ndash525 1997

[47] T AMilner B SMcEwen S Hayashi C J Li L P Reagan andS E Alves ldquoUltrastructural evidence that hippocampal alphaestrogen receptors are located at extranuclear sitesrdquoThe Journalof Comparative Neurology vol 429 no 3 pp 355ndash371 2001

[48] T A Milner L S Lubbers S E Alves and B S McEwenldquoNuclear and extranuclear estrogen binding sites in the ratforebrain and autonomic medullary areasrdquo Endocrinology vol149 no 7 pp 3306ndash3312 2008

[49] T A Milner K Ayoola C T Drake et al ldquoUltrastructurallocalization of estrogen receptor 120573 immunoreactivity in the rathippocampal formationrdquo Journal of ComparativeNeurology vol491 no 2 pp 81ndash95 2005

[50] A E Herbison andD TTheodosis ldquoAbsence of estrogen recep-tor immunoreactivity in somatostatin (SRIF) neurons of theperiventricular nucleus but sexually dimorphic colocalizationof estrogen receptor and SRIF immunoreactivities in neuronsof the bed nucleus of the stria terminalisrdquo Endocrinology vol132 no 4 pp 1707ndash1714 1993

[51] K Kalita S Szymczak and L Kaczmarek ldquoNon-nuclear estro-gen receptor 120573 and 120572 in the hippocampus of male and femaleratsrdquo Hippocampus vol 15 no 3 pp 404ndash412 2005

[52] T Ivanova and C Beyer ldquoOntogenetic expression and sexdifferences of aromatase and estrogen receptor-120572120573 mRNA inthe mouse hippocampusrdquo Cell and Tissue Research vol 300 no2 pp 231ndash237 2000

[53] C Y Pau K-Y F Pau and H G Spies ldquoPutative estrogenreceptor 120573 and 120572 mRNA expression in male and female rhesusmacaquesrdquo Molecular and Cellular Endocrinology vol 146 no1-2 pp 59ndash68 1998

[54] A L Wijayaratne and D P McDonnell ldquoThe human estrogenreceptor-120572 is a ubiquitinated protein whose stability is affected

12 ISRN Endocrinology

differentially by agonists antagonists and selective estrogenreceptor modulatorsrdquo Journal of Biological Chemistry vol 276no 38 pp 35684ndash35692 2001

[55] V Bartella P Rizza I Barone et al ldquoEstrogen receptor betabinds Sp1 and recruits a corepressor complex to the estrogenreceptor alpha gene promoterrdquo Breast Cancer Research andTreatment vol 134 no 2 pp 569ndash581 2012

[56] L C Li C C Yeh D Nojima and R Dahiya ldquoCloning andcharacterization of human estrogen receptor beta promoterrdquoBiochemical and Biophysical Research Communications vol 275no 2 pp 682ndash689 2000

[57] E A Vladusic A E Hornby F K Guerra-Vladusic J Lakinsand R Lupu ldquoExpression and regulation of estrogen receptor szligin human breast tumors and cell linesrdquoOncology Reports vol 7no 1 pp 157ndash167 2000

[58] T Hatsumi and Y Yamamuro ldquoDownregulation of estrogenreceptor gene expression by exogenous 17120573-estradiol in themammary glands of lactating micerdquo Experimental Biology andMedicine vol 231 no 3 pp 311ndash316 2006

[59] H B Patisaul P L Whitten and L J Young ldquoRegulation ofestrogen receptor beta mRNA in the brain opposite effectsof 17120573-estradiol and the phytoestrogen coumestrolrdquoMolecularBrain Research vol 67 no 1 pp 165ndash171 1999

[60] T J Brown N J MacLusky M Shanabrough and F NaftolinldquoComparison of age- and sex-related changes in cell nuclearestrogen-binding capacity and progestin receptor induction inthe rat brainrdquo Endocrinology vol 126 no 6 pp 2965ndash29721990

[61] B S Rubin T O Fox and R S Bridges ldquoEstrogen bindingin nuclear and cytosolic extracts from brain and pituitary ofmiddle-aged female ratsrdquo Brain Research vol 383 no 1-2 pp60ndash67 1986

[62] T Funabashi S P Kleopoulos P J Brooks et al ldquoChangesin estrogenic regulation of estrogen receptor 120572 mRNA andprogesterone receptor mRNA in the female rat hypothalamusduring aging an in situ hybridization studyrdquo NeuroscienceResearch vol 38 no 1 pp 85ndash92 2000

[63] M E Wilson K L Rosewell M L Kashon P J Shughrue IMerchenthaler and P M Wise ldquoAge differentially influencesestrogen receptor-120572 (ER120572) and estrogen receptor-120573 (ER120573) geneexpression in specific regions of the rat brainrdquo Mechanisms ofAgeing and Development vol 123 no 6 pp 593ndash601 2002

[64] W S Post P J Goldschmidt-Clermont C C Wilhide etal ldquoMethylation of the estrogen receptor gene is associatedwith aging and atherosclerosis in the cardiovascular systemrdquoCardiovascular Research vol 43 no 4 pp 985ndash991 1999

[65] J-P J Issa Y L Ottaviano P Celano S R Hamilton NE Davidson and S B Baylin ldquoMethylation of the oestrogenreceptor CpG island links ageing and neoplasia in humancolonrdquo Nature Genetics vol 7 no 4 pp 536ndash540 1994

[66] T Funabashi and F Kimura ldquoEffects of estrogen and estrogenreceptor messenger RNA levels in young and middle-agedfemale rats comparison ofmedial preoptic area andmediobasalhypothalamusrdquo Acta Biologica Hungarica vol 45 no 2ndash4 pp223ndash231 1994

[67] M AMiller P E Kolb B Planas andM A Raskind ldquoEstrogenreceptor and neurotensinneuromedin-N gene expression inthe preoptic area are unaltered with age in Fischer 344 femaleratsrdquo Endocrinology vol 135 no 5 pp 1986ndash1995 1994

[68] T R Chakraborty P R Hof L Ng and A C Gore ldquoStereologicanalysis of estrogen receptor alpha (ER alpha) expression in rat

hypothalamus and its regulation by aging and estrogenrdquo Journalof Comparative Neurology vol 466 no 3 pp 409ndash421 2003

[69] J M Westberry A L Trout and M E Wilson ldquoEpigeneticregulation of estrogen receptor beta expression in the rat cortexduring agingrdquo NeuroReport vol 22 no 9 pp 428ndash432 2011

[70] T R Chakraborty L Ng and A C Gore ldquoAge-related changesin estrogen receptor 120573 in rat hypothalamus a quantitativeanalysisrdquo Endocrinology vol 144 no 9 pp 4164ndash4171 2003

[71] I Poola S Koduri S Chatra and R Clarke ldquoIdentificationof twenty alternatively spliced estrogen receptor alpha mRNAsin breast cancer cell lines and tumors using splice targetedprimer approachrdquo Journal of Steroid Biochemistry andMolecularBiology vol 72 no 5 pp 249ndash258 2000

[72] T A Ishunina and D F Swaab ldquoHippocampal estrogenreceptor-alpha splice variant TADDI in the human brain inaging and Alzheimerrsquos diseaserdquoNeuroendocrinology vol 89 no2 pp 187ndash199 2009

[73] T A Ishunina and D F Swaab ldquoEstrogen receptor-120572 splicevariants in the human brainrdquo Gynecological Endocrinology vol24 no 2 pp 93ndash98 2008

[74] T A Ishunina F P M Kruijver R Balesar and D FSwaab ldquoDifferential expression of estrogen receptor 120572 and 120573immunoreactivity in the human supraoptic nucleus in rela-tion to sex and agingrdquo Journal of Clinical Endocrinology andMetabolism vol 85 no 9 pp 3283ndash3291 2000

[75] T A Ishunina D F Fischer andD F Swaab ldquoEstrogen receptor120572 and its splice variants in the hippocampus in aging andAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 28 no 11 pp1670ndash1681 2007

[76] J R Tollervey Z Wang T Hortobagyi et al ldquoAnalysis of alter-native splicing associated with aging and neurodegeneration inthe human brainrdquo Genome Research vol 21 no 10 pp 1572ndash1582 2011

[77] N NMott and T R Pak ldquoCharacterisation of human oestrogenreceptor beta (ER120573) splice variants in neuronal cellsrdquo Journal ofNeuroendocrinology vol 24 no 10 pp 1311ndash1321 2012

[78] S Inoue S-J Hoshino H Miyoshi et al ldquoIdentification ofa ovel isoform of estrogen receptor a potential inhibitor ofestrogen action in vascular smooth muscle cellsrdquo Biochemicaland Biophysical Research Communications vol 219 no 3 pp766ndash772 1996

[79] J K Skipper L J Young J M Bergeron M T Tetzlaff CT Osborn and D Crews ldquoIdentification of an isoform ofthe estrogen receptor messenger RNA lacking exon four andpresent in the brainrdquo Proceedings of the National Academy ofSciences of the United States of America vol 90 no 15 pp 7172ndash7175 1993

[80] R H Price Jr N Lorenzon and R J Handa ldquoDifferentialexpression of estrogen receptor beta splice variants in rat brainidentification and characterization of a novel variant missingexon 4rdquo Brain Research Molecular Brain Research vol 80 no2 pp 260ndash268 2000

[81] S Chu and P J Fuller ldquoIdentification of a splice variantof the rat estrogen receptor 120573 generdquo Molecular and CellularEndocrinology vol 132 no 1-2 pp 195ndash199 1997

[82] B Lu E Leygue H Dotzlaw L J Murphy L C Murphy andP H Watson ldquoEstrogen receptor-120573 mRNA variants in humanand murine tissuesrdquoMolecular and Cellular Endocrinology vol138 no 1-2 pp 199ndash203 1998

[83] T R Pak W C J Chung J L Roberts and R J HandaldquoLigand-independent effects of estrogen receptor 120573 on

ISRN Endocrinology 13

mouse gonadotropin-releasing hormone promoter activityrdquoEndocrinology vol 147 no 4 pp 1924ndash1931 2006

[84] T R Pak W C J Chung L R Hinds and R J HandaldquoEstrogen receptor-120573 mediates dihydrotestosterone-inducedstimulation of the arginine vasopressin promoter in neuronalcellsrdquo Endocrinology vol 148 no 7 pp 3371ndash3382 2007

[85] Y K Leung PMak S Hassan and SMHo ldquoEstrogen receptor(ER)-120573 isoforms a key to understanding ER-120573 signalingrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 103 no 35 pp 13162ndash13167 2006

[86] J M Wang X Hou S Adeosun et al ldquoA dominant negativeER120573 splice variant determines the effectiveness of early or lateestrogen therapy after ovariectomy in ratsrdquo PLoS One vol 7 no3 Article ID e33493 2012

[87] W C J Chung T R Pak S Suzuki W A Pouliot M EAndersen and R J Handa ldquoDetection and localization of anestrogen receptor beta splice variant protein (ER1205732) in theadult female rat forebrain and midbrain regionsrdquo Journal ofComparative Neurology vol 505 no 3 pp 249ndash267 2007

[88] R H Price Jr C A Butler P Webb R Uht P Kushner andR J Handa ldquoA splice variant of estrogen receptor 120573 missingexon 3 displays altered subnuclear localization and capacity fortranscriptional activationrdquo Endocrinology vol 142 no 5 pp2039ndash2049 2001

[89] Y Wang and R J Miksicek ldquoIdentification of a dominantnegative form of the human estrogen receptorrdquo MolecularEndocrinology vol 5 no 11 pp 1707ndash1715 1991

[90] E Kuppers and C Beyer ldquoExpression of estrogen receptor-120572and 120573 mRNA in the developing and adult mouse striatumrdquoNeuroscience Letters vol 276 no 2 pp 95ndash98 1999

[91] C Gundlah S G Kohama S J Mirkes V T Garyfallou H FUrbanski and C L Bethea ldquoDistribution of estrogen receptorbeta (ER120573) mRNA in hypothalamus midbrain and temporallobe of spayed macaque continued expression with hormonereplacementrdquo Brain Research Molecular Brain Research vol 76no 2 pp 191ndash204 2000

[92] Y Morishima P J M Murphy D-P Li E R Sanchez and WB Pratt ldquoStepwise assembly of a glucocorticoid receptorsdothsp90heterocomplex resolves two sequential ATP-dependent eventsinvolving first hsp70 and then hsp90 in opening of the steroidbinding pocketrdquo Journal of Biological Chemistry vol 275 no 24pp 18054ndash18060 2000

[93] K D Dittmar and W B Pratt ldquoFolding of the glucocorticoidreceptor by the reconstituted hsp90-based chaperone machin-eryThe initial hsp90sdotp60sdothsp70-dependent step is sufficient forcreating the steroid binding conformationrdquo Journal of BiologicalChemistry vol 272 no 20 pp 13047ndash13054 1997

[94] K I Kang X Meng J Devin-Leclerc et al ldquoThe molecularchaperone Hsp90 can negatively regulate the activity of aglucocorticosteroid-dependent promoterrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 4 pp 1439ndash1444 1999

[95] K Unno H Asakura Y Shibuya M Kaiho S Okada and NOku Naoto ldquoIncrease in basal level of Hsp70 consisting chieflyof constitutively expressed hsp70 (Hsc70) in aged rat brainrdquoJournals of Gerontology Series A vol 55 no 7 pp B329ndashB3352000

[96] U E Olazabal D W Pfaff and C V Mobbs ldquoSex differences inthe regulation of heat shock protein 70 kDa and 90 kDa in therat ventromedial hypothalamus by estrogenrdquo Brain Researchvol 596 no 1-2 pp 311ndash314 1992

[97] M A Pahlavani M D Harris S A Moore and A RichardsonldquoExpression of heat shock protein 70 in rat spleen lymphocytesis affected by age but not by food restrictionrdquo Journal ofNutrition vol 126 no 9 pp 2069ndash2075 1996

[98] A R Heydari B Wu R Takahashi R Strong and A Richard-son ldquoExpression of heat shock protein 70 is altered by age anddiet at the level of transcriptionrdquoMolecular andCellular Biologyvol 13 no 5 pp 2909ndash2918 1993

[99] M Sabbah K-I I Kang L Tora and G Redeuilh ldquoOestro-gen receptor facilitates the formation of preinitiation com-plex assembly involvement of the general transcription factorTFIIBrdquo Biochemical Journal vol 336 part 3 pp 639ndash646 1998

[100] S-Y Wu M C Thomas S Y Hou V Likhite and C-MChiang ldquoIsolation of mouse TFIID and functional character-ization of TBP and TFIID in mediating estrogen receptor andchromatin transcriptionrdquo Journal of Biological Chemistry vol274 no 33 pp 23480ndash23490 1999

[101] S Ghosh and M K Thakur ldquoTissue-specific expression ofreceptor-interacting protein in aging mouserdquo Age vol 30 no4 pp 237ndash243 2008

[102] J Frasor JM Danes B Komm K C N Chang C Richard Lyt-tle and B S Katzenellenbogen ldquoProfiling of estrogen up- anddown-regulated gene expression in human breast cancer cellsinsights into gene networks and pathways underlying estrogeniccontrol of proliferation and cell phenotyperdquo Endocrinology vol144 no 10 pp 4562ndash4574 2003

[103] J Frasor J M Danes C C Funk and B S Katzenellen-bogen ldquoEstrogen down-regulation of the corepressor N-CoRmechanism and implications for estrogen derepression of N-CoR-regulated genesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 102 no 37 pp13153ndash13157 2005

[104] N J McKenna and B W OrsquoMalley ldquoCombinatorial control ofgene expression by nuclear receptors and coregulatorsrdquoCell vol108 no 4 pp 465ndash474 2002

[105] T-P Yao G Ku N Zhou R Scully and D M Livingston ldquoThenuclear hormone receptor coactivator SRC-1 is a specific targetof p300rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 93 no 20 pp 10626ndash10631 1996

[106] B Hanstein R Eckner J DiRenzo et al ldquop300 is a componentof an estrogen receptor coactivator complexrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 93 no 21 pp 11540ndash11545 1996

[107] S Halachmi E Marden G Martin H MacKay C Abbon-danza and M Brown ldquoEstrogen receptor-associated proteinspossible mediators of hormone-induced transcriptionsrdquo Sci-ence vol 264 no 5164 pp 1455ndash1458 1994

[108] A J Horlein AM Naar T Heinzel et al ldquoLigand-independentrepression by the thyroid hormone receptor mediated by anuclear receptor co-repressorrdquo Nature vol 377 no 6548 pp397ndash404 1995

[109] J D Chen and R M Evans ldquoA transcriptional co-repressor thatinteracts with nuclear hormone receptorsrdquo Nature vol 377 no6548 pp 454ndash457 1995

[110] A Malovannaya R B Lanz S Y Jung et al ldquoAnalysis of thehuman endogenous coregulator complexomerdquoCell vol 145 no5 pp 787ndash799 2011

[111] Z Nawaz D M Lonard C L Smith et al ldquoThe Angelmansyndrome-associated protein E6-AP is a coactivator for thenuclear hormone receptor superfamilyrdquoMolecular and CellularBiology vol 19 no 2 pp 1182ndash1189 1999

14 ISRN Endocrinology

[112] B Zheng M Han M Bernier and J-K Wen ldquoNuclear actinand actin-binding proteins in the regulation of transcriptionand gene expressionrdquo FEBS Journal vol 276 no 10 pp 2669ndash2685 2009

[113] W A Hofmann L Stojiljkovic B Fuchsova et al ldquoActin is partof pre-initiation complexes and is necessary for transcription byRNA polymerase IIrdquoNature Cell Biology vol 6 no 11 pp 1094ndash1101 2004

[114] K Tokunaga T Shibuya Y Ishihama et al ldquoNucleocytoplasmictransport of fluorescent mRNA in living mammalian cellsnuclear mRNA export is coupled to ongoing gene transcrip-tionrdquo Genes to Cells vol 11 no 3 pp 305ndash317 2006

[115] R Metivier G Penot M R Hubner et al ldquoEstrogen receptor-120572 directs ordered cyclical and combinatorial recruitment ofcofactors on a natural target promoterrdquo Cell vol 115 no 6 pp751ndash763 2003

[116] C Ambrosino R Tarallo A Bamundo et al ldquoIdentification of ahormone-regulated dynamic nuclear actin network associatedwith estrogen receptor 120572 in human breast cancer cell nucleirdquoMolecular and Cellular Proteomics vol 9 no 6 pp 1352ndash13672010

[117] F Shao R Zhang L Dong and K Ying ldquoOverexpression ofgelsolin-like actin-capping protein is associated with progres-sion of lung adenocarcinomardquo Tohoku Journal of ExperimentalMedicine vol 225 no 2 pp 95ndash101 2011

[118] K Nishimura H-J Ting Y Harada et al ldquoModulation ofandrogen receptor transactivation by gelsolin a newly identi-fied androgen receptor coregulatorrdquo Cancer Research vol 63no 16 pp 4888ndash4894 2003

[119] J S Ahn I S Jang D I Kim et al ldquoAging-associated increaseof gelsolin for apoptosis resistancerdquoBiochemical and BiophysicalResearch Communications vol 312 no 4 pp 1335ndash1341 2003

[120] I Nalvarte T Schwend and J-A Gustafsson ldquoProteomicsanalysis of the estrogen receptor 120572 receptosomerdquoMolecular andCellular Proteomics vol 9 no 7 pp 1411ndash1422 2010

[121] L-H Miau C-J Chang B-J Shen W-H Tsai and S-C LeeldquoIdentification of heterogeneous nuclear ribonucleoprotein K(hnRNPK) as a repressor ofCEBP120573-mediated gene activationrdquoJournal of Biological Chemistry vol 273 no 17 pp 10784ndash107911998

[122] A Ostareck-Lederer D H Ostareck C Cans et al ldquoc-Src-mediated phosphorylation of hnRNP K drives translationalactivation of specifically silenced mRNAsrdquo Molecular and Cel-lular Biology vol 22 no 13 pp 4535ndash4543 2002

[123] P S Bagga G K Arhin and J Wilusz ldquoDSEF-1 is a member ofthe hnRNP H family of RNA-binding proteins and stimulatespre-mRNAcleavage and polyadenylation in vitrordquoNucleic AcidsResearch vol 26 no 23 pp 5343ndash5350 1998

[124] V Markovtsov J M Nikolic J A Goldman C W Turck M-Y Chou and D L Black ldquoCooperative assembly of an hnRNPcomplex induced by a tissue-specific homolog of polypyrimi-dine tract binding proteinrdquoMolecular and Cellular Biology vol20 no 20 pp 7463ndash7479 2000

[125] S Y Jung A Malovannaya J Wei B W OrsquoMalley and J QinldquoProteomic analysis of steady-state nuclear hormone receptorcoactivator complexesrdquoMolecular Endocrinology vol 19 no 10pp 2451ndash2465 2005

[126] W Hong R J Resnick C Rakowski D Shalloway S J Taylorand G A Blobel ldquoPhysical and functional interaction betweenthe transcriptional cofactor CBP and the KH domain proteinSam68rdquoMolecular Cancer Research vol 1 no 1 pp 48ndash55 2002

[127] R ShaoXWang BWeijdegard et al ldquoCoordinate regulation ofheterogeneous nuclear ribonucleoprotein dynamics by steroidhormones in the human fallopian tube and endometrium invivo and in vitrordquo American Journal of Physiology vol 302 no10 pp E1269ndashE1282 2012

[128] C SWoolley and B SMcEwen ldquoEstradiolmediates fluctuationin hippocampal synapse density during the estrous cycle in theadult ratrdquo Journal of Neuroscience vol 12 no 7 pp 2549ndash25541992

[129] C S Woolley H J Wenzel and P A Schwartzkroin ldquoEstradiolincreases the frequency of multiple synapse boutons in thehippocampal CA1 region of the adult female ratrdquo The Journalof Comparative Neurology vol 373 no 1 pp 108ndash117 1996

[130] C S Woolley ldquoEstrogen-mediated structural and functionalsynaptic plasticity in the female rat hippocampusrdquo Hormonesand Behavior vol 34 no 2 pp 140ndash148 1998

[131] D P Srivastava K M Woolfrey K A Jones et al ldquoRapidenhancement of two-step wiring plasticity by estrogen andNMDA receptor activityrdquo Proceedings of the National Academyof Sciences of the United States of America vol 105 no 38 pp14650ndash14655 2008

[132] M Ogiue-Ikeda N Tanabe H Mukai et al ldquoRapid modu-lation of synaptic plasticity by estrogens as well as endocrinedisrupters in hippocampal neuronsrdquo Brain Research Reviewsvol 57 no 2 pp 363ndash375 2008

[133] N J Sandstrom and C L Williams ldquoSpatial memory retentionis enhanced by acute and continuous estradiol replacementrdquoHormones and Behavior vol 45 no 2 pp 128ndash135 2004

[134] E Hogervorst J Williams M Budge W Riedel and JJolles ldquoThe nature of the effect of female gonadal hormonereplacement therapy on cognitive function in post-menopausalwomen a meta-analysisrdquo Neuroscience vol 101 no 3 pp 485ndash512 2000

[135] M E Bailey A C J Wang J Hao et al ldquoInteractive effects ofage and estrogen on cortical neurons implications for cognitiveagingrdquo Neuroscience vol 191 pp 148ndash158 2011

[136] A A Walf M E Rhodes and C A Frye ldquoOvarian steroidsenhance object recognition in naturally cycling and ovariec-tomized hormone-primed ratsrdquo Neurobiology of Learning andMemory vol 86 no 1 pp 35ndash46 2006

[137] V N Luine L F Jacome and N J Maclusky ldquoRapid enhance-ment of visual and place memory by estrogens in ratsrdquoEndocrinology vol 144 no 7 pp 2836ndash2844 2003

[138] L Fan Z Zhao P T Orr C H Chambers M C Lewis and KM Frick ldquoEstradiol-induced object memory consolidation inmiddle-aged femalemice requires dorsal hippocampal extracel-lular signal-regulated kinase and phosphatidylinositol 3-kinaseactivationrdquo Journal of Neuroscience vol 30 no 12 pp 4390ndash4400 2010

[139] D B Dubal and PMWise ldquoNeuroprotective effects of estradiolin middle-aged female ratsrdquo Endocrinology vol 142 no 1 pp43ndash48 2001

[140] S-H Yang J Shi A L Day and J W Simpkins ldquoEstradiolexerts neuroprotective effects when administered after ischemicinsultrdquo Stroke vol 31 no 3 pp 745ndash750 2000

[141] J W Simpkins G Rajakumar Y-Q Zhang et al ldquoEstrogensmay reduce mortality and ischemic damage caused by middlecerebral artery occlusion in the female ratrdquo Journal of Neuro-surgery vol 87 no 5 pp 724ndash730 1997

[142] J Shi K S Panickar S-H Yang O Rabbani A L Day and JWSimpkins ldquoEstrogen attenuates over-expression of 120573-amyloid

ISRN Endocrinology 15

precursor protein messager RNA in an animal model of focalischemiardquo Brain Research vol 810 no 1-2 pp 87ndash92 1998

[143] Q-H Zhang Y-H Huang Y-Z Hu et al ldquoDisruption ofestrogen receptor beta in mice brain results in pathologicalalterations resemblingAlzheimer diseaserdquoActa PharmacologicaSinica vol 25 no 4 pp 452ndash457 2004

[144] E F Rissman A L Heck J E Leonard M A Shupnik and J-A Gustafsson ldquoDisruption of estrogen receptor 120573 gene impairsspatial learning in female micerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no6 pp 3996ndash4001 2002

[145] M Day A Sung S Logue M Bowlby and R Arias ldquoBetaestrogen receptor knockout (BERKO) mice present attenuatedhippocampal CA1 long-term potentiation and related memorydeficits in contextual fear conditioningrdquo Behavioural BrainResearch vol 164 no 1 pp 128ndash131 2005

[146] R Vierk G Glassmeier L Zhou et al ldquoAromatase inhibitionabolishes LTP generation in female but not in male micerdquo TheJournal of Neuroscience vol 32 no 24 pp 8116ndash8126 2012

[147] R-M Vouimba M R Foy J G Foy and R FThompson ldquo17120573-estradiol suppresses expression of long-term depression in agedratsrdquo Brain Research Bulletin vol 53 no 6 pp 783ndash787 2000

[148] C E Andreescu B A Milojkovic E D Haasdijk et alldquoEstradiol improves cerebellar memory formation by activatingestrogen receptor 120573rdquo Journal of Neuroscience vol 27 no 40 pp10832ndash10839 2007

[149] Y-Y Huang P V Nguyen T Abel and E R Kandel ldquoLong-lasting forms of synaptic potentiation in the mammalian hip-pocampusrdquo Learning Memory vol 3 no 2-3 pp 74ndash85 1996

[150] H Mukai T Tsurugizawa G Murakami et al ldquoRapid mod-ulation of long-term depression and spinogenesis via synapticestrogen receptors in hippocampal principal neuronsrdquo Journalof Neurochemistry vol 100 no 4 pp 950ndash967 2007

[151] L Liu T P Wong M F Pozza et al ldquoRole of NMDA receptorsubtypes in governing the direction of hippocampal synapticplasticityrdquo Science vol 304 no 5673 pp 1021ndash1024 2004

[152] M Cyr O Ghribi C Thibault M Morissette M Landry andT di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[153] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[154] C C Smith and L L McMahon ldquoEstradiol-induced increasein the magnitude of long-term potentiation is prevented byblocking NR2B-containing receptorsrdquo Journal of Neurosciencevol 26 no 33 pp 8517ndash8522 2006

[155] Y Zhou J J Watters and D M Dorsa ldquoEstrogen rapidlyinduces the phosphorylation of the cAMP response elementbinding protein in rat brainrdquo Endocrinology vol 137 no 5 pp2163ndash2166 1996

[156] XGonda T TelekG Juhasz J Lazary AVargha andG BagdyldquoPatterns of mood changes throughout the reproductive cyclein healthy women without premenstrual dysphoric disordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 32 no 8 pp 1782ndash1788 2008

[157] E W Freeman ldquoPremenstrual syndrome and premenstrualdysphoric disorder definitions and diagnosisrdquo Psychoneuroen-docrinology vol 28 supplement 3 pp 25ndash37 2003

[158] T D Lund T Rovis W C J Chung and R J Handa ldquoNovelactions of estrogen receptor-120573 on anxiety-related behaviorsrdquoEndocrinology vol 146 no 2 pp 797ndash807 2005

[159] N Breslau L Schultz and E Peterson ldquoSex differences indepression a role for preexisting anxietyrdquo Psychiatry Researchvol 58 no 1 pp 1ndash12 1995

[160] P E Bebbington G Dunn R Jenkins et al ldquoThe influenceof age and sex on the prevalence of depressive conditionsreport from the National Survey of Psychiatric MorbidityrdquoPsychological Medicine vol 28 no 1 pp 9ndash19 1998

[161] G Aguilera J P Harwood and J X Wilson ldquoMechanisms ofaction of corticotropin-releasing factor and other regulators ofcorticotropin release in rat pituitary cellsrdquo Journal of BiologicalChemistry vol 258 no 13 pp 8039ndash8045 1983

[162] A Papadimitriou and K N Priftis ldquoRegulation of thehypothalamic-pituitary-adrenal axisrdquo NeuroImmunoModula-tion vol 16 no 5 pp 265ndash271 2009

[163] S Suzuki and R J Handa ldquoRegulation of estrogen receptor-120573expression in the female rat hypothalamus differential effectsof dexamethasone and estradiolrdquo Endocrinology vol 145 no 8pp 3658ndash3670 2004

[164] W J S Miller S Suzuki L K Miller R Handa and R M UhtldquoEstrogen receptor (ER)120573 isoforms rather than ER120572 regulatecorticotropin-releasing hormone promoter activity through analternate pathwayrdquo Journal of Neuroscience vol 24 no 47 pp10628ndash10635 2004

[165] C IsgorM CecchiM Kabbaj H Akil and S JWatson ldquoEstro-gen receptor 120573 in the paraventricular nucleus of hypothalamusregulates the neuroendocrine response to stress and is regulatedby corticosteronerdquo Neuroscience vol 121 no 4 pp 837ndash8452003

[166] M L Forsling I Kallo D E Hartley et al ldquoOestrogen receptor-120573 and neurohypophysial hormones functional interaction andneuroanatomical localisationrdquo Pharmacology Biochemistry andBehavior vol 76 no 3-4 pp 535ndash542 2003

[167] A S Lalmansingh and R M Uht ldquoEstradiol regulatescorticotropin-releasing hormone gene (crh) expression in arapid and phasic manner that parallels estrogen receptor-120572 and-120573 recruitment to a 3101584051015840-cyclic adenosine 51015840- monophosphateregulatory region of the proximal crh promoterrdquo Endocrinologyvol 149 no 1 pp 346ndash357 2008

[168] B N Roy R L Reid and D A van Vugt ldquoThe effects ofestrogen and progesterone on corticotropin-releasing hormoneand arginine vasopressin messenger ribonucleic acid levelsin the paraventricular nucleus and supraoptic nucleus of therhesus monkeyrdquo Endocrinology vol 140 no 5 pp 2191ndash21981999

[169] X Ni R C Nicholson B R King E-C Chan M A Read andR Smith ldquoEstrogen represses whereas the estrogen-antagonistICI 182780 stimulates placental CRH gene expressionrdquo Journalof Clinical Endocrinology and Metabolism vol 87 no 8 pp3774ndash3778 2002

[170] N C Vamvakopoulos and G P Chrousos ldquoEvidence of directestrogenic regulation of human corticotropin-releasing hor-mone gene expression Potential implications for the sexualdimophism of the stress response and immuneinflammatoryreactionrdquo Journal of Clinical Investigation vol 92 no 4 pp1896ndash1902 1993

[171] Y Hu D L Wu C X Luo et al ldquoHippocampal nitric oxidecontributes to sex difference in affective behaviorsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 35 pp 14224ndash14229 2012

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

EndocrinologyInternational Journal of

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Disease Markers

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OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Endocrinology 5

following LTED but E2deprivation had no effect on ER120573

[11] The same report demonstrated decreased levels of ER120573in very old rats (24-month females compared to 3-monthdiestrus females) In general most reports suggest that agingdecreases ER120573 expression but like ER120572 this effect may behighly region specific An age-related decrease in ER120573 expres-sion in the brain is underscored by a corresponding increaseinCpGmethylation of the ESR2 promoter inmiddle-aged (9ndash12months) rats [69] Other reports describe decreases in ER120573protein and message in some areas but not in others [63 70]Taken together there are a number of reports attemptingto identify the parameters that control ER expression suchas age sex and response to E

2 however with such vast

deviations in expression with cell type there is still much tobe learned about expression of these receptors especially inbrain regions controlling nonreproductive behaviors

6 Alternative Splice Variants

Based upon the highly variable reports that differ in sexand age of animals as well as exposure to hormone it maybe possible that these studies are unknowingly detectingchanges in splice variant expression which could change E

2

responsiveness as well as downstream gene regulation Notonly can ERs heterodimerize to regulate gene transcriptionbut there are a number of alternatively spliced variants of eachreceptor that are endogenously expressed and that potentiallycontribute to the diverse tissue-specific actions of E

2 Alter-

native splicing of ERs alters inherent signaling properties ofthe receptor including ligand and DNA-binding affinitiesnuclear localization and dimerization depending on wherethe alternative splice site is encoded A number of ER splicevariant transcripts and other proteins have been identifiedin demented human brains breast and prostate and insome reports an increase in alternative splicing is correlatedwith pathology [71ndash75] Also interesting age alone mayincrease alternative splicing of some gene products [76] Theidentified ER120573 human splice variants are truncated at the C-terminus of the receptor (Figure 1(a)) however we providedexperimental evidence that the C-terminus of the receptoris not required for ER120573-mediated transcription especiallywith regard to the identified human splice variants [77]Unlike the human splice variants rodent ER120573 splice variantsidentified to date have been shown to have either an exoninclusion in the ligand-binding domain creating (rER1205732)or an exon deletion in the DNA-binding domain rER1205731Δ3or rER1205731Δ4 or both rER1205732Δ3 and rER1205732Δ4 (Figure 1(b))[37 78 79] Exon inclusion (rER1205732 variants) has been shownto produce a protein that binds E

2with a 35-fold decrease

in affinity In contrast ERs with exon 3 and 4 deletions areunable to bind DNA but they can still mediate transcriptionthrough proteinprotein interactions with other transcriptionfactors such as AP-1 and it can bind E

2as well as rER1205731

[37 80] Importantly the transcriptional functions of rER1205731are significantly altered when coexpressed with other splicevariants likely due to a weaker interaction with coactivatorproteins [81 82] Despite lower E

2binding andor lack of

DNA binding the rodent and human splice variants retain a

constitutive ligand-independent transcriptional function atboth basic and complex promoters [77 83 84] suggestingthat these splice variants have an important endogenousbiological function Indeed unliganded ER1205731 or apo-ER1205731has been reported to regulate a subset of genes distinct fromthose regulated by ER1205731 when bound to E

2[41] Conversely

the human splice variants do not bind ligand with greataffinity [85] and they might therefore only regulate the classof genes that unliganded ER120573 targets

Thedownstream target genes of ER120573 splice variantsmightbe an important consideration at the time of menopauseas ER expression profiles and alternative splicing tend tochange with age [76] One recent report demonstrated anincrease in ER1205732 expression in the hippocampus of 9-month old middle-aged rats following short-term (6 days)E2deprivation that was significantly decreased compared to

the Sham group after E2administration [86] Importantly

E2replacement no longer affected ER1205732 expression in the

hippocampus after LTED (180 days)That study also reporteda decrease in hippocampal neurogenesis and increased float-ing behavior in a forced swim test thus functionally corre-lating increased ER1205732 with mood regulation and potentiallycognition Thus the expression and functions of ER120573 splicevariants are absolutely critical to understand the effects ofestrogen particularly at times of sustainedE

2deprivationwith

regard to cognition and affect While ER1205732 expression hasbeen assessed in the young male rat brain [87] and othervariants have been described in some brain regions [80 88]there is a general lack of data on most ER120573 splice variantsespecially in aged female brains

Some of the splice variants identified to date have beencharacterized as dominant negative receptors serving toinhibit activation of the full-length receptor [89] howevermost identified variants do not bind ligand with the sameaffinity and have the potential to differentially regulate targetgenes While several splice variants for ER120573 have been iden-tified in many model systems including mouse [90] rat [4546] and monkey [91] there is a general lack of comparativestudies on expression and functionality of human ER120573 vari-ants especially in neuronal systems Furthermore changingexpression levels of one or more alternatively spliced variantsduring a period of E

2deprivation may drastically change

general receptivity and downstream functions of E2

7 Novel ProteinProtein Interactions forE2-Mediated Nuclear Processes

Proteinprotein interactions are an essential relay in the reg-ulation of dynamic cellular processes Immediately followingtranslation ERs typically associate with a chaperone proteinto ensure proper folding protect from degradation and assistthe ER in becoming poised to accept ligand Once bound toligand ERs can dimerize and act as transcription factors tomediate gene regulation or associate withmembrane proteinsto initiate a signaling cascade When acting as transcriptionfactors ERs associate with a number of coregulatory proteinsthat assist in activating or repressing E

2-regulated genes

Coregulatory interactions are more characterized for ER120572

6 ISRN Endocrinology

than ER120573 and importantly less clear is how ER120573 mediatesligand-independent transcription In addition to the well-established ER interaction partners many novel interactingproteins have not yet been characterized and could be criticalfor nuclear processes not limited to gene transcription

8 HSPs and Chaperone Proteins

According to the classical two-step hypothesis inactivenuclear receptors are constantly accompanied and protectedfrom degradation by a number of chaperone proteins typi-cally members of the heat-shock protein (HSP) family Thisreceptorchaperone complex has been studied extensivelyand while the idea of a protective role for chaperones is wellsupported this complex can also perform other functionsFor instance HSPER complexes can serve to preactivatea hormone receptor by forcing a conformational changein ER such that it is able to bind its cognate hormoneThe initial HSP complex consists of the ER HSP70 andHSP70-interacting protein (HiP) as well as other accessoryand scaffolding proteins [92] HSP90 is recruited to thecomplex andHSP70 dissociates creating thematureHSPERcomplex [93] HSP90 induces a conformational change in thenuclear receptor and the ER is released from the complexready to dimerize and bind DNA or other transcriptionfactors to regulate gene transcription However some studiessuggest that HSPs could have a broader role than originallythought For example in Drosophila HSPs are required forDNA binding and in some instances they may regulateNR action [94] Interestingly aging and E

2can alter HSP70

in a cell-type specific manner [95ndash98] However recentdata from our lab (Table 1) demonstrated that HSP70 morereadily associates with ER120573 in aged female hippocampusfollowing E

2treatment compared to the young ones in which

HSP70ER120573 association decreased following E2treatment

We also observed no significant changes in HSP70 or ER120573expression suggesting that changes in the HSP70ER120573 inter-action with age in response to E

2change are a result of E

2

responsiveness andor activation of ER120573

9 Transcriptional Proteins and ERs

The process of transcribing DNA into RNA is a systematicprocess that involves multiprotein complexes binding toDNA modifying histone marks and initiating RNA synthe-sis ER120572 but not ER120573 has been shown to directly interactwith TFIIB IIE IIF and TIID proteins that initiate tran-scription [99 100] However experimental evidence from co-immunoprecipitation studies has demonstrated interactionsbetween ER120573 coregulatory proteins as well as other tran-scription factors Coregulatory proteins are transcriptionalaccessory proteins that enhance or repress transcription oftarget genes In general coactivators enhance gene tran-scription whereas corepressors block it However recentdata suggest that seemingly nontranscriptional proteins mayhave context-dependent coregulatory functions Importantly

certain coregulators can also be governed by age and E2[101ndash

103] thus recent discoveries imply that ER-mediated generegulation is not as well understood as previously thought

The best studied and well-established group of coregula-tory proteins that selectively associate with NRs is the steroidreceptor coactivator (SRCp160) family The SRC family iscomposed of three members SRC-1 SRC-2 and SRC-3all of which contain canonical LxxLL motifs known as thenuclear receptor (NR) box This motif interacts with AF-2 domains in ER120573 as well as other NR family memberssuch as glucocorticoid receptor (GR) progesterone receptor(PR) thyroid hormone receptor (TR) and ER120572 [104] SRCmembers have intrinsic histone acetyltransferase activity(HAT DNA activating) and interact with CREB-bindingprotein (CBP) [105] CBPp300 proteins are also coactivatorsthat have intrinsic HAT activity and can recruit ASC-2and other known coregulatory proteins [106] Confirmedcoregulatory interaction partners for several NRs that donot belong to the SRC family include estrogen-receptor-association protein (ERAP 140) [107] nuclear corepressor(NCoR) [108] silencing mediator of retinoic acid and thy-roid hormone receptor (SMRT) [109] and many othersAs is the case with our understanding of ER120573 interactionswith basic transcriptional machinery studies investigatingER120573coregulator interactions are sparse which may be dueto uniquely challenging issues associated with ER120573 such as alack of high-fidelity biochemical tools complicated structuralproperties and or pleiotropic physiological actions that arespecific to ER120573

In 2010 Anna Ma lovannaya and colleagues directeda high-throughput study (not including ER120573) aiming atcompiling a database for the endogenous coregulator poolldquonuclear receptor complexomerdquo [110] In this study a numberof novel protein interactions were identified and studiessuch as these are identifying proteins as ldquocoregulatorsrdquo thathad been previously thought to serve completely differentfunctionsOne group of relatively novel coregulatory proteinsare the E3 ubiquitin-protein ligases such as E6-associatedproteins (E6-AP) [111] While these proteins were thought toserve primarily as ubiquitin-conjugating enzymes they haverecently been highlighted as transcriptional enhancers ofNR-mediated activity independent of ligase function Similarlya group of E3-ligases that conjugate small ubiquitin likemodifier (SUMO) proteins to a target protein called PIASare also now considered NR coregulators and they utilize atypical LxxLLmotif In one study a decrease in ER expressionfollowing LTED or with advanced age coincided with anincrease in ER association with an E3-ubiquitin ligase CHIP[11] Together these newly described roles for HSPs and E3ligases raise novel questions about estrogen signaling such aswhen is an E3-ligaseER complex targeted for transcriptionalregulation versus degradation Also when are HSPs merelyperforming a chaperoneprotective function versus directingtranscriptional processes Future efforts aiming at elucidatingthe complexity of age-related changes in receptor structureand recruitment of coregulatory proteins could provideimportant insight into these seemingly paradoxical findings

ISRN Endocrinology 7

Table 1 Protein interactions with ER120573 were altered by age and 1198642 Selected proteins that were significantly altered (119875 lt 005) in their

association with ER120573 depending on age and 1198642treatment Experimental paradigm young (3 month) and aged (18 month) female Fischer 344

rats were ovariectomized and hormone deprived for 7 days Following deprivation animals were administered 25120583gkg 1198642(plasma levels =

7945 plusmn 225 pgmL) or vehicle (safflower oil) via subcutaneous injection onceday for 3 days Nuclear protein was isolated from the ventralhippocampus and coimmunoprecipitated for ER120573 (a beam 14C8) and associated proteins Protein interactions were identified and quantifiedusing 2D-DIGEDeCyder and ESI MSMS YV = young + vehicle YE = young + 119864

2 AV = aged + vehicle AE = aged + 119864

2

Accession noMolecularweight(Kda)

Estimatedisoelectricpoint

PEAKSscore Coverage ID

Interaction with ER120573FunctionYoung

vehicleYoung1198642

Agedvehicle

Aged1198642

gi| 149038929 80 575 494 643 Gelsolin mdash uarr mdash mdashActin-binding

coactivator

gi| 116242507 75 597 93 1458 Heat-shock protein70 mdash darr mdash uarr Chaperone

gi| 120538378 47 57 932 1072

Heterogeneousnuclear

ribonucleoproteinH12

mdash uarr mdash mdash RNA splicing

10 Nuclear Actin Setting the Stage

Coregulatory interactions may be poised upon a bed ofnuclear actin which has recently been identified as a dynamicmolecular stage for which many nuclear processes are per-formed such as transcription chromatin remodeling mRNAprocessing and nuclear importexport The general eventsthat initiate transcription are well established however theprocess by which all of the molecular components are tem-porally layered into a complex is still unclear Nuclear actin isessential in forming the preinitiation complex on a promoterelongation and RNP organization as well as remodeling ofchromatin [112ndash114] and as mentioned previously ERs arealso key factors in these processes In one study ER120572 and120573-actin were coimmunoprecipitated on the E

2responsive

pS2TFF1 promoter indicating that ER and nuclear actinmay work in concert to regulate transcriptional processesunder control of estrogens [115] The interaction betweenERs and actin is not yet fully investigated but data fromour lab (unpublished observations) and others [116] implythat both ER120572 and ER120573may utilize nuclear actin to performvarious functions Another actin-binding protein gelsolincaps actin filament ends and it has been shown to be anNR coactivator [117 118] Gelsolin may assist in actin poly-merization allowing transcriptionalmachinery to be broughtin proximity of target genes however it remains unclearhow gelsolin enhances ARER transcriptional activity Datafrom our lab indicate that gelsolinER120573 interactions increasewith E

2treatment in young but not aged animals (Table 1)

Gelsolin has been shown to increase with age [119] but alack of significant interaction with ER120573 despite increasedexpression of gelsolin could again suggest an alteration inER120573 function with age

Actin is also commonly associated with ubiquitous mul-tifunctional RNA-binding proteins such as heterologousnuclear riboproteins (hnRNPs) which also associate withERs [120] hnRNPs associate within the matrix of nuclearactin accompany transcripts out of the nucleus participatein alternative splicing and can modulate transcription [121]

Phosphorylated hnRNPK has been shown to mediate trans-lation of specific mRNAs [122] and hnRNPH is involvedin splicing and mRNA polyadenylation [123 124] In thepast the association of NRs with hnRNPs was thought to benonspecific due to the ubiquitous nature of these proteinsbut recent studies are no longer ruling out an importantinteraction between NRs and hnRNPs that may assist intranscription andor splicing [125 126] Data from our laband others demonstrate a dynamic interaction between bothER120572 and ER120573 and hnRNPs (Table 1) and furthermore datademonstrated that E

2might regulate expression of members

of the hnRNP family [127] As noted previously age-relatedincreases in splicing could lead to aberrant signaling not onlyfor E2-mediated processes but also for cellular processes in

generalNuclear ER interaction partners have historically been a

distinct class of nuclear receptor coregulators that seemedto solely assist ERs in gene transcription however thenumber of interaction partners for ERs is increasing Furtherinvestigation into ER120573-associated proteins is required as faras NRs are concerned data specific to ER120573 are inadequateto make broad conclusions Moreover post-translationalmodifications to coregulatory proteins ERs or changes intheir expression patterns due to age or sustained estrogendeprivation could all contribute to an altered microenviron-ment setting the stage for atypical estrogen signaling upontherapeutic reinstatement of hormones (Figure 3)

11 Estrogens and Cognition

Most empirical and observational data give merit to theidea that estrogens have a positive effect on cognitiveprocesses increased spine densities [128 129] enhancedsynaptic plasticity [130ndash132] and improved memory [133134] however the particular receptor(s) and the mechanismsthat regulate these processes remain unclear There are amyriad of behavioral studies suggesting that E

2enhances

prefrontal cortex (PFC) and hippocampal-dependent tasks

8 ISRN Endocrinology

Factor BER structureand function

Factor Ccoregulatory and

transcriptional interactions

120573

120573120573

120573

120572

120572

120572 120572

V

V

V

V

V

V

V

V

ESR1

ESR2

Age and E2

++

Context-dependentER-regulated

gene expression

Factor Atissue-specific

ER gene expression

Figure 3 Age and hormonalmilieu exponentially increase the potential diversity of estrogen receptor signaling leading to context-dependentgene regulation Age and E

2influence ER gene expression alternative splicing coregulatory protein expression and interaction which

ultimately direct ER-target gene transcription

For example long-term E2deprivation diminished aged

female rhesus macaquesrsquo performance in a delayed responsetask a PFC- dependent task [135] E

2also enhanced object

recognition under a number of different paradigms [136ndash138] and there are also multiple lines of evidence supportingE2-mediated neuroprotection which may be important for

cognition especially after stroke [139ndash142]Pharmacological targeting of the receptors with ER selec-

tive ligands has been a standard method for investigating thebehavioral physiological and cellular actions of E

2mediated

distinctly throughER120572 andor ER120573 however valuable insighthas also come from the ER120573-null (120573ERKO) mice 120573ERKOmice have significantly fewer neurons in the cortex hypotha-lamus amygdala and ventral tegmental area compared toWTThey also exhibit neuronal shrinkage and hyperprolifer-ation of glia by 3 months of age as well as having high levelsof apoE and apoE-dependent deposition of amyloid plaquesthroughout the CNS by 12 months of age [143] These micealso demonstrate spatial learning deficits in the Morris watermaze [144] and a decrease in hippocampal- and amygdala-dependent memory in a fear-conditioning paradigm that isaccompanied by decreased synaptic plasticity in hippocampalslice preparations [145] The critical role of ER120573 in higher-level brain functions has been deduced from these studiesand others warranting a full investigation of the wide-spreadmolecular actions of E

2known to contribute to cellular

processes on at least two levels at the synapse and on thegenome

Long-term potentiation (LTP) is an important compo-nent of learning and memory It represents an increasein synaptic transmission and plasticity that underlies cog-nitive behaviors and it is readily altered by E

2in many

circumstances In fact application of an aromatase inhibitoreliminates CA LTP generated by theta-burst stimulation inintact female neurons but not male or OVX animals posinga potentially serious concern for women using aromataseinhibitors for therapeutic treatment of breast cancer [146] E

2

can also enhance or suppress long-term depression (LTD)reducing synaptic transmission which may be dependentupon the specific receptors involved In aged male CA1cells E

2decreased LTD [147] however E

2enhanced LTP in

the cerebellum where ER120573 is the predominately expressedcognate receptor [148]

Although the majority of studies on cognitive processfocus on the rapid effects of E

2 late-phase long-term potenti-

ation (L-LTP) depends upon transcription and translation ofnewmRNA [149] to sustain an increase in synaptic transmis-sion E

2has been shown to regulate LTP in CA1 pyramidal

cells [150] over the span of 48 hours and this regulationappears to be dependent upon a higher ratio of NMDARrelative to AMPAR LTP induction requires activation ofNR2A-containing NMDARs however increased expressionof NR2B potentiates LTP magnitude [151] Notably E

2

increased expression of NR2B mRNA and NR2B expressionat the synapse [152 153] and the E

2-induced increase in

LTP can be abolished by blocking NR2B receptors [154]

ISRN Endocrinology 9

suggesting a transcriptional role for ERs in synaptic plasticityMoreover E

2application may increase CREB expression and

the amount of phosphorylated CREB in regions such as theamygdala [155] and BNST [117 155] which may be critical inthe formation of long-term memories Taken together thesedata demonstrate that E

2regulates neuronal plasticity and

memory through its original role as a transcription factor andalso by acting as a general intracellular signaling moleculethrough regulation of NMDARs and CREB However todate there are little data on the mechanisms by which ER120573regulates these processes or how the same principles ofplasticity may apply to other neurological issues

12 Estrogens and Mood Regulation

A range of behavioral experiments indicate that E2mod-

ulation of stress mood and affect is a complex storywith considerable conflicting data that may as in otherprocesses be explained in part by distinct roles for ER120572 andER120573 Anecdotally many women report mood fluctuationsas corresponding to changes in circulating estrogen levelssuch as what occurs during the menstrual cycle peripubertypostpartum and peripostmenopause Incidence of anxietyand depression are observed at perimenopause and whenhormone levels are fluctuating [156 157] However E

2can

also exhibit anxiogenic properties and often anxiety anddepression present in a comorbid fashion especially inwomen [158 159] Interestingly after the age of 55 bouts ofdepression and anxiety appear to decrease in women [160]As previously mentioned perimenopausal women receivingCEE in the KEEPs study reported an improvement in moodand the primary actions of CEE tend to be mediated throughER120573 [20] A plethora of behavioral studies has mountedin response to observational reports and at first glance itappears that ER120573 has an anxiolytic and antidepressive rolehowever there is still an immense void to be filled withrespect to biochemical and molecular mechanisms of ER120573and affective disorders Elucidating the precise molecularmechanisms that require ER120573 in plasticity and neurotrans-mitter processing in brain regions regulating these behaviorswill help clarify the role of E

2in stress- and mood-related

processesContemporary hypotheses concerning the onset of affec-

tive disorders revolve around perturbations to the cen-tral processing of environmental stress The hypothalamic-pituitary-adrenal (HPA) axis is the 3-tiered hierarchicalbiological system that mediates physical or psychologicalresponse to stressors The primary steroid regulating theHPA axis is cortisolcorticosterone (humansrats CORT) aglucocorticoid receptor (GR) ligand that is produced fromthe adrenals to exert negative feedback upon the HPAsystem to effectively modulate response to stressors Theparaventricular nucleus of hypothalamus (PVN) producestwo neuropeptides corticotropin-releasing hormone (CRH)and arginine vasopressin (AVP) to activate the HPA axisCRF and AVP synergistically stimulate release of adreno-corticotropic hormone (ACTH) from the anterior pituitarywhich acts on the adrenal cortex to produce CORT CORT

binds GR and negatively regulates CRF and AVP expressionsand releases through classical negative feedback mechanisms[161 162] ER120573 is themain ER expressed in the PVN [158 163ndash165] and regulation of AVP is an interesting example of howER action can vary AVP expression fluctuates during themenstrual cycle and is usually highest when E

2is low In fact

oral contraceptives appear to decrease AVP expression andE2is thought to inhibit AVP in the human SON [166] In

the rodent system ER120573 and its splice variants activate therodent AVP promoter independent of ligand [84] howeverthe human promoter is repressed by ER120573 and splice variantsThis discrepancy between the human and rat wasmediated byan AP-1 response element on the human AVP promoter thatis not present in the rat Importantly ER120573 acted similarly inthe two systems when the AP-1 sequence was deleted fromthe human promoter underscoring the striking alterationsthat small changes in DNA sequence can invoke in E

2

signaling pathways and the importance of understanding theexperimental context upon which such conclusions are based[77] On the contrary rat and human CRF expression wasincreased in response to E

2in rodent monkey and human

hypothalamus but it was inhibited in the placenta [167ndash170]In addition to AVP and CRF glutamatergic and GABAer-

gic projects from regions like the BNST AMY PFC andhippocampus all express ER120573 [45 46] and are likely targetsfor E2to exert effects on the HPA axis Moreover decreased

ER120573 mRNA in postmortem locus coeruleus has been foundto correlate with suicide [13] and even more recentlyER120573-mediated hippocampal nitric oxide levels have beenimplicated in affective behaviors in females but not males[171] Neurotransmitter release from these regions influencesmood affect and stress responses and E

2increases the rate

of monoamine oxidase degradation and serotonin transportwhich enhances serotonin at the synapse E

2also increases

serotonin receptor expression [172 173] Dopamine andserotonin [174] are diminished in the BNST POA and hip-pocampus and caudate putamen (dopamine) of 120573ERKOmice[174] further implicating an important role for ER120573 in theregulation of emotion and mood 120573ERKO mice also displayserious morphological and functional abnormalities in thebrain that correlate to increased depression and anxiety [12175ndash178] In addition to 120573ERKO studies administration ofER120573 selective agonists (diarylpoprionitrile DPN) decreasesboth stress markers and anxiety-related behaviors in rats[158] In fact there have been several studies implicatingER120573 and its variants in affective behaviors but the molecularmechanisms remain poorly understood

13 Summary

Estrogen-receptor-mediated signaling in the brain regulatesneurological processes many of which translate to cog-nitive and affective behavioral outputs When estrogen isdeclining and becomes replete as in menopause a num-ber of neurophysiological changes occur producing someunwanted changes The most common and logical remedyis replacement of bioidentical hormone E

2 however this

treatment can be problematic depending upon the length

10 ISRN Endocrinology

of time a woman has been in a postmenopausal estrogen-deprived state This suggests that there is a molecular switchin estrogen-mediated signaling that may allow for drasticchange in ER signaling not to mention the interaction of E

2

signaling components and the natural aging process Thesechanges are likely to include alterations to receptor profilesincluding expression of alternatively spliced variants thatrespond differently to E

2 changes in the cellular microenvi-

ronment that can alter the proteinprotein associations whichultimately leads to changes in ER-mediated gene transcrip-tion and synaptic transmission ER120573 in particular is widelyexpressed and implicated positively in the regulation ofmemory and mood fluctuations two of the most commonlyreported neurological issues in postmenopausal women Itis important to understand the actions of ER120573 in the areasregulating these processes to identify what when how andfor whom hormone therapy may be a useful treatment torectify cognitive and affective issues

Acknowledgments

This work was supported by NIA RO1 AG033605-01 andNIH T32 AG031780 The authors N N Mott and T R Pakhave nothing to disclose

References

[1] C Bengtsson O Lindquist and L Redvall ldquoIs the menopausalage rapidly changingrdquoMaturitas vol 1 no 3 pp 159ndash164 1979

[2] A Singh S Kaur and I Walia ldquoA historical perspective onmenopause andmenopausal agerdquo Bulletin of the Indian Instituteof History of Medicine (Hyderabad) vol 32 no 2 pp 121ndash1352002

[3] P Verhaeghen and J Cerella ldquoAging executive control andattention a review of meta-analysesrdquo Neuroscience and Biobe-havioral Reviews vol 26 no 7 pp 849ndash857 2002

[4] T E Wroolie H A Kenna K E Williams et al ldquoDifferencesin verbal memory performance in postmenopausal womenreceiving hormone therapy 17120573-estradiol versus conjugatedequine estrogensrdquoAmerican Journal of Geriatric Psychiatry vol19 no 9 pp 792ndash802 2011

[5] B B Sherwin ldquoEstrogenic effects on memory in womenrdquoAnnals of the New York Academy of Sciences vol 743 pp 213ndash230 1994

[6] B B Sherwin ldquoHormones mood and cognitive functioning inpostmenopausal womenrdquoObstetrics andGynecology vol 87 no2 supplement pp 20Sndash26S 1996

[7] B B Sherwin ldquoSex hormones and psychological functioning inpostmenopausalwomenrdquoExperimentalGerontology vol 29 no3-4 pp 423ndash430 1994

[8] SM Phillips and B B Sherwin ldquoEffects of estrogen onmemoryfunction in surgically menopausal womenrdquo Psychoneuroen-docrinology vol 17 no 5 pp 485ndash495 1992

[9] R Lindsay J M Aitken and J B Anderson ldquoLong term pre-vention of postmenopausal osteoporosis by oestrogen Evidencefor an increased bone mass after delayed onset of oestrogentreatmentrdquoThe Lancet vol 1 no 7968 pp 1038ndash1040 1976

[10] J E Rossouw R L Prentice J E Manson et al ldquoPost-menopausal hormone therapy and risk of cardiovascular dis-ease by age and years since menopauserdquo The Journal of the

American Medical Association vol 297 no 13 pp 1465ndash14772007

[11] Q-G Zhang D Han R-M Wang et al ldquoC terminusof Hsc70-interacting protein (CHIP)-mediated degradationof hippocampal estrogen receptor-120572 and the critical periodhypothesis of estrogen neuroprotectionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 108 no 35 pp E617ndashE624 2011

[12] W Krezel S Dupont A Krust P Chambon and P F ChapmanldquoIncreased anxiety and synaptic plasticity in estrogen receptor120573-deficient micerdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 21 pp 12278ndash12282 2001

[13] H Ostlund E Keller and Y L Hurd ldquoEstrogen receptor geneexpression in relation to neuropsychiatric disordersrdquo Annals ofthe New York Academy of Sciences vol 1007 pp 54ndash63 2003

[14] S A Shumaker C Legault S R Rapp et al ldquoEstrogen plusprogestin and the incidence of dementia and mild cognitiveimpairment in postmenopausal women the Womenrsquos HealthInitiative Memory Study a randomized controlled trialrdquo Jour-nal of the American Medical Association vol 289 no 20 pp2651ndash2662 2003

[15] S A Shumaker C Legault L Kuller et al ldquoConjugated equineestrogens and incidence of probable dementia and mild cog-nitive impairment in postmenopausal women womenrsquos HealthInitiative Memory Studyrdquo Journal of the American MedicalAssociation vol 291 no 24 pp 2947ndash2958 2004

[16] S R Rapp M A Espeland S A Shumaker et al ldquoEffect ofestrogen plus progestin on global cognitive function in post-menopausal women the Womenrsquos Health Initiative MemoryStudy a randomized controlled trialrdquo Journal of the AmericanMedical Association vol 289 no 20 pp 2663ndash2672 2003

[17] VWHenderson K S Benke R C Green L A Cupples and LA Farrer ldquoPostmenopausal hormone therapy and Alzheimerrsquosdisease risk interaction with agerdquo Journal of Neurology Neuro-surgery and Psychiatry vol 76 no 1 pp 103ndash105 2005

[18] E Garbe and S Suissa ldquoHormone replacement therapy andacute coronary syndromes methodological issues betweenrandomized and observational studiesrdquo Human Reproductionvol 19 no 1 pp 8ndash13 2004

[19] B B Braden A N Garcia S E Mennenga et al ldquoCognitive-impairing effects of medroxyprogesterone acetate in the ratindependent and interactive effects across timerdquo Psychophar-macology vol 218 no 2 pp 405ndash418 2011

[20] B R Bhavnani S-P Tam and X Lu ldquoStructure activity rela-tionships and differential interactions and functional activity ofvarious equine estrogens mediated via estrogen receptors (ERs)ER120572 and ER120573rdquo Endocrinology vol 149 no 10 pp 4857ndash48702008

[21] E Hogervorst and S Bandelow ldquoSex steroids to maintaincognitive function in women after the menopause a meta-analyses of treatment trialsrdquoMaturitas vol 66 no 1 pp 56ndash712010

[22] D J Mangelsdorf C Thummel M Beato et al ldquoThe nuclearreceptor super-family the second decaderdquo Cell vol 83 no 6pp 835ndash839 1995

[23] E V Jensen T Suzuki T Kawashima W E Stumpf P WJungblut and E R DeSombre ldquoA two-step mechanism forthe interaction of estradiol with rat uterusrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 59 no 2 pp 632ndash638 1968

ISRN Endocrinology 11

[24] F Naftolin T L Horvath R L Jakab C Leranth N Haradaand J Balthazart ldquoAromatase immunoreactivity in axon termi-nals of the vertebrate brain an immunocytochemical study onquail rat monkey and human tissuesrdquoNeuroendocrinology vol63 no 2 pp 149ndash155 1996

[25] C E Roselli S E Abdelgadir O K Roslashnnekleiv and S AKlosterman ldquoAnatomic distribution and regulation of aro-matase gene expression in the rat brainrdquo Biology of Reproduc-tion vol 58 no 1 pp 79ndash87 1998

[26] J Balthazart and G F Ball ldquoIs brain estradiol a hormone or aneurotransmitterrdquo Trends in Neurosciences vol 29 no 5 pp241ndash249 2006

[27] T R Pak Y S Rao S A Prins and N N Mott ldquoAn emergingrole for microRNAs in sexually dimorphic neurobiologicalsystemsrdquo Pflugers Archiv vol 465 no 5 pp 655ndash667 2013

[28] K Yamagata S Fujiyama S Ito et al ldquoMaturation ofmicroRNAis hormonally regulated by a nuclear receptorrdquo Molecular Cellvol 36 no 2 pp 340ndash347 2009

[29] Y Masuhiro Y Mezaki M Sakari et al ldquoSplicing potentiationby growth factor signals via estrogen receptor phosphorylationrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 23 pp 8126ndash8131 2005

[30] A Tremblay G B Tremblay F Labrie and V Giguere ldquoLigand-Independent recruitment of SRC-1 to estrogen receptor 120573through phosphorylation of activation function AF-1rdquo Molec-ular Cell vol 3 no 4 pp 513ndash519 1999

[31] S H Meijsing M A Pufall A Y So D L Bates L Chenand K R Yamamoto ldquoDNA binding site sequence directsglucocorticoid receptor structure and activityrdquo Science vol 324no 5925 pp 407ndash410 2009

[32] W Bourguet P Germain and H Gronemeyer ldquoNuclearreceptor ligand-binding domains three-dimensional struc-tures molecular interactions and pharmacological implica-tionsrdquo Trends in Pharmacological Sciences vol 21 no 10 pp381ndash388 2000

[33] A Koide C Zhao M Naganuma et al ldquoIdentification ofregions within the F domain of the human estrogen receptor 120572that are important for modulating transactivation and protein-protein interactionsrdquoMolecular Endocrinology vol 21 no 4 pp829ndash842 2007

[34] D F Skafar and S Koide ldquoUnderstanding the human estrogenreceptor-alpha using targeted mutagenesisrdquoMolecular and Cel-lular Endocrinology vol 246 no 1-2 pp 83ndash90 2006

[35] E C Chang J Frasor B Komm and B S KatzenellenbogenldquoImpact of estrogen receptor 120573 on gene networks regulated byestrogen receptor 120572 in breast cancer cellsrdquo Endocrinology vol147 no 10 pp 4831ndash4842 2006

[36] X Zhu I Leav Y-K Leung et al ldquoDynamic regulation ofestrogen receptor-120573 expression by DNA methylation duringprostate cancer development andmetastasisrdquoAmerican Journalof Pathology vol 164 no 6 pp 2003ndash2012 2004

[37] D N Petersen G T Tkalcevic P H Koza-Taylor T G Turiand T A Brown ldquoIdentification of estrogen receptor 1205732 afunctional variant of estrogen receptor 120573 expressed in normalrat tissuesrdquo Endocrinology vol 139 no 3 pp 1082ndash1092 1998

[38] L A Helguero M H Faulds J-A Gustafsson and L-AHaldosen ldquoEstrogen receptors alfa (ER120572) and beta (ER120573)differentially regulate proliferation and apoptosis of the normalmurine mammary epithelial cell line HC11rdquo Oncogene vol 24no 44 pp 6605ndash6616 2005

[39] P C Kulakosky M A McCarty S C Jernigan K E Risingerand C M Klinge ldquoResponse element sequence modulates

estrogen receptor 120572 and 120573 affinity and activityrdquo Journal ofMolecular Endocrinology vol 29 no 1 pp 137ndash152 2002

[40] OM V Grober MMutarelli G Giurato et al ldquoGlobal analysisof estrogen receptor beta binding to breast cancer cell genomereveals an extensive interplay with estrogen receptor alpha fortarget gene regulationrdquo BMC Genomics vol 12 article 36 2011

[41] O I Vivar X Zhao E F Saunier et al ldquoEstrogen receptor 120573binds to and regulates three distinct classes of target genesrdquoJournal of Biological Chemistry vol 285 no 29 pp 22059ndash22066 2010

[42] G G J M Kuiper E Enmark M Pelto-Huikko S Nilssonand J-A Gustafsson ldquoCloning of a novel estrogen receptorexpressed in rat prostate and ovaryrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 93 no12 pp 5925ndash5930 1996

[43] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and 120572 and 120573rdquo Endocrinology vol 138no 3 pp 863ndash870 1997

[44] D B Dubal H Zhu J Yu et al ldquoEstrogen receptor alpha notbeta is a critical link in estradiol-mediated protection againstbrain injuryrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 98 no 4 pp 1952ndash1957 2001

[45] P J Shughrue P J Scrimo and I Merchenthaler ldquoEvidence forthe colocalization of estrogen receptor-120573 mRNA and estrogenreceptor-120572 immunoreactivity in neurons of the rat forebrainrdquoEndocrinology vol 139 no 12 pp 5267ndash5270 1998

[46] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in therat central nervous systemrdquo Journal of Comparative Neurologyvol 388 no 4 pp 507ndash525 1997

[47] T AMilner B SMcEwen S Hayashi C J Li L P Reagan andS E Alves ldquoUltrastructural evidence that hippocampal alphaestrogen receptors are located at extranuclear sitesrdquoThe Journalof Comparative Neurology vol 429 no 3 pp 355ndash371 2001

[48] T A Milner L S Lubbers S E Alves and B S McEwenldquoNuclear and extranuclear estrogen binding sites in the ratforebrain and autonomic medullary areasrdquo Endocrinology vol149 no 7 pp 3306ndash3312 2008

[49] T A Milner K Ayoola C T Drake et al ldquoUltrastructurallocalization of estrogen receptor 120573 immunoreactivity in the rathippocampal formationrdquo Journal of ComparativeNeurology vol491 no 2 pp 81ndash95 2005

[50] A E Herbison andD TTheodosis ldquoAbsence of estrogen recep-tor immunoreactivity in somatostatin (SRIF) neurons of theperiventricular nucleus but sexually dimorphic colocalizationof estrogen receptor and SRIF immunoreactivities in neuronsof the bed nucleus of the stria terminalisrdquo Endocrinology vol132 no 4 pp 1707ndash1714 1993

[51] K Kalita S Szymczak and L Kaczmarek ldquoNon-nuclear estro-gen receptor 120573 and 120572 in the hippocampus of male and femaleratsrdquo Hippocampus vol 15 no 3 pp 404ndash412 2005

[52] T Ivanova and C Beyer ldquoOntogenetic expression and sexdifferences of aromatase and estrogen receptor-120572120573 mRNA inthe mouse hippocampusrdquo Cell and Tissue Research vol 300 no2 pp 231ndash237 2000

[53] C Y Pau K-Y F Pau and H G Spies ldquoPutative estrogenreceptor 120573 and 120572 mRNA expression in male and female rhesusmacaquesrdquo Molecular and Cellular Endocrinology vol 146 no1-2 pp 59ndash68 1998

[54] A L Wijayaratne and D P McDonnell ldquoThe human estrogenreceptor-120572 is a ubiquitinated protein whose stability is affected

12 ISRN Endocrinology

differentially by agonists antagonists and selective estrogenreceptor modulatorsrdquo Journal of Biological Chemistry vol 276no 38 pp 35684ndash35692 2001

[55] V Bartella P Rizza I Barone et al ldquoEstrogen receptor betabinds Sp1 and recruits a corepressor complex to the estrogenreceptor alpha gene promoterrdquo Breast Cancer Research andTreatment vol 134 no 2 pp 569ndash581 2012

[56] L C Li C C Yeh D Nojima and R Dahiya ldquoCloning andcharacterization of human estrogen receptor beta promoterrdquoBiochemical and Biophysical Research Communications vol 275no 2 pp 682ndash689 2000

[57] E A Vladusic A E Hornby F K Guerra-Vladusic J Lakinsand R Lupu ldquoExpression and regulation of estrogen receptor szligin human breast tumors and cell linesrdquoOncology Reports vol 7no 1 pp 157ndash167 2000

[58] T Hatsumi and Y Yamamuro ldquoDownregulation of estrogenreceptor gene expression by exogenous 17120573-estradiol in themammary glands of lactating micerdquo Experimental Biology andMedicine vol 231 no 3 pp 311ndash316 2006

[59] H B Patisaul P L Whitten and L J Young ldquoRegulation ofestrogen receptor beta mRNA in the brain opposite effectsof 17120573-estradiol and the phytoestrogen coumestrolrdquoMolecularBrain Research vol 67 no 1 pp 165ndash171 1999

[60] T J Brown N J MacLusky M Shanabrough and F NaftolinldquoComparison of age- and sex-related changes in cell nuclearestrogen-binding capacity and progestin receptor induction inthe rat brainrdquo Endocrinology vol 126 no 6 pp 2965ndash29721990

[61] B S Rubin T O Fox and R S Bridges ldquoEstrogen bindingin nuclear and cytosolic extracts from brain and pituitary ofmiddle-aged female ratsrdquo Brain Research vol 383 no 1-2 pp60ndash67 1986

[62] T Funabashi S P Kleopoulos P J Brooks et al ldquoChangesin estrogenic regulation of estrogen receptor 120572 mRNA andprogesterone receptor mRNA in the female rat hypothalamusduring aging an in situ hybridization studyrdquo NeuroscienceResearch vol 38 no 1 pp 85ndash92 2000

[63] M E Wilson K L Rosewell M L Kashon P J Shughrue IMerchenthaler and P M Wise ldquoAge differentially influencesestrogen receptor-120572 (ER120572) and estrogen receptor-120573 (ER120573) geneexpression in specific regions of the rat brainrdquo Mechanisms ofAgeing and Development vol 123 no 6 pp 593ndash601 2002

[64] W S Post P J Goldschmidt-Clermont C C Wilhide etal ldquoMethylation of the estrogen receptor gene is associatedwith aging and atherosclerosis in the cardiovascular systemrdquoCardiovascular Research vol 43 no 4 pp 985ndash991 1999

[65] J-P J Issa Y L Ottaviano P Celano S R Hamilton NE Davidson and S B Baylin ldquoMethylation of the oestrogenreceptor CpG island links ageing and neoplasia in humancolonrdquo Nature Genetics vol 7 no 4 pp 536ndash540 1994

[66] T Funabashi and F Kimura ldquoEffects of estrogen and estrogenreceptor messenger RNA levels in young and middle-agedfemale rats comparison ofmedial preoptic area andmediobasalhypothalamusrdquo Acta Biologica Hungarica vol 45 no 2ndash4 pp223ndash231 1994

[67] M AMiller P E Kolb B Planas andM A Raskind ldquoEstrogenreceptor and neurotensinneuromedin-N gene expression inthe preoptic area are unaltered with age in Fischer 344 femaleratsrdquo Endocrinology vol 135 no 5 pp 1986ndash1995 1994

[68] T R Chakraborty P R Hof L Ng and A C Gore ldquoStereologicanalysis of estrogen receptor alpha (ER alpha) expression in rat

hypothalamus and its regulation by aging and estrogenrdquo Journalof Comparative Neurology vol 466 no 3 pp 409ndash421 2003

[69] J M Westberry A L Trout and M E Wilson ldquoEpigeneticregulation of estrogen receptor beta expression in the rat cortexduring agingrdquo NeuroReport vol 22 no 9 pp 428ndash432 2011

[70] T R Chakraborty L Ng and A C Gore ldquoAge-related changesin estrogen receptor 120573 in rat hypothalamus a quantitativeanalysisrdquo Endocrinology vol 144 no 9 pp 4164ndash4171 2003

[71] I Poola S Koduri S Chatra and R Clarke ldquoIdentificationof twenty alternatively spliced estrogen receptor alpha mRNAsin breast cancer cell lines and tumors using splice targetedprimer approachrdquo Journal of Steroid Biochemistry andMolecularBiology vol 72 no 5 pp 249ndash258 2000

[72] T A Ishunina and D F Swaab ldquoHippocampal estrogenreceptor-alpha splice variant TADDI in the human brain inaging and Alzheimerrsquos diseaserdquoNeuroendocrinology vol 89 no2 pp 187ndash199 2009

[73] T A Ishunina and D F Swaab ldquoEstrogen receptor-120572 splicevariants in the human brainrdquo Gynecological Endocrinology vol24 no 2 pp 93ndash98 2008

[74] T A Ishunina F P M Kruijver R Balesar and D FSwaab ldquoDifferential expression of estrogen receptor 120572 and 120573immunoreactivity in the human supraoptic nucleus in rela-tion to sex and agingrdquo Journal of Clinical Endocrinology andMetabolism vol 85 no 9 pp 3283ndash3291 2000

[75] T A Ishunina D F Fischer andD F Swaab ldquoEstrogen receptor120572 and its splice variants in the hippocampus in aging andAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 28 no 11 pp1670ndash1681 2007

[76] J R Tollervey Z Wang T Hortobagyi et al ldquoAnalysis of alter-native splicing associated with aging and neurodegeneration inthe human brainrdquo Genome Research vol 21 no 10 pp 1572ndash1582 2011

[77] N NMott and T R Pak ldquoCharacterisation of human oestrogenreceptor beta (ER120573) splice variants in neuronal cellsrdquo Journal ofNeuroendocrinology vol 24 no 10 pp 1311ndash1321 2012

[78] S Inoue S-J Hoshino H Miyoshi et al ldquoIdentification ofa ovel isoform of estrogen receptor a potential inhibitor ofestrogen action in vascular smooth muscle cellsrdquo Biochemicaland Biophysical Research Communications vol 219 no 3 pp766ndash772 1996

[79] J K Skipper L J Young J M Bergeron M T Tetzlaff CT Osborn and D Crews ldquoIdentification of an isoform ofthe estrogen receptor messenger RNA lacking exon four andpresent in the brainrdquo Proceedings of the National Academy ofSciences of the United States of America vol 90 no 15 pp 7172ndash7175 1993

[80] R H Price Jr N Lorenzon and R J Handa ldquoDifferentialexpression of estrogen receptor beta splice variants in rat brainidentification and characterization of a novel variant missingexon 4rdquo Brain Research Molecular Brain Research vol 80 no2 pp 260ndash268 2000

[81] S Chu and P J Fuller ldquoIdentification of a splice variantof the rat estrogen receptor 120573 generdquo Molecular and CellularEndocrinology vol 132 no 1-2 pp 195ndash199 1997

[82] B Lu E Leygue H Dotzlaw L J Murphy L C Murphy andP H Watson ldquoEstrogen receptor-120573 mRNA variants in humanand murine tissuesrdquoMolecular and Cellular Endocrinology vol138 no 1-2 pp 199ndash203 1998

[83] T R Pak W C J Chung J L Roberts and R J HandaldquoLigand-independent effects of estrogen receptor 120573 on

ISRN Endocrinology 13

mouse gonadotropin-releasing hormone promoter activityrdquoEndocrinology vol 147 no 4 pp 1924ndash1931 2006

[84] T R Pak W C J Chung L R Hinds and R J HandaldquoEstrogen receptor-120573 mediates dihydrotestosterone-inducedstimulation of the arginine vasopressin promoter in neuronalcellsrdquo Endocrinology vol 148 no 7 pp 3371ndash3382 2007

[85] Y K Leung PMak S Hassan and SMHo ldquoEstrogen receptor(ER)-120573 isoforms a key to understanding ER-120573 signalingrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 103 no 35 pp 13162ndash13167 2006

[86] J M Wang X Hou S Adeosun et al ldquoA dominant negativeER120573 splice variant determines the effectiveness of early or lateestrogen therapy after ovariectomy in ratsrdquo PLoS One vol 7 no3 Article ID e33493 2012

[87] W C J Chung T R Pak S Suzuki W A Pouliot M EAndersen and R J Handa ldquoDetection and localization of anestrogen receptor beta splice variant protein (ER1205732) in theadult female rat forebrain and midbrain regionsrdquo Journal ofComparative Neurology vol 505 no 3 pp 249ndash267 2007

[88] R H Price Jr C A Butler P Webb R Uht P Kushner andR J Handa ldquoA splice variant of estrogen receptor 120573 missingexon 3 displays altered subnuclear localization and capacity fortranscriptional activationrdquo Endocrinology vol 142 no 5 pp2039ndash2049 2001

[89] Y Wang and R J Miksicek ldquoIdentification of a dominantnegative form of the human estrogen receptorrdquo MolecularEndocrinology vol 5 no 11 pp 1707ndash1715 1991

[90] E Kuppers and C Beyer ldquoExpression of estrogen receptor-120572and 120573 mRNA in the developing and adult mouse striatumrdquoNeuroscience Letters vol 276 no 2 pp 95ndash98 1999

[91] C Gundlah S G Kohama S J Mirkes V T Garyfallou H FUrbanski and C L Bethea ldquoDistribution of estrogen receptorbeta (ER120573) mRNA in hypothalamus midbrain and temporallobe of spayed macaque continued expression with hormonereplacementrdquo Brain Research Molecular Brain Research vol 76no 2 pp 191ndash204 2000

[92] Y Morishima P J M Murphy D-P Li E R Sanchez and WB Pratt ldquoStepwise assembly of a glucocorticoid receptorsdothsp90heterocomplex resolves two sequential ATP-dependent eventsinvolving first hsp70 and then hsp90 in opening of the steroidbinding pocketrdquo Journal of Biological Chemistry vol 275 no 24pp 18054ndash18060 2000

[93] K D Dittmar and W B Pratt ldquoFolding of the glucocorticoidreceptor by the reconstituted hsp90-based chaperone machin-eryThe initial hsp90sdotp60sdothsp70-dependent step is sufficient forcreating the steroid binding conformationrdquo Journal of BiologicalChemistry vol 272 no 20 pp 13047ndash13054 1997

[94] K I Kang X Meng J Devin-Leclerc et al ldquoThe molecularchaperone Hsp90 can negatively regulate the activity of aglucocorticosteroid-dependent promoterrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 4 pp 1439ndash1444 1999

[95] K Unno H Asakura Y Shibuya M Kaiho S Okada and NOku Naoto ldquoIncrease in basal level of Hsp70 consisting chieflyof constitutively expressed hsp70 (Hsc70) in aged rat brainrdquoJournals of Gerontology Series A vol 55 no 7 pp B329ndashB3352000

[96] U E Olazabal D W Pfaff and C V Mobbs ldquoSex differences inthe regulation of heat shock protein 70 kDa and 90 kDa in therat ventromedial hypothalamus by estrogenrdquo Brain Researchvol 596 no 1-2 pp 311ndash314 1992

[97] M A Pahlavani M D Harris S A Moore and A RichardsonldquoExpression of heat shock protein 70 in rat spleen lymphocytesis affected by age but not by food restrictionrdquo Journal ofNutrition vol 126 no 9 pp 2069ndash2075 1996

[98] A R Heydari B Wu R Takahashi R Strong and A Richard-son ldquoExpression of heat shock protein 70 is altered by age anddiet at the level of transcriptionrdquoMolecular andCellular Biologyvol 13 no 5 pp 2909ndash2918 1993

[99] M Sabbah K-I I Kang L Tora and G Redeuilh ldquoOestro-gen receptor facilitates the formation of preinitiation com-plex assembly involvement of the general transcription factorTFIIBrdquo Biochemical Journal vol 336 part 3 pp 639ndash646 1998

[100] S-Y Wu M C Thomas S Y Hou V Likhite and C-MChiang ldquoIsolation of mouse TFIID and functional character-ization of TBP and TFIID in mediating estrogen receptor andchromatin transcriptionrdquo Journal of Biological Chemistry vol274 no 33 pp 23480ndash23490 1999

[101] S Ghosh and M K Thakur ldquoTissue-specific expression ofreceptor-interacting protein in aging mouserdquo Age vol 30 no4 pp 237ndash243 2008

[102] J Frasor JM Danes B Komm K C N Chang C Richard Lyt-tle and B S Katzenellenbogen ldquoProfiling of estrogen up- anddown-regulated gene expression in human breast cancer cellsinsights into gene networks and pathways underlying estrogeniccontrol of proliferation and cell phenotyperdquo Endocrinology vol144 no 10 pp 4562ndash4574 2003

[103] J Frasor J M Danes C C Funk and B S Katzenellen-bogen ldquoEstrogen down-regulation of the corepressor N-CoRmechanism and implications for estrogen derepression of N-CoR-regulated genesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 102 no 37 pp13153ndash13157 2005

[104] N J McKenna and B W OrsquoMalley ldquoCombinatorial control ofgene expression by nuclear receptors and coregulatorsrdquoCell vol108 no 4 pp 465ndash474 2002

[105] T-P Yao G Ku N Zhou R Scully and D M Livingston ldquoThenuclear hormone receptor coactivator SRC-1 is a specific targetof p300rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 93 no 20 pp 10626ndash10631 1996

[106] B Hanstein R Eckner J DiRenzo et al ldquop300 is a componentof an estrogen receptor coactivator complexrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 93 no 21 pp 11540ndash11545 1996

[107] S Halachmi E Marden G Martin H MacKay C Abbon-danza and M Brown ldquoEstrogen receptor-associated proteinspossible mediators of hormone-induced transcriptionsrdquo Sci-ence vol 264 no 5164 pp 1455ndash1458 1994

[108] A J Horlein AM Naar T Heinzel et al ldquoLigand-independentrepression by the thyroid hormone receptor mediated by anuclear receptor co-repressorrdquo Nature vol 377 no 6548 pp397ndash404 1995

[109] J D Chen and R M Evans ldquoA transcriptional co-repressor thatinteracts with nuclear hormone receptorsrdquo Nature vol 377 no6548 pp 454ndash457 1995

[110] A Malovannaya R B Lanz S Y Jung et al ldquoAnalysis of thehuman endogenous coregulator complexomerdquoCell vol 145 no5 pp 787ndash799 2011

[111] Z Nawaz D M Lonard C L Smith et al ldquoThe Angelmansyndrome-associated protein E6-AP is a coactivator for thenuclear hormone receptor superfamilyrdquoMolecular and CellularBiology vol 19 no 2 pp 1182ndash1189 1999

14 ISRN Endocrinology

[112] B Zheng M Han M Bernier and J-K Wen ldquoNuclear actinand actin-binding proteins in the regulation of transcriptionand gene expressionrdquo FEBS Journal vol 276 no 10 pp 2669ndash2685 2009

[113] W A Hofmann L Stojiljkovic B Fuchsova et al ldquoActin is partof pre-initiation complexes and is necessary for transcription byRNA polymerase IIrdquoNature Cell Biology vol 6 no 11 pp 1094ndash1101 2004

[114] K Tokunaga T Shibuya Y Ishihama et al ldquoNucleocytoplasmictransport of fluorescent mRNA in living mammalian cellsnuclear mRNA export is coupled to ongoing gene transcrip-tionrdquo Genes to Cells vol 11 no 3 pp 305ndash317 2006

[115] R Metivier G Penot M R Hubner et al ldquoEstrogen receptor-120572 directs ordered cyclical and combinatorial recruitment ofcofactors on a natural target promoterrdquo Cell vol 115 no 6 pp751ndash763 2003

[116] C Ambrosino R Tarallo A Bamundo et al ldquoIdentification of ahormone-regulated dynamic nuclear actin network associatedwith estrogen receptor 120572 in human breast cancer cell nucleirdquoMolecular and Cellular Proteomics vol 9 no 6 pp 1352ndash13672010

[117] F Shao R Zhang L Dong and K Ying ldquoOverexpression ofgelsolin-like actin-capping protein is associated with progres-sion of lung adenocarcinomardquo Tohoku Journal of ExperimentalMedicine vol 225 no 2 pp 95ndash101 2011

[118] K Nishimura H-J Ting Y Harada et al ldquoModulation ofandrogen receptor transactivation by gelsolin a newly identi-fied androgen receptor coregulatorrdquo Cancer Research vol 63no 16 pp 4888ndash4894 2003

[119] J S Ahn I S Jang D I Kim et al ldquoAging-associated increaseof gelsolin for apoptosis resistancerdquoBiochemical and BiophysicalResearch Communications vol 312 no 4 pp 1335ndash1341 2003

[120] I Nalvarte T Schwend and J-A Gustafsson ldquoProteomicsanalysis of the estrogen receptor 120572 receptosomerdquoMolecular andCellular Proteomics vol 9 no 7 pp 1411ndash1422 2010

[121] L-H Miau C-J Chang B-J Shen W-H Tsai and S-C LeeldquoIdentification of heterogeneous nuclear ribonucleoprotein K(hnRNPK) as a repressor ofCEBP120573-mediated gene activationrdquoJournal of Biological Chemistry vol 273 no 17 pp 10784ndash107911998

[122] A Ostareck-Lederer D H Ostareck C Cans et al ldquoc-Src-mediated phosphorylation of hnRNP K drives translationalactivation of specifically silenced mRNAsrdquo Molecular and Cel-lular Biology vol 22 no 13 pp 4535ndash4543 2002

[123] P S Bagga G K Arhin and J Wilusz ldquoDSEF-1 is a member ofthe hnRNP H family of RNA-binding proteins and stimulatespre-mRNAcleavage and polyadenylation in vitrordquoNucleic AcidsResearch vol 26 no 23 pp 5343ndash5350 1998

[124] V Markovtsov J M Nikolic J A Goldman C W Turck M-Y Chou and D L Black ldquoCooperative assembly of an hnRNPcomplex induced by a tissue-specific homolog of polypyrimi-dine tract binding proteinrdquoMolecular and Cellular Biology vol20 no 20 pp 7463ndash7479 2000

[125] S Y Jung A Malovannaya J Wei B W OrsquoMalley and J QinldquoProteomic analysis of steady-state nuclear hormone receptorcoactivator complexesrdquoMolecular Endocrinology vol 19 no 10pp 2451ndash2465 2005

[126] W Hong R J Resnick C Rakowski D Shalloway S J Taylorand G A Blobel ldquoPhysical and functional interaction betweenthe transcriptional cofactor CBP and the KH domain proteinSam68rdquoMolecular Cancer Research vol 1 no 1 pp 48ndash55 2002

[127] R ShaoXWang BWeijdegard et al ldquoCoordinate regulation ofheterogeneous nuclear ribonucleoprotein dynamics by steroidhormones in the human fallopian tube and endometrium invivo and in vitrordquo American Journal of Physiology vol 302 no10 pp E1269ndashE1282 2012

[128] C SWoolley and B SMcEwen ldquoEstradiolmediates fluctuationin hippocampal synapse density during the estrous cycle in theadult ratrdquo Journal of Neuroscience vol 12 no 7 pp 2549ndash25541992

[129] C S Woolley H J Wenzel and P A Schwartzkroin ldquoEstradiolincreases the frequency of multiple synapse boutons in thehippocampal CA1 region of the adult female ratrdquo The Journalof Comparative Neurology vol 373 no 1 pp 108ndash117 1996

[130] C S Woolley ldquoEstrogen-mediated structural and functionalsynaptic plasticity in the female rat hippocampusrdquo Hormonesand Behavior vol 34 no 2 pp 140ndash148 1998

[131] D P Srivastava K M Woolfrey K A Jones et al ldquoRapidenhancement of two-step wiring plasticity by estrogen andNMDA receptor activityrdquo Proceedings of the National Academyof Sciences of the United States of America vol 105 no 38 pp14650ndash14655 2008

[132] M Ogiue-Ikeda N Tanabe H Mukai et al ldquoRapid modu-lation of synaptic plasticity by estrogens as well as endocrinedisrupters in hippocampal neuronsrdquo Brain Research Reviewsvol 57 no 2 pp 363ndash375 2008

[133] N J Sandstrom and C L Williams ldquoSpatial memory retentionis enhanced by acute and continuous estradiol replacementrdquoHormones and Behavior vol 45 no 2 pp 128ndash135 2004

[134] E Hogervorst J Williams M Budge W Riedel and JJolles ldquoThe nature of the effect of female gonadal hormonereplacement therapy on cognitive function in post-menopausalwomen a meta-analysisrdquo Neuroscience vol 101 no 3 pp 485ndash512 2000

[135] M E Bailey A C J Wang J Hao et al ldquoInteractive effects ofage and estrogen on cortical neurons implications for cognitiveagingrdquo Neuroscience vol 191 pp 148ndash158 2011

[136] A A Walf M E Rhodes and C A Frye ldquoOvarian steroidsenhance object recognition in naturally cycling and ovariec-tomized hormone-primed ratsrdquo Neurobiology of Learning andMemory vol 86 no 1 pp 35ndash46 2006

[137] V N Luine L F Jacome and N J Maclusky ldquoRapid enhance-ment of visual and place memory by estrogens in ratsrdquoEndocrinology vol 144 no 7 pp 2836ndash2844 2003

[138] L Fan Z Zhao P T Orr C H Chambers M C Lewis and KM Frick ldquoEstradiol-induced object memory consolidation inmiddle-aged femalemice requires dorsal hippocampal extracel-lular signal-regulated kinase and phosphatidylinositol 3-kinaseactivationrdquo Journal of Neuroscience vol 30 no 12 pp 4390ndash4400 2010

[139] D B Dubal and PMWise ldquoNeuroprotective effects of estradiolin middle-aged female ratsrdquo Endocrinology vol 142 no 1 pp43ndash48 2001

[140] S-H Yang J Shi A L Day and J W Simpkins ldquoEstradiolexerts neuroprotective effects when administered after ischemicinsultrdquo Stroke vol 31 no 3 pp 745ndash750 2000

[141] J W Simpkins G Rajakumar Y-Q Zhang et al ldquoEstrogensmay reduce mortality and ischemic damage caused by middlecerebral artery occlusion in the female ratrdquo Journal of Neuro-surgery vol 87 no 5 pp 724ndash730 1997

[142] J Shi K S Panickar S-H Yang O Rabbani A L Day and JWSimpkins ldquoEstrogen attenuates over-expression of 120573-amyloid

ISRN Endocrinology 15

precursor protein messager RNA in an animal model of focalischemiardquo Brain Research vol 810 no 1-2 pp 87ndash92 1998

[143] Q-H Zhang Y-H Huang Y-Z Hu et al ldquoDisruption ofestrogen receptor beta in mice brain results in pathologicalalterations resemblingAlzheimer diseaserdquoActa PharmacologicaSinica vol 25 no 4 pp 452ndash457 2004

[144] E F Rissman A L Heck J E Leonard M A Shupnik and J-A Gustafsson ldquoDisruption of estrogen receptor 120573 gene impairsspatial learning in female micerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no6 pp 3996ndash4001 2002

[145] M Day A Sung S Logue M Bowlby and R Arias ldquoBetaestrogen receptor knockout (BERKO) mice present attenuatedhippocampal CA1 long-term potentiation and related memorydeficits in contextual fear conditioningrdquo Behavioural BrainResearch vol 164 no 1 pp 128ndash131 2005

[146] R Vierk G Glassmeier L Zhou et al ldquoAromatase inhibitionabolishes LTP generation in female but not in male micerdquo TheJournal of Neuroscience vol 32 no 24 pp 8116ndash8126 2012

[147] R-M Vouimba M R Foy J G Foy and R FThompson ldquo17120573-estradiol suppresses expression of long-term depression in agedratsrdquo Brain Research Bulletin vol 53 no 6 pp 783ndash787 2000

[148] C E Andreescu B A Milojkovic E D Haasdijk et alldquoEstradiol improves cerebellar memory formation by activatingestrogen receptor 120573rdquo Journal of Neuroscience vol 27 no 40 pp10832ndash10839 2007

[149] Y-Y Huang P V Nguyen T Abel and E R Kandel ldquoLong-lasting forms of synaptic potentiation in the mammalian hip-pocampusrdquo Learning Memory vol 3 no 2-3 pp 74ndash85 1996

[150] H Mukai T Tsurugizawa G Murakami et al ldquoRapid mod-ulation of long-term depression and spinogenesis via synapticestrogen receptors in hippocampal principal neuronsrdquo Journalof Neurochemistry vol 100 no 4 pp 950ndash967 2007

[151] L Liu T P Wong M F Pozza et al ldquoRole of NMDA receptorsubtypes in governing the direction of hippocampal synapticplasticityrdquo Science vol 304 no 5673 pp 1021ndash1024 2004

[152] M Cyr O Ghribi C Thibault M Morissette M Landry andT di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[153] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[154] C C Smith and L L McMahon ldquoEstradiol-induced increasein the magnitude of long-term potentiation is prevented byblocking NR2B-containing receptorsrdquo Journal of Neurosciencevol 26 no 33 pp 8517ndash8522 2006

[155] Y Zhou J J Watters and D M Dorsa ldquoEstrogen rapidlyinduces the phosphorylation of the cAMP response elementbinding protein in rat brainrdquo Endocrinology vol 137 no 5 pp2163ndash2166 1996

[156] XGonda T TelekG Juhasz J Lazary AVargha andG BagdyldquoPatterns of mood changes throughout the reproductive cyclein healthy women without premenstrual dysphoric disordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 32 no 8 pp 1782ndash1788 2008

[157] E W Freeman ldquoPremenstrual syndrome and premenstrualdysphoric disorder definitions and diagnosisrdquo Psychoneuroen-docrinology vol 28 supplement 3 pp 25ndash37 2003

[158] T D Lund T Rovis W C J Chung and R J Handa ldquoNovelactions of estrogen receptor-120573 on anxiety-related behaviorsrdquoEndocrinology vol 146 no 2 pp 797ndash807 2005

[159] N Breslau L Schultz and E Peterson ldquoSex differences indepression a role for preexisting anxietyrdquo Psychiatry Researchvol 58 no 1 pp 1ndash12 1995

[160] P E Bebbington G Dunn R Jenkins et al ldquoThe influenceof age and sex on the prevalence of depressive conditionsreport from the National Survey of Psychiatric MorbidityrdquoPsychological Medicine vol 28 no 1 pp 9ndash19 1998

[161] G Aguilera J P Harwood and J X Wilson ldquoMechanisms ofaction of corticotropin-releasing factor and other regulators ofcorticotropin release in rat pituitary cellsrdquo Journal of BiologicalChemistry vol 258 no 13 pp 8039ndash8045 1983

[162] A Papadimitriou and K N Priftis ldquoRegulation of thehypothalamic-pituitary-adrenal axisrdquo NeuroImmunoModula-tion vol 16 no 5 pp 265ndash271 2009

[163] S Suzuki and R J Handa ldquoRegulation of estrogen receptor-120573expression in the female rat hypothalamus differential effectsof dexamethasone and estradiolrdquo Endocrinology vol 145 no 8pp 3658ndash3670 2004

[164] W J S Miller S Suzuki L K Miller R Handa and R M UhtldquoEstrogen receptor (ER)120573 isoforms rather than ER120572 regulatecorticotropin-releasing hormone promoter activity through analternate pathwayrdquo Journal of Neuroscience vol 24 no 47 pp10628ndash10635 2004

[165] C IsgorM CecchiM Kabbaj H Akil and S JWatson ldquoEstro-gen receptor 120573 in the paraventricular nucleus of hypothalamusregulates the neuroendocrine response to stress and is regulatedby corticosteronerdquo Neuroscience vol 121 no 4 pp 837ndash8452003

[166] M L Forsling I Kallo D E Hartley et al ldquoOestrogen receptor-120573 and neurohypophysial hormones functional interaction andneuroanatomical localisationrdquo Pharmacology Biochemistry andBehavior vol 76 no 3-4 pp 535ndash542 2003

[167] A S Lalmansingh and R M Uht ldquoEstradiol regulatescorticotropin-releasing hormone gene (crh) expression in arapid and phasic manner that parallels estrogen receptor-120572 and-120573 recruitment to a 3101584051015840-cyclic adenosine 51015840- monophosphateregulatory region of the proximal crh promoterrdquo Endocrinologyvol 149 no 1 pp 346ndash357 2008

[168] B N Roy R L Reid and D A van Vugt ldquoThe effects ofestrogen and progesterone on corticotropin-releasing hormoneand arginine vasopressin messenger ribonucleic acid levelsin the paraventricular nucleus and supraoptic nucleus of therhesus monkeyrdquo Endocrinology vol 140 no 5 pp 2191ndash21981999

[169] X Ni R C Nicholson B R King E-C Chan M A Read andR Smith ldquoEstrogen represses whereas the estrogen-antagonistICI 182780 stimulates placental CRH gene expressionrdquo Journalof Clinical Endocrinology and Metabolism vol 87 no 8 pp3774ndash3778 2002

[170] N C Vamvakopoulos and G P Chrousos ldquoEvidence of directestrogenic regulation of human corticotropin-releasing hor-mone gene expression Potential implications for the sexualdimophism of the stress response and immuneinflammatoryreactionrdquo Journal of Clinical Investigation vol 92 no 4 pp1896ndash1902 1993

[171] Y Hu D L Wu C X Luo et al ldquoHippocampal nitric oxidecontributes to sex difference in affective behaviorsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 35 pp 14224ndash14229 2012

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

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Disease Markers

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OncologyJournal of

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Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

6 ISRN Endocrinology

than ER120573 and importantly less clear is how ER120573 mediatesligand-independent transcription In addition to the well-established ER interaction partners many novel interactingproteins have not yet been characterized and could be criticalfor nuclear processes not limited to gene transcription

8 HSPs and Chaperone Proteins

According to the classical two-step hypothesis inactivenuclear receptors are constantly accompanied and protectedfrom degradation by a number of chaperone proteins typi-cally members of the heat-shock protein (HSP) family Thisreceptorchaperone complex has been studied extensivelyand while the idea of a protective role for chaperones is wellsupported this complex can also perform other functionsFor instance HSPER complexes can serve to preactivatea hormone receptor by forcing a conformational changein ER such that it is able to bind its cognate hormoneThe initial HSP complex consists of the ER HSP70 andHSP70-interacting protein (HiP) as well as other accessoryand scaffolding proteins [92] HSP90 is recruited to thecomplex andHSP70 dissociates creating thematureHSPERcomplex [93] HSP90 induces a conformational change in thenuclear receptor and the ER is released from the complexready to dimerize and bind DNA or other transcriptionfactors to regulate gene transcription However some studiessuggest that HSPs could have a broader role than originallythought For example in Drosophila HSPs are required forDNA binding and in some instances they may regulateNR action [94] Interestingly aging and E

2can alter HSP70

in a cell-type specific manner [95ndash98] However recentdata from our lab (Table 1) demonstrated that HSP70 morereadily associates with ER120573 in aged female hippocampusfollowing E

2treatment compared to the young ones in which

HSP70ER120573 association decreased following E2treatment

We also observed no significant changes in HSP70 or ER120573expression suggesting that changes in the HSP70ER120573 inter-action with age in response to E

2change are a result of E

2

responsiveness andor activation of ER120573

9 Transcriptional Proteins and ERs

The process of transcribing DNA into RNA is a systematicprocess that involves multiprotein complexes binding toDNA modifying histone marks and initiating RNA synthe-sis ER120572 but not ER120573 has been shown to directly interactwith TFIIB IIE IIF and TIID proteins that initiate tran-scription [99 100] However experimental evidence from co-immunoprecipitation studies has demonstrated interactionsbetween ER120573 coregulatory proteins as well as other tran-scription factors Coregulatory proteins are transcriptionalaccessory proteins that enhance or repress transcription oftarget genes In general coactivators enhance gene tran-scription whereas corepressors block it However recentdata suggest that seemingly nontranscriptional proteins mayhave context-dependent coregulatory functions Importantly

certain coregulators can also be governed by age and E2[101ndash

103] thus recent discoveries imply that ER-mediated generegulation is not as well understood as previously thought

The best studied and well-established group of coregula-tory proteins that selectively associate with NRs is the steroidreceptor coactivator (SRCp160) family The SRC family iscomposed of three members SRC-1 SRC-2 and SRC-3all of which contain canonical LxxLL motifs known as thenuclear receptor (NR) box This motif interacts with AF-2 domains in ER120573 as well as other NR family memberssuch as glucocorticoid receptor (GR) progesterone receptor(PR) thyroid hormone receptor (TR) and ER120572 [104] SRCmembers have intrinsic histone acetyltransferase activity(HAT DNA activating) and interact with CREB-bindingprotein (CBP) [105] CBPp300 proteins are also coactivatorsthat have intrinsic HAT activity and can recruit ASC-2and other known coregulatory proteins [106] Confirmedcoregulatory interaction partners for several NRs that donot belong to the SRC family include estrogen-receptor-association protein (ERAP 140) [107] nuclear corepressor(NCoR) [108] silencing mediator of retinoic acid and thy-roid hormone receptor (SMRT) [109] and many othersAs is the case with our understanding of ER120573 interactionswith basic transcriptional machinery studies investigatingER120573coregulator interactions are sparse which may be dueto uniquely challenging issues associated with ER120573 such as alack of high-fidelity biochemical tools complicated structuralproperties and or pleiotropic physiological actions that arespecific to ER120573

In 2010 Anna Ma lovannaya and colleagues directeda high-throughput study (not including ER120573) aiming atcompiling a database for the endogenous coregulator poolldquonuclear receptor complexomerdquo [110] In this study a numberof novel protein interactions were identified and studiessuch as these are identifying proteins as ldquocoregulatorsrdquo thathad been previously thought to serve completely differentfunctionsOne group of relatively novel coregulatory proteinsare the E3 ubiquitin-protein ligases such as E6-associatedproteins (E6-AP) [111] While these proteins were thought toserve primarily as ubiquitin-conjugating enzymes they haverecently been highlighted as transcriptional enhancers ofNR-mediated activity independent of ligase function Similarlya group of E3-ligases that conjugate small ubiquitin likemodifier (SUMO) proteins to a target protein called PIASare also now considered NR coregulators and they utilize atypical LxxLLmotif In one study a decrease in ER expressionfollowing LTED or with advanced age coincided with anincrease in ER association with an E3-ubiquitin ligase CHIP[11] Together these newly described roles for HSPs and E3ligases raise novel questions about estrogen signaling such aswhen is an E3-ligaseER complex targeted for transcriptionalregulation versus degradation Also when are HSPs merelyperforming a chaperoneprotective function versus directingtranscriptional processes Future efforts aiming at elucidatingthe complexity of age-related changes in receptor structureand recruitment of coregulatory proteins could provideimportant insight into these seemingly paradoxical findings

ISRN Endocrinology 7

Table 1 Protein interactions with ER120573 were altered by age and 1198642 Selected proteins that were significantly altered (119875 lt 005) in their

association with ER120573 depending on age and 1198642treatment Experimental paradigm young (3 month) and aged (18 month) female Fischer 344

rats were ovariectomized and hormone deprived for 7 days Following deprivation animals were administered 25120583gkg 1198642(plasma levels =

7945 plusmn 225 pgmL) or vehicle (safflower oil) via subcutaneous injection onceday for 3 days Nuclear protein was isolated from the ventralhippocampus and coimmunoprecipitated for ER120573 (a beam 14C8) and associated proteins Protein interactions were identified and quantifiedusing 2D-DIGEDeCyder and ESI MSMS YV = young + vehicle YE = young + 119864

2 AV = aged + vehicle AE = aged + 119864

2

Accession noMolecularweight(Kda)

Estimatedisoelectricpoint

PEAKSscore Coverage ID

Interaction with ER120573FunctionYoung

vehicleYoung1198642

Agedvehicle

Aged1198642

gi| 149038929 80 575 494 643 Gelsolin mdash uarr mdash mdashActin-binding

coactivator

gi| 116242507 75 597 93 1458 Heat-shock protein70 mdash darr mdash uarr Chaperone

gi| 120538378 47 57 932 1072

Heterogeneousnuclear

ribonucleoproteinH12

mdash uarr mdash mdash RNA splicing

10 Nuclear Actin Setting the Stage

Coregulatory interactions may be poised upon a bed ofnuclear actin which has recently been identified as a dynamicmolecular stage for which many nuclear processes are per-formed such as transcription chromatin remodeling mRNAprocessing and nuclear importexport The general eventsthat initiate transcription are well established however theprocess by which all of the molecular components are tem-porally layered into a complex is still unclear Nuclear actin isessential in forming the preinitiation complex on a promoterelongation and RNP organization as well as remodeling ofchromatin [112ndash114] and as mentioned previously ERs arealso key factors in these processes In one study ER120572 and120573-actin were coimmunoprecipitated on the E

2responsive

pS2TFF1 promoter indicating that ER and nuclear actinmay work in concert to regulate transcriptional processesunder control of estrogens [115] The interaction betweenERs and actin is not yet fully investigated but data fromour lab (unpublished observations) and others [116] implythat both ER120572 and ER120573may utilize nuclear actin to performvarious functions Another actin-binding protein gelsolincaps actin filament ends and it has been shown to be anNR coactivator [117 118] Gelsolin may assist in actin poly-merization allowing transcriptionalmachinery to be broughtin proximity of target genes however it remains unclearhow gelsolin enhances ARER transcriptional activity Datafrom our lab indicate that gelsolinER120573 interactions increasewith E

2treatment in young but not aged animals (Table 1)

Gelsolin has been shown to increase with age [119] but alack of significant interaction with ER120573 despite increasedexpression of gelsolin could again suggest an alteration inER120573 function with age

Actin is also commonly associated with ubiquitous mul-tifunctional RNA-binding proteins such as heterologousnuclear riboproteins (hnRNPs) which also associate withERs [120] hnRNPs associate within the matrix of nuclearactin accompany transcripts out of the nucleus participatein alternative splicing and can modulate transcription [121]

Phosphorylated hnRNPK has been shown to mediate trans-lation of specific mRNAs [122] and hnRNPH is involvedin splicing and mRNA polyadenylation [123 124] In thepast the association of NRs with hnRNPs was thought to benonspecific due to the ubiquitous nature of these proteinsbut recent studies are no longer ruling out an importantinteraction between NRs and hnRNPs that may assist intranscription andor splicing [125 126] Data from our laband others demonstrate a dynamic interaction between bothER120572 and ER120573 and hnRNPs (Table 1) and furthermore datademonstrated that E

2might regulate expression of members

of the hnRNP family [127] As noted previously age-relatedincreases in splicing could lead to aberrant signaling not onlyfor E2-mediated processes but also for cellular processes in

generalNuclear ER interaction partners have historically been a

distinct class of nuclear receptor coregulators that seemedto solely assist ERs in gene transcription however thenumber of interaction partners for ERs is increasing Furtherinvestigation into ER120573-associated proteins is required as faras NRs are concerned data specific to ER120573 are inadequateto make broad conclusions Moreover post-translationalmodifications to coregulatory proteins ERs or changes intheir expression patterns due to age or sustained estrogendeprivation could all contribute to an altered microenviron-ment setting the stage for atypical estrogen signaling upontherapeutic reinstatement of hormones (Figure 3)

11 Estrogens and Cognition

Most empirical and observational data give merit to theidea that estrogens have a positive effect on cognitiveprocesses increased spine densities [128 129] enhancedsynaptic plasticity [130ndash132] and improved memory [133134] however the particular receptor(s) and the mechanismsthat regulate these processes remain unclear There are amyriad of behavioral studies suggesting that E

2enhances

prefrontal cortex (PFC) and hippocampal-dependent tasks

8 ISRN Endocrinology

Factor BER structureand function

Factor Ccoregulatory and

transcriptional interactions

120573

120573120573

120573

120572

120572

120572 120572

V

V

V

V

V

V

V

V

ESR1

ESR2

Age and E2

++

Context-dependentER-regulated

gene expression

Factor Atissue-specific

ER gene expression

Figure 3 Age and hormonalmilieu exponentially increase the potential diversity of estrogen receptor signaling leading to context-dependentgene regulation Age and E

2influence ER gene expression alternative splicing coregulatory protein expression and interaction which

ultimately direct ER-target gene transcription

For example long-term E2deprivation diminished aged

female rhesus macaquesrsquo performance in a delayed responsetask a PFC- dependent task [135] E

2also enhanced object

recognition under a number of different paradigms [136ndash138] and there are also multiple lines of evidence supportingE2-mediated neuroprotection which may be important for

cognition especially after stroke [139ndash142]Pharmacological targeting of the receptors with ER selec-

tive ligands has been a standard method for investigating thebehavioral physiological and cellular actions of E

2mediated

distinctly throughER120572 andor ER120573 however valuable insighthas also come from the ER120573-null (120573ERKO) mice 120573ERKOmice have significantly fewer neurons in the cortex hypotha-lamus amygdala and ventral tegmental area compared toWTThey also exhibit neuronal shrinkage and hyperprolifer-ation of glia by 3 months of age as well as having high levelsof apoE and apoE-dependent deposition of amyloid plaquesthroughout the CNS by 12 months of age [143] These micealso demonstrate spatial learning deficits in the Morris watermaze [144] and a decrease in hippocampal- and amygdala-dependent memory in a fear-conditioning paradigm that isaccompanied by decreased synaptic plasticity in hippocampalslice preparations [145] The critical role of ER120573 in higher-level brain functions has been deduced from these studiesand others warranting a full investigation of the wide-spreadmolecular actions of E

2known to contribute to cellular

processes on at least two levels at the synapse and on thegenome

Long-term potentiation (LTP) is an important compo-nent of learning and memory It represents an increasein synaptic transmission and plasticity that underlies cog-nitive behaviors and it is readily altered by E

2in many

circumstances In fact application of an aromatase inhibitoreliminates CA LTP generated by theta-burst stimulation inintact female neurons but not male or OVX animals posinga potentially serious concern for women using aromataseinhibitors for therapeutic treatment of breast cancer [146] E

2

can also enhance or suppress long-term depression (LTD)reducing synaptic transmission which may be dependentupon the specific receptors involved In aged male CA1cells E

2decreased LTD [147] however E

2enhanced LTP in

the cerebellum where ER120573 is the predominately expressedcognate receptor [148]

Although the majority of studies on cognitive processfocus on the rapid effects of E

2 late-phase long-term potenti-

ation (L-LTP) depends upon transcription and translation ofnewmRNA [149] to sustain an increase in synaptic transmis-sion E

2has been shown to regulate LTP in CA1 pyramidal

cells [150] over the span of 48 hours and this regulationappears to be dependent upon a higher ratio of NMDARrelative to AMPAR LTP induction requires activation ofNR2A-containing NMDARs however increased expressionof NR2B potentiates LTP magnitude [151] Notably E

2

increased expression of NR2B mRNA and NR2B expressionat the synapse [152 153] and the E

2-induced increase in

LTP can be abolished by blocking NR2B receptors [154]

ISRN Endocrinology 9

suggesting a transcriptional role for ERs in synaptic plasticityMoreover E

2application may increase CREB expression and

the amount of phosphorylated CREB in regions such as theamygdala [155] and BNST [117 155] which may be critical inthe formation of long-term memories Taken together thesedata demonstrate that E

2regulates neuronal plasticity and

memory through its original role as a transcription factor andalso by acting as a general intracellular signaling moleculethrough regulation of NMDARs and CREB However todate there are little data on the mechanisms by which ER120573regulates these processes or how the same principles ofplasticity may apply to other neurological issues

12 Estrogens and Mood Regulation

A range of behavioral experiments indicate that E2mod-

ulation of stress mood and affect is a complex storywith considerable conflicting data that may as in otherprocesses be explained in part by distinct roles for ER120572 andER120573 Anecdotally many women report mood fluctuationsas corresponding to changes in circulating estrogen levelssuch as what occurs during the menstrual cycle peripubertypostpartum and peripostmenopause Incidence of anxietyand depression are observed at perimenopause and whenhormone levels are fluctuating [156 157] However E

2can

also exhibit anxiogenic properties and often anxiety anddepression present in a comorbid fashion especially inwomen [158 159] Interestingly after the age of 55 bouts ofdepression and anxiety appear to decrease in women [160]As previously mentioned perimenopausal women receivingCEE in the KEEPs study reported an improvement in moodand the primary actions of CEE tend to be mediated throughER120573 [20] A plethora of behavioral studies has mountedin response to observational reports and at first glance itappears that ER120573 has an anxiolytic and antidepressive rolehowever there is still an immense void to be filled withrespect to biochemical and molecular mechanisms of ER120573and affective disorders Elucidating the precise molecularmechanisms that require ER120573 in plasticity and neurotrans-mitter processing in brain regions regulating these behaviorswill help clarify the role of E

2in stress- and mood-related

processesContemporary hypotheses concerning the onset of affec-

tive disorders revolve around perturbations to the cen-tral processing of environmental stress The hypothalamic-pituitary-adrenal (HPA) axis is the 3-tiered hierarchicalbiological system that mediates physical or psychologicalresponse to stressors The primary steroid regulating theHPA axis is cortisolcorticosterone (humansrats CORT) aglucocorticoid receptor (GR) ligand that is produced fromthe adrenals to exert negative feedback upon the HPAsystem to effectively modulate response to stressors Theparaventricular nucleus of hypothalamus (PVN) producestwo neuropeptides corticotropin-releasing hormone (CRH)and arginine vasopressin (AVP) to activate the HPA axisCRF and AVP synergistically stimulate release of adreno-corticotropic hormone (ACTH) from the anterior pituitarywhich acts on the adrenal cortex to produce CORT CORT

binds GR and negatively regulates CRF and AVP expressionsand releases through classical negative feedback mechanisms[161 162] ER120573 is themain ER expressed in the PVN [158 163ndash165] and regulation of AVP is an interesting example of howER action can vary AVP expression fluctuates during themenstrual cycle and is usually highest when E

2is low In fact

oral contraceptives appear to decrease AVP expression andE2is thought to inhibit AVP in the human SON [166] In

the rodent system ER120573 and its splice variants activate therodent AVP promoter independent of ligand [84] howeverthe human promoter is repressed by ER120573 and splice variantsThis discrepancy between the human and rat wasmediated byan AP-1 response element on the human AVP promoter thatis not present in the rat Importantly ER120573 acted similarly inthe two systems when the AP-1 sequence was deleted fromthe human promoter underscoring the striking alterationsthat small changes in DNA sequence can invoke in E

2

signaling pathways and the importance of understanding theexperimental context upon which such conclusions are based[77] On the contrary rat and human CRF expression wasincreased in response to E

2in rodent monkey and human

hypothalamus but it was inhibited in the placenta [167ndash170]In addition to AVP and CRF glutamatergic and GABAer-

gic projects from regions like the BNST AMY PFC andhippocampus all express ER120573 [45 46] and are likely targetsfor E2to exert effects on the HPA axis Moreover decreased

ER120573 mRNA in postmortem locus coeruleus has been foundto correlate with suicide [13] and even more recentlyER120573-mediated hippocampal nitric oxide levels have beenimplicated in affective behaviors in females but not males[171] Neurotransmitter release from these regions influencesmood affect and stress responses and E

2increases the rate

of monoamine oxidase degradation and serotonin transportwhich enhances serotonin at the synapse E

2also increases

serotonin receptor expression [172 173] Dopamine andserotonin [174] are diminished in the BNST POA and hip-pocampus and caudate putamen (dopamine) of 120573ERKOmice[174] further implicating an important role for ER120573 in theregulation of emotion and mood 120573ERKO mice also displayserious morphological and functional abnormalities in thebrain that correlate to increased depression and anxiety [12175ndash178] In addition to 120573ERKO studies administration ofER120573 selective agonists (diarylpoprionitrile DPN) decreasesboth stress markers and anxiety-related behaviors in rats[158] In fact there have been several studies implicatingER120573 and its variants in affective behaviors but the molecularmechanisms remain poorly understood

13 Summary

Estrogen-receptor-mediated signaling in the brain regulatesneurological processes many of which translate to cog-nitive and affective behavioral outputs When estrogen isdeclining and becomes replete as in menopause a num-ber of neurophysiological changes occur producing someunwanted changes The most common and logical remedyis replacement of bioidentical hormone E

2 however this

treatment can be problematic depending upon the length

10 ISRN Endocrinology

of time a woman has been in a postmenopausal estrogen-deprived state This suggests that there is a molecular switchin estrogen-mediated signaling that may allow for drasticchange in ER signaling not to mention the interaction of E

2

signaling components and the natural aging process Thesechanges are likely to include alterations to receptor profilesincluding expression of alternatively spliced variants thatrespond differently to E

2 changes in the cellular microenvi-

ronment that can alter the proteinprotein associations whichultimately leads to changes in ER-mediated gene transcrip-tion and synaptic transmission ER120573 in particular is widelyexpressed and implicated positively in the regulation ofmemory and mood fluctuations two of the most commonlyreported neurological issues in postmenopausal women Itis important to understand the actions of ER120573 in the areasregulating these processes to identify what when how andfor whom hormone therapy may be a useful treatment torectify cognitive and affective issues

Acknowledgments

This work was supported by NIA RO1 AG033605-01 andNIH T32 AG031780 The authors N N Mott and T R Pakhave nothing to disclose

References

[1] C Bengtsson O Lindquist and L Redvall ldquoIs the menopausalage rapidly changingrdquoMaturitas vol 1 no 3 pp 159ndash164 1979

[2] A Singh S Kaur and I Walia ldquoA historical perspective onmenopause andmenopausal agerdquo Bulletin of the Indian Instituteof History of Medicine (Hyderabad) vol 32 no 2 pp 121ndash1352002

[3] P Verhaeghen and J Cerella ldquoAging executive control andattention a review of meta-analysesrdquo Neuroscience and Biobe-havioral Reviews vol 26 no 7 pp 849ndash857 2002

[4] T E Wroolie H A Kenna K E Williams et al ldquoDifferencesin verbal memory performance in postmenopausal womenreceiving hormone therapy 17120573-estradiol versus conjugatedequine estrogensrdquoAmerican Journal of Geriatric Psychiatry vol19 no 9 pp 792ndash802 2011

[5] B B Sherwin ldquoEstrogenic effects on memory in womenrdquoAnnals of the New York Academy of Sciences vol 743 pp 213ndash230 1994

[6] B B Sherwin ldquoHormones mood and cognitive functioning inpostmenopausal womenrdquoObstetrics andGynecology vol 87 no2 supplement pp 20Sndash26S 1996

[7] B B Sherwin ldquoSex hormones and psychological functioning inpostmenopausalwomenrdquoExperimentalGerontology vol 29 no3-4 pp 423ndash430 1994

[8] SM Phillips and B B Sherwin ldquoEffects of estrogen onmemoryfunction in surgically menopausal womenrdquo Psychoneuroen-docrinology vol 17 no 5 pp 485ndash495 1992

[9] R Lindsay J M Aitken and J B Anderson ldquoLong term pre-vention of postmenopausal osteoporosis by oestrogen Evidencefor an increased bone mass after delayed onset of oestrogentreatmentrdquoThe Lancet vol 1 no 7968 pp 1038ndash1040 1976

[10] J E Rossouw R L Prentice J E Manson et al ldquoPost-menopausal hormone therapy and risk of cardiovascular dis-ease by age and years since menopauserdquo The Journal of the

American Medical Association vol 297 no 13 pp 1465ndash14772007

[11] Q-G Zhang D Han R-M Wang et al ldquoC terminusof Hsc70-interacting protein (CHIP)-mediated degradationof hippocampal estrogen receptor-120572 and the critical periodhypothesis of estrogen neuroprotectionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 108 no 35 pp E617ndashE624 2011

[12] W Krezel S Dupont A Krust P Chambon and P F ChapmanldquoIncreased anxiety and synaptic plasticity in estrogen receptor120573-deficient micerdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 21 pp 12278ndash12282 2001

[13] H Ostlund E Keller and Y L Hurd ldquoEstrogen receptor geneexpression in relation to neuropsychiatric disordersrdquo Annals ofthe New York Academy of Sciences vol 1007 pp 54ndash63 2003

[14] S A Shumaker C Legault S R Rapp et al ldquoEstrogen plusprogestin and the incidence of dementia and mild cognitiveimpairment in postmenopausal women the Womenrsquos HealthInitiative Memory Study a randomized controlled trialrdquo Jour-nal of the American Medical Association vol 289 no 20 pp2651ndash2662 2003

[15] S A Shumaker C Legault L Kuller et al ldquoConjugated equineestrogens and incidence of probable dementia and mild cog-nitive impairment in postmenopausal women womenrsquos HealthInitiative Memory Studyrdquo Journal of the American MedicalAssociation vol 291 no 24 pp 2947ndash2958 2004

[16] S R Rapp M A Espeland S A Shumaker et al ldquoEffect ofestrogen plus progestin on global cognitive function in post-menopausal women the Womenrsquos Health Initiative MemoryStudy a randomized controlled trialrdquo Journal of the AmericanMedical Association vol 289 no 20 pp 2663ndash2672 2003

[17] VWHenderson K S Benke R C Green L A Cupples and LA Farrer ldquoPostmenopausal hormone therapy and Alzheimerrsquosdisease risk interaction with agerdquo Journal of Neurology Neuro-surgery and Psychiatry vol 76 no 1 pp 103ndash105 2005

[18] E Garbe and S Suissa ldquoHormone replacement therapy andacute coronary syndromes methodological issues betweenrandomized and observational studiesrdquo Human Reproductionvol 19 no 1 pp 8ndash13 2004

[19] B B Braden A N Garcia S E Mennenga et al ldquoCognitive-impairing effects of medroxyprogesterone acetate in the ratindependent and interactive effects across timerdquo Psychophar-macology vol 218 no 2 pp 405ndash418 2011

[20] B R Bhavnani S-P Tam and X Lu ldquoStructure activity rela-tionships and differential interactions and functional activity ofvarious equine estrogens mediated via estrogen receptors (ERs)ER120572 and ER120573rdquo Endocrinology vol 149 no 10 pp 4857ndash48702008

[21] E Hogervorst and S Bandelow ldquoSex steroids to maintaincognitive function in women after the menopause a meta-analyses of treatment trialsrdquoMaturitas vol 66 no 1 pp 56ndash712010

[22] D J Mangelsdorf C Thummel M Beato et al ldquoThe nuclearreceptor super-family the second decaderdquo Cell vol 83 no 6pp 835ndash839 1995

[23] E V Jensen T Suzuki T Kawashima W E Stumpf P WJungblut and E R DeSombre ldquoA two-step mechanism forthe interaction of estradiol with rat uterusrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 59 no 2 pp 632ndash638 1968

ISRN Endocrinology 11

[24] F Naftolin T L Horvath R L Jakab C Leranth N Haradaand J Balthazart ldquoAromatase immunoreactivity in axon termi-nals of the vertebrate brain an immunocytochemical study onquail rat monkey and human tissuesrdquoNeuroendocrinology vol63 no 2 pp 149ndash155 1996

[25] C E Roselli S E Abdelgadir O K Roslashnnekleiv and S AKlosterman ldquoAnatomic distribution and regulation of aro-matase gene expression in the rat brainrdquo Biology of Reproduc-tion vol 58 no 1 pp 79ndash87 1998

[26] J Balthazart and G F Ball ldquoIs brain estradiol a hormone or aneurotransmitterrdquo Trends in Neurosciences vol 29 no 5 pp241ndash249 2006

[27] T R Pak Y S Rao S A Prins and N N Mott ldquoAn emergingrole for microRNAs in sexually dimorphic neurobiologicalsystemsrdquo Pflugers Archiv vol 465 no 5 pp 655ndash667 2013

[28] K Yamagata S Fujiyama S Ito et al ldquoMaturation ofmicroRNAis hormonally regulated by a nuclear receptorrdquo Molecular Cellvol 36 no 2 pp 340ndash347 2009

[29] Y Masuhiro Y Mezaki M Sakari et al ldquoSplicing potentiationby growth factor signals via estrogen receptor phosphorylationrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 23 pp 8126ndash8131 2005

[30] A Tremblay G B Tremblay F Labrie and V Giguere ldquoLigand-Independent recruitment of SRC-1 to estrogen receptor 120573through phosphorylation of activation function AF-1rdquo Molec-ular Cell vol 3 no 4 pp 513ndash519 1999

[31] S H Meijsing M A Pufall A Y So D L Bates L Chenand K R Yamamoto ldquoDNA binding site sequence directsglucocorticoid receptor structure and activityrdquo Science vol 324no 5925 pp 407ndash410 2009

[32] W Bourguet P Germain and H Gronemeyer ldquoNuclearreceptor ligand-binding domains three-dimensional struc-tures molecular interactions and pharmacological implica-tionsrdquo Trends in Pharmacological Sciences vol 21 no 10 pp381ndash388 2000

[33] A Koide C Zhao M Naganuma et al ldquoIdentification ofregions within the F domain of the human estrogen receptor 120572that are important for modulating transactivation and protein-protein interactionsrdquoMolecular Endocrinology vol 21 no 4 pp829ndash842 2007

[34] D F Skafar and S Koide ldquoUnderstanding the human estrogenreceptor-alpha using targeted mutagenesisrdquoMolecular and Cel-lular Endocrinology vol 246 no 1-2 pp 83ndash90 2006

[35] E C Chang J Frasor B Komm and B S KatzenellenbogenldquoImpact of estrogen receptor 120573 on gene networks regulated byestrogen receptor 120572 in breast cancer cellsrdquo Endocrinology vol147 no 10 pp 4831ndash4842 2006

[36] X Zhu I Leav Y-K Leung et al ldquoDynamic regulation ofestrogen receptor-120573 expression by DNA methylation duringprostate cancer development andmetastasisrdquoAmerican Journalof Pathology vol 164 no 6 pp 2003ndash2012 2004

[37] D N Petersen G T Tkalcevic P H Koza-Taylor T G Turiand T A Brown ldquoIdentification of estrogen receptor 1205732 afunctional variant of estrogen receptor 120573 expressed in normalrat tissuesrdquo Endocrinology vol 139 no 3 pp 1082ndash1092 1998

[38] L A Helguero M H Faulds J-A Gustafsson and L-AHaldosen ldquoEstrogen receptors alfa (ER120572) and beta (ER120573)differentially regulate proliferation and apoptosis of the normalmurine mammary epithelial cell line HC11rdquo Oncogene vol 24no 44 pp 6605ndash6616 2005

[39] P C Kulakosky M A McCarty S C Jernigan K E Risingerand C M Klinge ldquoResponse element sequence modulates

estrogen receptor 120572 and 120573 affinity and activityrdquo Journal ofMolecular Endocrinology vol 29 no 1 pp 137ndash152 2002

[40] OM V Grober MMutarelli G Giurato et al ldquoGlobal analysisof estrogen receptor beta binding to breast cancer cell genomereveals an extensive interplay with estrogen receptor alpha fortarget gene regulationrdquo BMC Genomics vol 12 article 36 2011

[41] O I Vivar X Zhao E F Saunier et al ldquoEstrogen receptor 120573binds to and regulates three distinct classes of target genesrdquoJournal of Biological Chemistry vol 285 no 29 pp 22059ndash22066 2010

[42] G G J M Kuiper E Enmark M Pelto-Huikko S Nilssonand J-A Gustafsson ldquoCloning of a novel estrogen receptorexpressed in rat prostate and ovaryrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 93 no12 pp 5925ndash5930 1996

[43] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and 120572 and 120573rdquo Endocrinology vol 138no 3 pp 863ndash870 1997

[44] D B Dubal H Zhu J Yu et al ldquoEstrogen receptor alpha notbeta is a critical link in estradiol-mediated protection againstbrain injuryrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 98 no 4 pp 1952ndash1957 2001

[45] P J Shughrue P J Scrimo and I Merchenthaler ldquoEvidence forthe colocalization of estrogen receptor-120573 mRNA and estrogenreceptor-120572 immunoreactivity in neurons of the rat forebrainrdquoEndocrinology vol 139 no 12 pp 5267ndash5270 1998

[46] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in therat central nervous systemrdquo Journal of Comparative Neurologyvol 388 no 4 pp 507ndash525 1997

[47] T AMilner B SMcEwen S Hayashi C J Li L P Reagan andS E Alves ldquoUltrastructural evidence that hippocampal alphaestrogen receptors are located at extranuclear sitesrdquoThe Journalof Comparative Neurology vol 429 no 3 pp 355ndash371 2001

[48] T A Milner L S Lubbers S E Alves and B S McEwenldquoNuclear and extranuclear estrogen binding sites in the ratforebrain and autonomic medullary areasrdquo Endocrinology vol149 no 7 pp 3306ndash3312 2008

[49] T A Milner K Ayoola C T Drake et al ldquoUltrastructurallocalization of estrogen receptor 120573 immunoreactivity in the rathippocampal formationrdquo Journal of ComparativeNeurology vol491 no 2 pp 81ndash95 2005

[50] A E Herbison andD TTheodosis ldquoAbsence of estrogen recep-tor immunoreactivity in somatostatin (SRIF) neurons of theperiventricular nucleus but sexually dimorphic colocalizationof estrogen receptor and SRIF immunoreactivities in neuronsof the bed nucleus of the stria terminalisrdquo Endocrinology vol132 no 4 pp 1707ndash1714 1993

[51] K Kalita S Szymczak and L Kaczmarek ldquoNon-nuclear estro-gen receptor 120573 and 120572 in the hippocampus of male and femaleratsrdquo Hippocampus vol 15 no 3 pp 404ndash412 2005

[52] T Ivanova and C Beyer ldquoOntogenetic expression and sexdifferences of aromatase and estrogen receptor-120572120573 mRNA inthe mouse hippocampusrdquo Cell and Tissue Research vol 300 no2 pp 231ndash237 2000

[53] C Y Pau K-Y F Pau and H G Spies ldquoPutative estrogenreceptor 120573 and 120572 mRNA expression in male and female rhesusmacaquesrdquo Molecular and Cellular Endocrinology vol 146 no1-2 pp 59ndash68 1998

[54] A L Wijayaratne and D P McDonnell ldquoThe human estrogenreceptor-120572 is a ubiquitinated protein whose stability is affected

12 ISRN Endocrinology

differentially by agonists antagonists and selective estrogenreceptor modulatorsrdquo Journal of Biological Chemistry vol 276no 38 pp 35684ndash35692 2001

[55] V Bartella P Rizza I Barone et al ldquoEstrogen receptor betabinds Sp1 and recruits a corepressor complex to the estrogenreceptor alpha gene promoterrdquo Breast Cancer Research andTreatment vol 134 no 2 pp 569ndash581 2012

[56] L C Li C C Yeh D Nojima and R Dahiya ldquoCloning andcharacterization of human estrogen receptor beta promoterrdquoBiochemical and Biophysical Research Communications vol 275no 2 pp 682ndash689 2000

[57] E A Vladusic A E Hornby F K Guerra-Vladusic J Lakinsand R Lupu ldquoExpression and regulation of estrogen receptor szligin human breast tumors and cell linesrdquoOncology Reports vol 7no 1 pp 157ndash167 2000

[58] T Hatsumi and Y Yamamuro ldquoDownregulation of estrogenreceptor gene expression by exogenous 17120573-estradiol in themammary glands of lactating micerdquo Experimental Biology andMedicine vol 231 no 3 pp 311ndash316 2006

[59] H B Patisaul P L Whitten and L J Young ldquoRegulation ofestrogen receptor beta mRNA in the brain opposite effectsof 17120573-estradiol and the phytoestrogen coumestrolrdquoMolecularBrain Research vol 67 no 1 pp 165ndash171 1999

[60] T J Brown N J MacLusky M Shanabrough and F NaftolinldquoComparison of age- and sex-related changes in cell nuclearestrogen-binding capacity and progestin receptor induction inthe rat brainrdquo Endocrinology vol 126 no 6 pp 2965ndash29721990

[61] B S Rubin T O Fox and R S Bridges ldquoEstrogen bindingin nuclear and cytosolic extracts from brain and pituitary ofmiddle-aged female ratsrdquo Brain Research vol 383 no 1-2 pp60ndash67 1986

[62] T Funabashi S P Kleopoulos P J Brooks et al ldquoChangesin estrogenic regulation of estrogen receptor 120572 mRNA andprogesterone receptor mRNA in the female rat hypothalamusduring aging an in situ hybridization studyrdquo NeuroscienceResearch vol 38 no 1 pp 85ndash92 2000

[63] M E Wilson K L Rosewell M L Kashon P J Shughrue IMerchenthaler and P M Wise ldquoAge differentially influencesestrogen receptor-120572 (ER120572) and estrogen receptor-120573 (ER120573) geneexpression in specific regions of the rat brainrdquo Mechanisms ofAgeing and Development vol 123 no 6 pp 593ndash601 2002

[64] W S Post P J Goldschmidt-Clermont C C Wilhide etal ldquoMethylation of the estrogen receptor gene is associatedwith aging and atherosclerosis in the cardiovascular systemrdquoCardiovascular Research vol 43 no 4 pp 985ndash991 1999

[65] J-P J Issa Y L Ottaviano P Celano S R Hamilton NE Davidson and S B Baylin ldquoMethylation of the oestrogenreceptor CpG island links ageing and neoplasia in humancolonrdquo Nature Genetics vol 7 no 4 pp 536ndash540 1994

[66] T Funabashi and F Kimura ldquoEffects of estrogen and estrogenreceptor messenger RNA levels in young and middle-agedfemale rats comparison ofmedial preoptic area andmediobasalhypothalamusrdquo Acta Biologica Hungarica vol 45 no 2ndash4 pp223ndash231 1994

[67] M AMiller P E Kolb B Planas andM A Raskind ldquoEstrogenreceptor and neurotensinneuromedin-N gene expression inthe preoptic area are unaltered with age in Fischer 344 femaleratsrdquo Endocrinology vol 135 no 5 pp 1986ndash1995 1994

[68] T R Chakraborty P R Hof L Ng and A C Gore ldquoStereologicanalysis of estrogen receptor alpha (ER alpha) expression in rat

hypothalamus and its regulation by aging and estrogenrdquo Journalof Comparative Neurology vol 466 no 3 pp 409ndash421 2003

[69] J M Westberry A L Trout and M E Wilson ldquoEpigeneticregulation of estrogen receptor beta expression in the rat cortexduring agingrdquo NeuroReport vol 22 no 9 pp 428ndash432 2011

[70] T R Chakraborty L Ng and A C Gore ldquoAge-related changesin estrogen receptor 120573 in rat hypothalamus a quantitativeanalysisrdquo Endocrinology vol 144 no 9 pp 4164ndash4171 2003

[71] I Poola S Koduri S Chatra and R Clarke ldquoIdentificationof twenty alternatively spliced estrogen receptor alpha mRNAsin breast cancer cell lines and tumors using splice targetedprimer approachrdquo Journal of Steroid Biochemistry andMolecularBiology vol 72 no 5 pp 249ndash258 2000

[72] T A Ishunina and D F Swaab ldquoHippocampal estrogenreceptor-alpha splice variant TADDI in the human brain inaging and Alzheimerrsquos diseaserdquoNeuroendocrinology vol 89 no2 pp 187ndash199 2009

[73] T A Ishunina and D F Swaab ldquoEstrogen receptor-120572 splicevariants in the human brainrdquo Gynecological Endocrinology vol24 no 2 pp 93ndash98 2008

[74] T A Ishunina F P M Kruijver R Balesar and D FSwaab ldquoDifferential expression of estrogen receptor 120572 and 120573immunoreactivity in the human supraoptic nucleus in rela-tion to sex and agingrdquo Journal of Clinical Endocrinology andMetabolism vol 85 no 9 pp 3283ndash3291 2000

[75] T A Ishunina D F Fischer andD F Swaab ldquoEstrogen receptor120572 and its splice variants in the hippocampus in aging andAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 28 no 11 pp1670ndash1681 2007

[76] J R Tollervey Z Wang T Hortobagyi et al ldquoAnalysis of alter-native splicing associated with aging and neurodegeneration inthe human brainrdquo Genome Research vol 21 no 10 pp 1572ndash1582 2011

[77] N NMott and T R Pak ldquoCharacterisation of human oestrogenreceptor beta (ER120573) splice variants in neuronal cellsrdquo Journal ofNeuroendocrinology vol 24 no 10 pp 1311ndash1321 2012

[78] S Inoue S-J Hoshino H Miyoshi et al ldquoIdentification ofa ovel isoform of estrogen receptor a potential inhibitor ofestrogen action in vascular smooth muscle cellsrdquo Biochemicaland Biophysical Research Communications vol 219 no 3 pp766ndash772 1996

[79] J K Skipper L J Young J M Bergeron M T Tetzlaff CT Osborn and D Crews ldquoIdentification of an isoform ofthe estrogen receptor messenger RNA lacking exon four andpresent in the brainrdquo Proceedings of the National Academy ofSciences of the United States of America vol 90 no 15 pp 7172ndash7175 1993

[80] R H Price Jr N Lorenzon and R J Handa ldquoDifferentialexpression of estrogen receptor beta splice variants in rat brainidentification and characterization of a novel variant missingexon 4rdquo Brain Research Molecular Brain Research vol 80 no2 pp 260ndash268 2000

[81] S Chu and P J Fuller ldquoIdentification of a splice variantof the rat estrogen receptor 120573 generdquo Molecular and CellularEndocrinology vol 132 no 1-2 pp 195ndash199 1997

[82] B Lu E Leygue H Dotzlaw L J Murphy L C Murphy andP H Watson ldquoEstrogen receptor-120573 mRNA variants in humanand murine tissuesrdquoMolecular and Cellular Endocrinology vol138 no 1-2 pp 199ndash203 1998

[83] T R Pak W C J Chung J L Roberts and R J HandaldquoLigand-independent effects of estrogen receptor 120573 on

ISRN Endocrinology 13

mouse gonadotropin-releasing hormone promoter activityrdquoEndocrinology vol 147 no 4 pp 1924ndash1931 2006

[84] T R Pak W C J Chung L R Hinds and R J HandaldquoEstrogen receptor-120573 mediates dihydrotestosterone-inducedstimulation of the arginine vasopressin promoter in neuronalcellsrdquo Endocrinology vol 148 no 7 pp 3371ndash3382 2007

[85] Y K Leung PMak S Hassan and SMHo ldquoEstrogen receptor(ER)-120573 isoforms a key to understanding ER-120573 signalingrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 103 no 35 pp 13162ndash13167 2006

[86] J M Wang X Hou S Adeosun et al ldquoA dominant negativeER120573 splice variant determines the effectiveness of early or lateestrogen therapy after ovariectomy in ratsrdquo PLoS One vol 7 no3 Article ID e33493 2012

[87] W C J Chung T R Pak S Suzuki W A Pouliot M EAndersen and R J Handa ldquoDetection and localization of anestrogen receptor beta splice variant protein (ER1205732) in theadult female rat forebrain and midbrain regionsrdquo Journal ofComparative Neurology vol 505 no 3 pp 249ndash267 2007

[88] R H Price Jr C A Butler P Webb R Uht P Kushner andR J Handa ldquoA splice variant of estrogen receptor 120573 missingexon 3 displays altered subnuclear localization and capacity fortranscriptional activationrdquo Endocrinology vol 142 no 5 pp2039ndash2049 2001

[89] Y Wang and R J Miksicek ldquoIdentification of a dominantnegative form of the human estrogen receptorrdquo MolecularEndocrinology vol 5 no 11 pp 1707ndash1715 1991

[90] E Kuppers and C Beyer ldquoExpression of estrogen receptor-120572and 120573 mRNA in the developing and adult mouse striatumrdquoNeuroscience Letters vol 276 no 2 pp 95ndash98 1999

[91] C Gundlah S G Kohama S J Mirkes V T Garyfallou H FUrbanski and C L Bethea ldquoDistribution of estrogen receptorbeta (ER120573) mRNA in hypothalamus midbrain and temporallobe of spayed macaque continued expression with hormonereplacementrdquo Brain Research Molecular Brain Research vol 76no 2 pp 191ndash204 2000

[92] Y Morishima P J M Murphy D-P Li E R Sanchez and WB Pratt ldquoStepwise assembly of a glucocorticoid receptorsdothsp90heterocomplex resolves two sequential ATP-dependent eventsinvolving first hsp70 and then hsp90 in opening of the steroidbinding pocketrdquo Journal of Biological Chemistry vol 275 no 24pp 18054ndash18060 2000

[93] K D Dittmar and W B Pratt ldquoFolding of the glucocorticoidreceptor by the reconstituted hsp90-based chaperone machin-eryThe initial hsp90sdotp60sdothsp70-dependent step is sufficient forcreating the steroid binding conformationrdquo Journal of BiologicalChemistry vol 272 no 20 pp 13047ndash13054 1997

[94] K I Kang X Meng J Devin-Leclerc et al ldquoThe molecularchaperone Hsp90 can negatively regulate the activity of aglucocorticosteroid-dependent promoterrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 4 pp 1439ndash1444 1999

[95] K Unno H Asakura Y Shibuya M Kaiho S Okada and NOku Naoto ldquoIncrease in basal level of Hsp70 consisting chieflyof constitutively expressed hsp70 (Hsc70) in aged rat brainrdquoJournals of Gerontology Series A vol 55 no 7 pp B329ndashB3352000

[96] U E Olazabal D W Pfaff and C V Mobbs ldquoSex differences inthe regulation of heat shock protein 70 kDa and 90 kDa in therat ventromedial hypothalamus by estrogenrdquo Brain Researchvol 596 no 1-2 pp 311ndash314 1992

[97] M A Pahlavani M D Harris S A Moore and A RichardsonldquoExpression of heat shock protein 70 in rat spleen lymphocytesis affected by age but not by food restrictionrdquo Journal ofNutrition vol 126 no 9 pp 2069ndash2075 1996

[98] A R Heydari B Wu R Takahashi R Strong and A Richard-son ldquoExpression of heat shock protein 70 is altered by age anddiet at the level of transcriptionrdquoMolecular andCellular Biologyvol 13 no 5 pp 2909ndash2918 1993

[99] M Sabbah K-I I Kang L Tora and G Redeuilh ldquoOestro-gen receptor facilitates the formation of preinitiation com-plex assembly involvement of the general transcription factorTFIIBrdquo Biochemical Journal vol 336 part 3 pp 639ndash646 1998

[100] S-Y Wu M C Thomas S Y Hou V Likhite and C-MChiang ldquoIsolation of mouse TFIID and functional character-ization of TBP and TFIID in mediating estrogen receptor andchromatin transcriptionrdquo Journal of Biological Chemistry vol274 no 33 pp 23480ndash23490 1999

[101] S Ghosh and M K Thakur ldquoTissue-specific expression ofreceptor-interacting protein in aging mouserdquo Age vol 30 no4 pp 237ndash243 2008

[102] J Frasor JM Danes B Komm K C N Chang C Richard Lyt-tle and B S Katzenellenbogen ldquoProfiling of estrogen up- anddown-regulated gene expression in human breast cancer cellsinsights into gene networks and pathways underlying estrogeniccontrol of proliferation and cell phenotyperdquo Endocrinology vol144 no 10 pp 4562ndash4574 2003

[103] J Frasor J M Danes C C Funk and B S Katzenellen-bogen ldquoEstrogen down-regulation of the corepressor N-CoRmechanism and implications for estrogen derepression of N-CoR-regulated genesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 102 no 37 pp13153ndash13157 2005

[104] N J McKenna and B W OrsquoMalley ldquoCombinatorial control ofgene expression by nuclear receptors and coregulatorsrdquoCell vol108 no 4 pp 465ndash474 2002

[105] T-P Yao G Ku N Zhou R Scully and D M Livingston ldquoThenuclear hormone receptor coactivator SRC-1 is a specific targetof p300rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 93 no 20 pp 10626ndash10631 1996

[106] B Hanstein R Eckner J DiRenzo et al ldquop300 is a componentof an estrogen receptor coactivator complexrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 93 no 21 pp 11540ndash11545 1996

[107] S Halachmi E Marden G Martin H MacKay C Abbon-danza and M Brown ldquoEstrogen receptor-associated proteinspossible mediators of hormone-induced transcriptionsrdquo Sci-ence vol 264 no 5164 pp 1455ndash1458 1994

[108] A J Horlein AM Naar T Heinzel et al ldquoLigand-independentrepression by the thyroid hormone receptor mediated by anuclear receptor co-repressorrdquo Nature vol 377 no 6548 pp397ndash404 1995

[109] J D Chen and R M Evans ldquoA transcriptional co-repressor thatinteracts with nuclear hormone receptorsrdquo Nature vol 377 no6548 pp 454ndash457 1995

[110] A Malovannaya R B Lanz S Y Jung et al ldquoAnalysis of thehuman endogenous coregulator complexomerdquoCell vol 145 no5 pp 787ndash799 2011

[111] Z Nawaz D M Lonard C L Smith et al ldquoThe Angelmansyndrome-associated protein E6-AP is a coactivator for thenuclear hormone receptor superfamilyrdquoMolecular and CellularBiology vol 19 no 2 pp 1182ndash1189 1999

14 ISRN Endocrinology

[112] B Zheng M Han M Bernier and J-K Wen ldquoNuclear actinand actin-binding proteins in the regulation of transcriptionand gene expressionrdquo FEBS Journal vol 276 no 10 pp 2669ndash2685 2009

[113] W A Hofmann L Stojiljkovic B Fuchsova et al ldquoActin is partof pre-initiation complexes and is necessary for transcription byRNA polymerase IIrdquoNature Cell Biology vol 6 no 11 pp 1094ndash1101 2004

[114] K Tokunaga T Shibuya Y Ishihama et al ldquoNucleocytoplasmictransport of fluorescent mRNA in living mammalian cellsnuclear mRNA export is coupled to ongoing gene transcrip-tionrdquo Genes to Cells vol 11 no 3 pp 305ndash317 2006

[115] R Metivier G Penot M R Hubner et al ldquoEstrogen receptor-120572 directs ordered cyclical and combinatorial recruitment ofcofactors on a natural target promoterrdquo Cell vol 115 no 6 pp751ndash763 2003

[116] C Ambrosino R Tarallo A Bamundo et al ldquoIdentification of ahormone-regulated dynamic nuclear actin network associatedwith estrogen receptor 120572 in human breast cancer cell nucleirdquoMolecular and Cellular Proteomics vol 9 no 6 pp 1352ndash13672010

[117] F Shao R Zhang L Dong and K Ying ldquoOverexpression ofgelsolin-like actin-capping protein is associated with progres-sion of lung adenocarcinomardquo Tohoku Journal of ExperimentalMedicine vol 225 no 2 pp 95ndash101 2011

[118] K Nishimura H-J Ting Y Harada et al ldquoModulation ofandrogen receptor transactivation by gelsolin a newly identi-fied androgen receptor coregulatorrdquo Cancer Research vol 63no 16 pp 4888ndash4894 2003

[119] J S Ahn I S Jang D I Kim et al ldquoAging-associated increaseof gelsolin for apoptosis resistancerdquoBiochemical and BiophysicalResearch Communications vol 312 no 4 pp 1335ndash1341 2003

[120] I Nalvarte T Schwend and J-A Gustafsson ldquoProteomicsanalysis of the estrogen receptor 120572 receptosomerdquoMolecular andCellular Proteomics vol 9 no 7 pp 1411ndash1422 2010

[121] L-H Miau C-J Chang B-J Shen W-H Tsai and S-C LeeldquoIdentification of heterogeneous nuclear ribonucleoprotein K(hnRNPK) as a repressor ofCEBP120573-mediated gene activationrdquoJournal of Biological Chemistry vol 273 no 17 pp 10784ndash107911998

[122] A Ostareck-Lederer D H Ostareck C Cans et al ldquoc-Src-mediated phosphorylation of hnRNP K drives translationalactivation of specifically silenced mRNAsrdquo Molecular and Cel-lular Biology vol 22 no 13 pp 4535ndash4543 2002

[123] P S Bagga G K Arhin and J Wilusz ldquoDSEF-1 is a member ofthe hnRNP H family of RNA-binding proteins and stimulatespre-mRNAcleavage and polyadenylation in vitrordquoNucleic AcidsResearch vol 26 no 23 pp 5343ndash5350 1998

[124] V Markovtsov J M Nikolic J A Goldman C W Turck M-Y Chou and D L Black ldquoCooperative assembly of an hnRNPcomplex induced by a tissue-specific homolog of polypyrimi-dine tract binding proteinrdquoMolecular and Cellular Biology vol20 no 20 pp 7463ndash7479 2000

[125] S Y Jung A Malovannaya J Wei B W OrsquoMalley and J QinldquoProteomic analysis of steady-state nuclear hormone receptorcoactivator complexesrdquoMolecular Endocrinology vol 19 no 10pp 2451ndash2465 2005

[126] W Hong R J Resnick C Rakowski D Shalloway S J Taylorand G A Blobel ldquoPhysical and functional interaction betweenthe transcriptional cofactor CBP and the KH domain proteinSam68rdquoMolecular Cancer Research vol 1 no 1 pp 48ndash55 2002

[127] R ShaoXWang BWeijdegard et al ldquoCoordinate regulation ofheterogeneous nuclear ribonucleoprotein dynamics by steroidhormones in the human fallopian tube and endometrium invivo and in vitrordquo American Journal of Physiology vol 302 no10 pp E1269ndashE1282 2012

[128] C SWoolley and B SMcEwen ldquoEstradiolmediates fluctuationin hippocampal synapse density during the estrous cycle in theadult ratrdquo Journal of Neuroscience vol 12 no 7 pp 2549ndash25541992

[129] C S Woolley H J Wenzel and P A Schwartzkroin ldquoEstradiolincreases the frequency of multiple synapse boutons in thehippocampal CA1 region of the adult female ratrdquo The Journalof Comparative Neurology vol 373 no 1 pp 108ndash117 1996

[130] C S Woolley ldquoEstrogen-mediated structural and functionalsynaptic plasticity in the female rat hippocampusrdquo Hormonesand Behavior vol 34 no 2 pp 140ndash148 1998

[131] D P Srivastava K M Woolfrey K A Jones et al ldquoRapidenhancement of two-step wiring plasticity by estrogen andNMDA receptor activityrdquo Proceedings of the National Academyof Sciences of the United States of America vol 105 no 38 pp14650ndash14655 2008

[132] M Ogiue-Ikeda N Tanabe H Mukai et al ldquoRapid modu-lation of synaptic plasticity by estrogens as well as endocrinedisrupters in hippocampal neuronsrdquo Brain Research Reviewsvol 57 no 2 pp 363ndash375 2008

[133] N J Sandstrom and C L Williams ldquoSpatial memory retentionis enhanced by acute and continuous estradiol replacementrdquoHormones and Behavior vol 45 no 2 pp 128ndash135 2004

[134] E Hogervorst J Williams M Budge W Riedel and JJolles ldquoThe nature of the effect of female gonadal hormonereplacement therapy on cognitive function in post-menopausalwomen a meta-analysisrdquo Neuroscience vol 101 no 3 pp 485ndash512 2000

[135] M E Bailey A C J Wang J Hao et al ldquoInteractive effects ofage and estrogen on cortical neurons implications for cognitiveagingrdquo Neuroscience vol 191 pp 148ndash158 2011

[136] A A Walf M E Rhodes and C A Frye ldquoOvarian steroidsenhance object recognition in naturally cycling and ovariec-tomized hormone-primed ratsrdquo Neurobiology of Learning andMemory vol 86 no 1 pp 35ndash46 2006

[137] V N Luine L F Jacome and N J Maclusky ldquoRapid enhance-ment of visual and place memory by estrogens in ratsrdquoEndocrinology vol 144 no 7 pp 2836ndash2844 2003

[138] L Fan Z Zhao P T Orr C H Chambers M C Lewis and KM Frick ldquoEstradiol-induced object memory consolidation inmiddle-aged femalemice requires dorsal hippocampal extracel-lular signal-regulated kinase and phosphatidylinositol 3-kinaseactivationrdquo Journal of Neuroscience vol 30 no 12 pp 4390ndash4400 2010

[139] D B Dubal and PMWise ldquoNeuroprotective effects of estradiolin middle-aged female ratsrdquo Endocrinology vol 142 no 1 pp43ndash48 2001

[140] S-H Yang J Shi A L Day and J W Simpkins ldquoEstradiolexerts neuroprotective effects when administered after ischemicinsultrdquo Stroke vol 31 no 3 pp 745ndash750 2000

[141] J W Simpkins G Rajakumar Y-Q Zhang et al ldquoEstrogensmay reduce mortality and ischemic damage caused by middlecerebral artery occlusion in the female ratrdquo Journal of Neuro-surgery vol 87 no 5 pp 724ndash730 1997

[142] J Shi K S Panickar S-H Yang O Rabbani A L Day and JWSimpkins ldquoEstrogen attenuates over-expression of 120573-amyloid

ISRN Endocrinology 15

precursor protein messager RNA in an animal model of focalischemiardquo Brain Research vol 810 no 1-2 pp 87ndash92 1998

[143] Q-H Zhang Y-H Huang Y-Z Hu et al ldquoDisruption ofestrogen receptor beta in mice brain results in pathologicalalterations resemblingAlzheimer diseaserdquoActa PharmacologicaSinica vol 25 no 4 pp 452ndash457 2004

[144] E F Rissman A L Heck J E Leonard M A Shupnik and J-A Gustafsson ldquoDisruption of estrogen receptor 120573 gene impairsspatial learning in female micerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no6 pp 3996ndash4001 2002

[145] M Day A Sung S Logue M Bowlby and R Arias ldquoBetaestrogen receptor knockout (BERKO) mice present attenuatedhippocampal CA1 long-term potentiation and related memorydeficits in contextual fear conditioningrdquo Behavioural BrainResearch vol 164 no 1 pp 128ndash131 2005

[146] R Vierk G Glassmeier L Zhou et al ldquoAromatase inhibitionabolishes LTP generation in female but not in male micerdquo TheJournal of Neuroscience vol 32 no 24 pp 8116ndash8126 2012

[147] R-M Vouimba M R Foy J G Foy and R FThompson ldquo17120573-estradiol suppresses expression of long-term depression in agedratsrdquo Brain Research Bulletin vol 53 no 6 pp 783ndash787 2000

[148] C E Andreescu B A Milojkovic E D Haasdijk et alldquoEstradiol improves cerebellar memory formation by activatingestrogen receptor 120573rdquo Journal of Neuroscience vol 27 no 40 pp10832ndash10839 2007

[149] Y-Y Huang P V Nguyen T Abel and E R Kandel ldquoLong-lasting forms of synaptic potentiation in the mammalian hip-pocampusrdquo Learning Memory vol 3 no 2-3 pp 74ndash85 1996

[150] H Mukai T Tsurugizawa G Murakami et al ldquoRapid mod-ulation of long-term depression and spinogenesis via synapticestrogen receptors in hippocampal principal neuronsrdquo Journalof Neurochemistry vol 100 no 4 pp 950ndash967 2007

[151] L Liu T P Wong M F Pozza et al ldquoRole of NMDA receptorsubtypes in governing the direction of hippocampal synapticplasticityrdquo Science vol 304 no 5673 pp 1021ndash1024 2004

[152] M Cyr O Ghribi C Thibault M Morissette M Landry andT di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[153] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[154] C C Smith and L L McMahon ldquoEstradiol-induced increasein the magnitude of long-term potentiation is prevented byblocking NR2B-containing receptorsrdquo Journal of Neurosciencevol 26 no 33 pp 8517ndash8522 2006

[155] Y Zhou J J Watters and D M Dorsa ldquoEstrogen rapidlyinduces the phosphorylation of the cAMP response elementbinding protein in rat brainrdquo Endocrinology vol 137 no 5 pp2163ndash2166 1996

[156] XGonda T TelekG Juhasz J Lazary AVargha andG BagdyldquoPatterns of mood changes throughout the reproductive cyclein healthy women without premenstrual dysphoric disordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 32 no 8 pp 1782ndash1788 2008

[157] E W Freeman ldquoPremenstrual syndrome and premenstrualdysphoric disorder definitions and diagnosisrdquo Psychoneuroen-docrinology vol 28 supplement 3 pp 25ndash37 2003

[158] T D Lund T Rovis W C J Chung and R J Handa ldquoNovelactions of estrogen receptor-120573 on anxiety-related behaviorsrdquoEndocrinology vol 146 no 2 pp 797ndash807 2005

[159] N Breslau L Schultz and E Peterson ldquoSex differences indepression a role for preexisting anxietyrdquo Psychiatry Researchvol 58 no 1 pp 1ndash12 1995

[160] P E Bebbington G Dunn R Jenkins et al ldquoThe influenceof age and sex on the prevalence of depressive conditionsreport from the National Survey of Psychiatric MorbidityrdquoPsychological Medicine vol 28 no 1 pp 9ndash19 1998

[161] G Aguilera J P Harwood and J X Wilson ldquoMechanisms ofaction of corticotropin-releasing factor and other regulators ofcorticotropin release in rat pituitary cellsrdquo Journal of BiologicalChemistry vol 258 no 13 pp 8039ndash8045 1983

[162] A Papadimitriou and K N Priftis ldquoRegulation of thehypothalamic-pituitary-adrenal axisrdquo NeuroImmunoModula-tion vol 16 no 5 pp 265ndash271 2009

[163] S Suzuki and R J Handa ldquoRegulation of estrogen receptor-120573expression in the female rat hypothalamus differential effectsof dexamethasone and estradiolrdquo Endocrinology vol 145 no 8pp 3658ndash3670 2004

[164] W J S Miller S Suzuki L K Miller R Handa and R M UhtldquoEstrogen receptor (ER)120573 isoforms rather than ER120572 regulatecorticotropin-releasing hormone promoter activity through analternate pathwayrdquo Journal of Neuroscience vol 24 no 47 pp10628ndash10635 2004

[165] C IsgorM CecchiM Kabbaj H Akil and S JWatson ldquoEstro-gen receptor 120573 in the paraventricular nucleus of hypothalamusregulates the neuroendocrine response to stress and is regulatedby corticosteronerdquo Neuroscience vol 121 no 4 pp 837ndash8452003

[166] M L Forsling I Kallo D E Hartley et al ldquoOestrogen receptor-120573 and neurohypophysial hormones functional interaction andneuroanatomical localisationrdquo Pharmacology Biochemistry andBehavior vol 76 no 3-4 pp 535ndash542 2003

[167] A S Lalmansingh and R M Uht ldquoEstradiol regulatescorticotropin-releasing hormone gene (crh) expression in arapid and phasic manner that parallels estrogen receptor-120572 and-120573 recruitment to a 3101584051015840-cyclic adenosine 51015840- monophosphateregulatory region of the proximal crh promoterrdquo Endocrinologyvol 149 no 1 pp 346ndash357 2008

[168] B N Roy R L Reid and D A van Vugt ldquoThe effects ofestrogen and progesterone on corticotropin-releasing hormoneand arginine vasopressin messenger ribonucleic acid levelsin the paraventricular nucleus and supraoptic nucleus of therhesus monkeyrdquo Endocrinology vol 140 no 5 pp 2191ndash21981999

[169] X Ni R C Nicholson B R King E-C Chan M A Read andR Smith ldquoEstrogen represses whereas the estrogen-antagonistICI 182780 stimulates placental CRH gene expressionrdquo Journalof Clinical Endocrinology and Metabolism vol 87 no 8 pp3774ndash3778 2002

[170] N C Vamvakopoulos and G P Chrousos ldquoEvidence of directestrogenic regulation of human corticotropin-releasing hor-mone gene expression Potential implications for the sexualdimophism of the stress response and immuneinflammatoryreactionrdquo Journal of Clinical Investigation vol 92 no 4 pp1896ndash1902 1993

[171] Y Hu D L Wu C X Luo et al ldquoHippocampal nitric oxidecontributes to sex difference in affective behaviorsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 35 pp 14224ndash14229 2012

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

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ISRN Endocrinology 7

Table 1 Protein interactions with ER120573 were altered by age and 1198642 Selected proteins that were significantly altered (119875 lt 005) in their

association with ER120573 depending on age and 1198642treatment Experimental paradigm young (3 month) and aged (18 month) female Fischer 344

rats were ovariectomized and hormone deprived for 7 days Following deprivation animals were administered 25120583gkg 1198642(plasma levels =

7945 plusmn 225 pgmL) or vehicle (safflower oil) via subcutaneous injection onceday for 3 days Nuclear protein was isolated from the ventralhippocampus and coimmunoprecipitated for ER120573 (a beam 14C8) and associated proteins Protein interactions were identified and quantifiedusing 2D-DIGEDeCyder and ESI MSMS YV = young + vehicle YE = young + 119864

2 AV = aged + vehicle AE = aged + 119864

2

Accession noMolecularweight(Kda)

Estimatedisoelectricpoint

PEAKSscore Coverage ID

Interaction with ER120573FunctionYoung

vehicleYoung1198642

Agedvehicle

Aged1198642

gi| 149038929 80 575 494 643 Gelsolin mdash uarr mdash mdashActin-binding

coactivator

gi| 116242507 75 597 93 1458 Heat-shock protein70 mdash darr mdash uarr Chaperone

gi| 120538378 47 57 932 1072

Heterogeneousnuclear

ribonucleoproteinH12

mdash uarr mdash mdash RNA splicing

10 Nuclear Actin Setting the Stage

Coregulatory interactions may be poised upon a bed ofnuclear actin which has recently been identified as a dynamicmolecular stage for which many nuclear processes are per-formed such as transcription chromatin remodeling mRNAprocessing and nuclear importexport The general eventsthat initiate transcription are well established however theprocess by which all of the molecular components are tem-porally layered into a complex is still unclear Nuclear actin isessential in forming the preinitiation complex on a promoterelongation and RNP organization as well as remodeling ofchromatin [112ndash114] and as mentioned previously ERs arealso key factors in these processes In one study ER120572 and120573-actin were coimmunoprecipitated on the E

2responsive

pS2TFF1 promoter indicating that ER and nuclear actinmay work in concert to regulate transcriptional processesunder control of estrogens [115] The interaction betweenERs and actin is not yet fully investigated but data fromour lab (unpublished observations) and others [116] implythat both ER120572 and ER120573may utilize nuclear actin to performvarious functions Another actin-binding protein gelsolincaps actin filament ends and it has been shown to be anNR coactivator [117 118] Gelsolin may assist in actin poly-merization allowing transcriptionalmachinery to be broughtin proximity of target genes however it remains unclearhow gelsolin enhances ARER transcriptional activity Datafrom our lab indicate that gelsolinER120573 interactions increasewith E

2treatment in young but not aged animals (Table 1)

Gelsolin has been shown to increase with age [119] but alack of significant interaction with ER120573 despite increasedexpression of gelsolin could again suggest an alteration inER120573 function with age

Actin is also commonly associated with ubiquitous mul-tifunctional RNA-binding proteins such as heterologousnuclear riboproteins (hnRNPs) which also associate withERs [120] hnRNPs associate within the matrix of nuclearactin accompany transcripts out of the nucleus participatein alternative splicing and can modulate transcription [121]

Phosphorylated hnRNPK has been shown to mediate trans-lation of specific mRNAs [122] and hnRNPH is involvedin splicing and mRNA polyadenylation [123 124] In thepast the association of NRs with hnRNPs was thought to benonspecific due to the ubiquitous nature of these proteinsbut recent studies are no longer ruling out an importantinteraction between NRs and hnRNPs that may assist intranscription andor splicing [125 126] Data from our laband others demonstrate a dynamic interaction between bothER120572 and ER120573 and hnRNPs (Table 1) and furthermore datademonstrated that E

2might regulate expression of members

of the hnRNP family [127] As noted previously age-relatedincreases in splicing could lead to aberrant signaling not onlyfor E2-mediated processes but also for cellular processes in

generalNuclear ER interaction partners have historically been a

distinct class of nuclear receptor coregulators that seemedto solely assist ERs in gene transcription however thenumber of interaction partners for ERs is increasing Furtherinvestigation into ER120573-associated proteins is required as faras NRs are concerned data specific to ER120573 are inadequateto make broad conclusions Moreover post-translationalmodifications to coregulatory proteins ERs or changes intheir expression patterns due to age or sustained estrogendeprivation could all contribute to an altered microenviron-ment setting the stage for atypical estrogen signaling upontherapeutic reinstatement of hormones (Figure 3)

11 Estrogens and Cognition

Most empirical and observational data give merit to theidea that estrogens have a positive effect on cognitiveprocesses increased spine densities [128 129] enhancedsynaptic plasticity [130ndash132] and improved memory [133134] however the particular receptor(s) and the mechanismsthat regulate these processes remain unclear There are amyriad of behavioral studies suggesting that E

2enhances

prefrontal cortex (PFC) and hippocampal-dependent tasks

8 ISRN Endocrinology

Factor BER structureand function

Factor Ccoregulatory and

transcriptional interactions

120573

120573120573

120573

120572

120572

120572 120572

V

V

V

V

V

V

V

V

ESR1

ESR2

Age and E2

++

Context-dependentER-regulated

gene expression

Factor Atissue-specific

ER gene expression

Figure 3 Age and hormonalmilieu exponentially increase the potential diversity of estrogen receptor signaling leading to context-dependentgene regulation Age and E

2influence ER gene expression alternative splicing coregulatory protein expression and interaction which

ultimately direct ER-target gene transcription

For example long-term E2deprivation diminished aged

female rhesus macaquesrsquo performance in a delayed responsetask a PFC- dependent task [135] E

2also enhanced object

recognition under a number of different paradigms [136ndash138] and there are also multiple lines of evidence supportingE2-mediated neuroprotection which may be important for

cognition especially after stroke [139ndash142]Pharmacological targeting of the receptors with ER selec-

tive ligands has been a standard method for investigating thebehavioral physiological and cellular actions of E

2mediated

distinctly throughER120572 andor ER120573 however valuable insighthas also come from the ER120573-null (120573ERKO) mice 120573ERKOmice have significantly fewer neurons in the cortex hypotha-lamus amygdala and ventral tegmental area compared toWTThey also exhibit neuronal shrinkage and hyperprolifer-ation of glia by 3 months of age as well as having high levelsof apoE and apoE-dependent deposition of amyloid plaquesthroughout the CNS by 12 months of age [143] These micealso demonstrate spatial learning deficits in the Morris watermaze [144] and a decrease in hippocampal- and amygdala-dependent memory in a fear-conditioning paradigm that isaccompanied by decreased synaptic plasticity in hippocampalslice preparations [145] The critical role of ER120573 in higher-level brain functions has been deduced from these studiesand others warranting a full investigation of the wide-spreadmolecular actions of E

2known to contribute to cellular

processes on at least two levels at the synapse and on thegenome

Long-term potentiation (LTP) is an important compo-nent of learning and memory It represents an increasein synaptic transmission and plasticity that underlies cog-nitive behaviors and it is readily altered by E

2in many

circumstances In fact application of an aromatase inhibitoreliminates CA LTP generated by theta-burst stimulation inintact female neurons but not male or OVX animals posinga potentially serious concern for women using aromataseinhibitors for therapeutic treatment of breast cancer [146] E

2

can also enhance or suppress long-term depression (LTD)reducing synaptic transmission which may be dependentupon the specific receptors involved In aged male CA1cells E

2decreased LTD [147] however E

2enhanced LTP in

the cerebellum where ER120573 is the predominately expressedcognate receptor [148]

Although the majority of studies on cognitive processfocus on the rapid effects of E

2 late-phase long-term potenti-

ation (L-LTP) depends upon transcription and translation ofnewmRNA [149] to sustain an increase in synaptic transmis-sion E

2has been shown to regulate LTP in CA1 pyramidal

cells [150] over the span of 48 hours and this regulationappears to be dependent upon a higher ratio of NMDARrelative to AMPAR LTP induction requires activation ofNR2A-containing NMDARs however increased expressionof NR2B potentiates LTP magnitude [151] Notably E

2

increased expression of NR2B mRNA and NR2B expressionat the synapse [152 153] and the E

2-induced increase in

LTP can be abolished by blocking NR2B receptors [154]

ISRN Endocrinology 9

suggesting a transcriptional role for ERs in synaptic plasticityMoreover E

2application may increase CREB expression and

the amount of phosphorylated CREB in regions such as theamygdala [155] and BNST [117 155] which may be critical inthe formation of long-term memories Taken together thesedata demonstrate that E

2regulates neuronal plasticity and

memory through its original role as a transcription factor andalso by acting as a general intracellular signaling moleculethrough regulation of NMDARs and CREB However todate there are little data on the mechanisms by which ER120573regulates these processes or how the same principles ofplasticity may apply to other neurological issues

12 Estrogens and Mood Regulation

A range of behavioral experiments indicate that E2mod-

ulation of stress mood and affect is a complex storywith considerable conflicting data that may as in otherprocesses be explained in part by distinct roles for ER120572 andER120573 Anecdotally many women report mood fluctuationsas corresponding to changes in circulating estrogen levelssuch as what occurs during the menstrual cycle peripubertypostpartum and peripostmenopause Incidence of anxietyand depression are observed at perimenopause and whenhormone levels are fluctuating [156 157] However E

2can

also exhibit anxiogenic properties and often anxiety anddepression present in a comorbid fashion especially inwomen [158 159] Interestingly after the age of 55 bouts ofdepression and anxiety appear to decrease in women [160]As previously mentioned perimenopausal women receivingCEE in the KEEPs study reported an improvement in moodand the primary actions of CEE tend to be mediated throughER120573 [20] A plethora of behavioral studies has mountedin response to observational reports and at first glance itappears that ER120573 has an anxiolytic and antidepressive rolehowever there is still an immense void to be filled withrespect to biochemical and molecular mechanisms of ER120573and affective disorders Elucidating the precise molecularmechanisms that require ER120573 in plasticity and neurotrans-mitter processing in brain regions regulating these behaviorswill help clarify the role of E

2in stress- and mood-related

processesContemporary hypotheses concerning the onset of affec-

tive disorders revolve around perturbations to the cen-tral processing of environmental stress The hypothalamic-pituitary-adrenal (HPA) axis is the 3-tiered hierarchicalbiological system that mediates physical or psychologicalresponse to stressors The primary steroid regulating theHPA axis is cortisolcorticosterone (humansrats CORT) aglucocorticoid receptor (GR) ligand that is produced fromthe adrenals to exert negative feedback upon the HPAsystem to effectively modulate response to stressors Theparaventricular nucleus of hypothalamus (PVN) producestwo neuropeptides corticotropin-releasing hormone (CRH)and arginine vasopressin (AVP) to activate the HPA axisCRF and AVP synergistically stimulate release of adreno-corticotropic hormone (ACTH) from the anterior pituitarywhich acts on the adrenal cortex to produce CORT CORT

binds GR and negatively regulates CRF and AVP expressionsand releases through classical negative feedback mechanisms[161 162] ER120573 is themain ER expressed in the PVN [158 163ndash165] and regulation of AVP is an interesting example of howER action can vary AVP expression fluctuates during themenstrual cycle and is usually highest when E

2is low In fact

oral contraceptives appear to decrease AVP expression andE2is thought to inhibit AVP in the human SON [166] In

the rodent system ER120573 and its splice variants activate therodent AVP promoter independent of ligand [84] howeverthe human promoter is repressed by ER120573 and splice variantsThis discrepancy between the human and rat wasmediated byan AP-1 response element on the human AVP promoter thatis not present in the rat Importantly ER120573 acted similarly inthe two systems when the AP-1 sequence was deleted fromthe human promoter underscoring the striking alterationsthat small changes in DNA sequence can invoke in E

2

signaling pathways and the importance of understanding theexperimental context upon which such conclusions are based[77] On the contrary rat and human CRF expression wasincreased in response to E

2in rodent monkey and human

hypothalamus but it was inhibited in the placenta [167ndash170]In addition to AVP and CRF glutamatergic and GABAer-

gic projects from regions like the BNST AMY PFC andhippocampus all express ER120573 [45 46] and are likely targetsfor E2to exert effects on the HPA axis Moreover decreased

ER120573 mRNA in postmortem locus coeruleus has been foundto correlate with suicide [13] and even more recentlyER120573-mediated hippocampal nitric oxide levels have beenimplicated in affective behaviors in females but not males[171] Neurotransmitter release from these regions influencesmood affect and stress responses and E

2increases the rate

of monoamine oxidase degradation and serotonin transportwhich enhances serotonin at the synapse E

2also increases

serotonin receptor expression [172 173] Dopamine andserotonin [174] are diminished in the BNST POA and hip-pocampus and caudate putamen (dopamine) of 120573ERKOmice[174] further implicating an important role for ER120573 in theregulation of emotion and mood 120573ERKO mice also displayserious morphological and functional abnormalities in thebrain that correlate to increased depression and anxiety [12175ndash178] In addition to 120573ERKO studies administration ofER120573 selective agonists (diarylpoprionitrile DPN) decreasesboth stress markers and anxiety-related behaviors in rats[158] In fact there have been several studies implicatingER120573 and its variants in affective behaviors but the molecularmechanisms remain poorly understood

13 Summary

Estrogen-receptor-mediated signaling in the brain regulatesneurological processes many of which translate to cog-nitive and affective behavioral outputs When estrogen isdeclining and becomes replete as in menopause a num-ber of neurophysiological changes occur producing someunwanted changes The most common and logical remedyis replacement of bioidentical hormone E

2 however this

treatment can be problematic depending upon the length

10 ISRN Endocrinology

of time a woman has been in a postmenopausal estrogen-deprived state This suggests that there is a molecular switchin estrogen-mediated signaling that may allow for drasticchange in ER signaling not to mention the interaction of E

2

signaling components and the natural aging process Thesechanges are likely to include alterations to receptor profilesincluding expression of alternatively spliced variants thatrespond differently to E

2 changes in the cellular microenvi-

ronment that can alter the proteinprotein associations whichultimately leads to changes in ER-mediated gene transcrip-tion and synaptic transmission ER120573 in particular is widelyexpressed and implicated positively in the regulation ofmemory and mood fluctuations two of the most commonlyreported neurological issues in postmenopausal women Itis important to understand the actions of ER120573 in the areasregulating these processes to identify what when how andfor whom hormone therapy may be a useful treatment torectify cognitive and affective issues

Acknowledgments

This work was supported by NIA RO1 AG033605-01 andNIH T32 AG031780 The authors N N Mott and T R Pakhave nothing to disclose

References

[1] C Bengtsson O Lindquist and L Redvall ldquoIs the menopausalage rapidly changingrdquoMaturitas vol 1 no 3 pp 159ndash164 1979

[2] A Singh S Kaur and I Walia ldquoA historical perspective onmenopause andmenopausal agerdquo Bulletin of the Indian Instituteof History of Medicine (Hyderabad) vol 32 no 2 pp 121ndash1352002

[3] P Verhaeghen and J Cerella ldquoAging executive control andattention a review of meta-analysesrdquo Neuroscience and Biobe-havioral Reviews vol 26 no 7 pp 849ndash857 2002

[4] T E Wroolie H A Kenna K E Williams et al ldquoDifferencesin verbal memory performance in postmenopausal womenreceiving hormone therapy 17120573-estradiol versus conjugatedequine estrogensrdquoAmerican Journal of Geriatric Psychiatry vol19 no 9 pp 792ndash802 2011

[5] B B Sherwin ldquoEstrogenic effects on memory in womenrdquoAnnals of the New York Academy of Sciences vol 743 pp 213ndash230 1994

[6] B B Sherwin ldquoHormones mood and cognitive functioning inpostmenopausal womenrdquoObstetrics andGynecology vol 87 no2 supplement pp 20Sndash26S 1996

[7] B B Sherwin ldquoSex hormones and psychological functioning inpostmenopausalwomenrdquoExperimentalGerontology vol 29 no3-4 pp 423ndash430 1994

[8] SM Phillips and B B Sherwin ldquoEffects of estrogen onmemoryfunction in surgically menopausal womenrdquo Psychoneuroen-docrinology vol 17 no 5 pp 485ndash495 1992

[9] R Lindsay J M Aitken and J B Anderson ldquoLong term pre-vention of postmenopausal osteoporosis by oestrogen Evidencefor an increased bone mass after delayed onset of oestrogentreatmentrdquoThe Lancet vol 1 no 7968 pp 1038ndash1040 1976

[10] J E Rossouw R L Prentice J E Manson et al ldquoPost-menopausal hormone therapy and risk of cardiovascular dis-ease by age and years since menopauserdquo The Journal of the

American Medical Association vol 297 no 13 pp 1465ndash14772007

[11] Q-G Zhang D Han R-M Wang et al ldquoC terminusof Hsc70-interacting protein (CHIP)-mediated degradationof hippocampal estrogen receptor-120572 and the critical periodhypothesis of estrogen neuroprotectionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 108 no 35 pp E617ndashE624 2011

[12] W Krezel S Dupont A Krust P Chambon and P F ChapmanldquoIncreased anxiety and synaptic plasticity in estrogen receptor120573-deficient micerdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 21 pp 12278ndash12282 2001

[13] H Ostlund E Keller and Y L Hurd ldquoEstrogen receptor geneexpression in relation to neuropsychiatric disordersrdquo Annals ofthe New York Academy of Sciences vol 1007 pp 54ndash63 2003

[14] S A Shumaker C Legault S R Rapp et al ldquoEstrogen plusprogestin and the incidence of dementia and mild cognitiveimpairment in postmenopausal women the Womenrsquos HealthInitiative Memory Study a randomized controlled trialrdquo Jour-nal of the American Medical Association vol 289 no 20 pp2651ndash2662 2003

[15] S A Shumaker C Legault L Kuller et al ldquoConjugated equineestrogens and incidence of probable dementia and mild cog-nitive impairment in postmenopausal women womenrsquos HealthInitiative Memory Studyrdquo Journal of the American MedicalAssociation vol 291 no 24 pp 2947ndash2958 2004

[16] S R Rapp M A Espeland S A Shumaker et al ldquoEffect ofestrogen plus progestin on global cognitive function in post-menopausal women the Womenrsquos Health Initiative MemoryStudy a randomized controlled trialrdquo Journal of the AmericanMedical Association vol 289 no 20 pp 2663ndash2672 2003

[17] VWHenderson K S Benke R C Green L A Cupples and LA Farrer ldquoPostmenopausal hormone therapy and Alzheimerrsquosdisease risk interaction with agerdquo Journal of Neurology Neuro-surgery and Psychiatry vol 76 no 1 pp 103ndash105 2005

[18] E Garbe and S Suissa ldquoHormone replacement therapy andacute coronary syndromes methodological issues betweenrandomized and observational studiesrdquo Human Reproductionvol 19 no 1 pp 8ndash13 2004

[19] B B Braden A N Garcia S E Mennenga et al ldquoCognitive-impairing effects of medroxyprogesterone acetate in the ratindependent and interactive effects across timerdquo Psychophar-macology vol 218 no 2 pp 405ndash418 2011

[20] B R Bhavnani S-P Tam and X Lu ldquoStructure activity rela-tionships and differential interactions and functional activity ofvarious equine estrogens mediated via estrogen receptors (ERs)ER120572 and ER120573rdquo Endocrinology vol 149 no 10 pp 4857ndash48702008

[21] E Hogervorst and S Bandelow ldquoSex steroids to maintaincognitive function in women after the menopause a meta-analyses of treatment trialsrdquoMaturitas vol 66 no 1 pp 56ndash712010

[22] D J Mangelsdorf C Thummel M Beato et al ldquoThe nuclearreceptor super-family the second decaderdquo Cell vol 83 no 6pp 835ndash839 1995

[23] E V Jensen T Suzuki T Kawashima W E Stumpf P WJungblut and E R DeSombre ldquoA two-step mechanism forthe interaction of estradiol with rat uterusrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 59 no 2 pp 632ndash638 1968

ISRN Endocrinology 11

[24] F Naftolin T L Horvath R L Jakab C Leranth N Haradaand J Balthazart ldquoAromatase immunoreactivity in axon termi-nals of the vertebrate brain an immunocytochemical study onquail rat monkey and human tissuesrdquoNeuroendocrinology vol63 no 2 pp 149ndash155 1996

[25] C E Roselli S E Abdelgadir O K Roslashnnekleiv and S AKlosterman ldquoAnatomic distribution and regulation of aro-matase gene expression in the rat brainrdquo Biology of Reproduc-tion vol 58 no 1 pp 79ndash87 1998

[26] J Balthazart and G F Ball ldquoIs brain estradiol a hormone or aneurotransmitterrdquo Trends in Neurosciences vol 29 no 5 pp241ndash249 2006

[27] T R Pak Y S Rao S A Prins and N N Mott ldquoAn emergingrole for microRNAs in sexually dimorphic neurobiologicalsystemsrdquo Pflugers Archiv vol 465 no 5 pp 655ndash667 2013

[28] K Yamagata S Fujiyama S Ito et al ldquoMaturation ofmicroRNAis hormonally regulated by a nuclear receptorrdquo Molecular Cellvol 36 no 2 pp 340ndash347 2009

[29] Y Masuhiro Y Mezaki M Sakari et al ldquoSplicing potentiationby growth factor signals via estrogen receptor phosphorylationrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 23 pp 8126ndash8131 2005

[30] A Tremblay G B Tremblay F Labrie and V Giguere ldquoLigand-Independent recruitment of SRC-1 to estrogen receptor 120573through phosphorylation of activation function AF-1rdquo Molec-ular Cell vol 3 no 4 pp 513ndash519 1999

[31] S H Meijsing M A Pufall A Y So D L Bates L Chenand K R Yamamoto ldquoDNA binding site sequence directsglucocorticoid receptor structure and activityrdquo Science vol 324no 5925 pp 407ndash410 2009

[32] W Bourguet P Germain and H Gronemeyer ldquoNuclearreceptor ligand-binding domains three-dimensional struc-tures molecular interactions and pharmacological implica-tionsrdquo Trends in Pharmacological Sciences vol 21 no 10 pp381ndash388 2000

[33] A Koide C Zhao M Naganuma et al ldquoIdentification ofregions within the F domain of the human estrogen receptor 120572that are important for modulating transactivation and protein-protein interactionsrdquoMolecular Endocrinology vol 21 no 4 pp829ndash842 2007

[34] D F Skafar and S Koide ldquoUnderstanding the human estrogenreceptor-alpha using targeted mutagenesisrdquoMolecular and Cel-lular Endocrinology vol 246 no 1-2 pp 83ndash90 2006

[35] E C Chang J Frasor B Komm and B S KatzenellenbogenldquoImpact of estrogen receptor 120573 on gene networks regulated byestrogen receptor 120572 in breast cancer cellsrdquo Endocrinology vol147 no 10 pp 4831ndash4842 2006

[36] X Zhu I Leav Y-K Leung et al ldquoDynamic regulation ofestrogen receptor-120573 expression by DNA methylation duringprostate cancer development andmetastasisrdquoAmerican Journalof Pathology vol 164 no 6 pp 2003ndash2012 2004

[37] D N Petersen G T Tkalcevic P H Koza-Taylor T G Turiand T A Brown ldquoIdentification of estrogen receptor 1205732 afunctional variant of estrogen receptor 120573 expressed in normalrat tissuesrdquo Endocrinology vol 139 no 3 pp 1082ndash1092 1998

[38] L A Helguero M H Faulds J-A Gustafsson and L-AHaldosen ldquoEstrogen receptors alfa (ER120572) and beta (ER120573)differentially regulate proliferation and apoptosis of the normalmurine mammary epithelial cell line HC11rdquo Oncogene vol 24no 44 pp 6605ndash6616 2005

[39] P C Kulakosky M A McCarty S C Jernigan K E Risingerand C M Klinge ldquoResponse element sequence modulates

estrogen receptor 120572 and 120573 affinity and activityrdquo Journal ofMolecular Endocrinology vol 29 no 1 pp 137ndash152 2002

[40] OM V Grober MMutarelli G Giurato et al ldquoGlobal analysisof estrogen receptor beta binding to breast cancer cell genomereveals an extensive interplay with estrogen receptor alpha fortarget gene regulationrdquo BMC Genomics vol 12 article 36 2011

[41] O I Vivar X Zhao E F Saunier et al ldquoEstrogen receptor 120573binds to and regulates three distinct classes of target genesrdquoJournal of Biological Chemistry vol 285 no 29 pp 22059ndash22066 2010

[42] G G J M Kuiper E Enmark M Pelto-Huikko S Nilssonand J-A Gustafsson ldquoCloning of a novel estrogen receptorexpressed in rat prostate and ovaryrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 93 no12 pp 5925ndash5930 1996

[43] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and 120572 and 120573rdquo Endocrinology vol 138no 3 pp 863ndash870 1997

[44] D B Dubal H Zhu J Yu et al ldquoEstrogen receptor alpha notbeta is a critical link in estradiol-mediated protection againstbrain injuryrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 98 no 4 pp 1952ndash1957 2001

[45] P J Shughrue P J Scrimo and I Merchenthaler ldquoEvidence forthe colocalization of estrogen receptor-120573 mRNA and estrogenreceptor-120572 immunoreactivity in neurons of the rat forebrainrdquoEndocrinology vol 139 no 12 pp 5267ndash5270 1998

[46] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in therat central nervous systemrdquo Journal of Comparative Neurologyvol 388 no 4 pp 507ndash525 1997

[47] T AMilner B SMcEwen S Hayashi C J Li L P Reagan andS E Alves ldquoUltrastructural evidence that hippocampal alphaestrogen receptors are located at extranuclear sitesrdquoThe Journalof Comparative Neurology vol 429 no 3 pp 355ndash371 2001

[48] T A Milner L S Lubbers S E Alves and B S McEwenldquoNuclear and extranuclear estrogen binding sites in the ratforebrain and autonomic medullary areasrdquo Endocrinology vol149 no 7 pp 3306ndash3312 2008

[49] T A Milner K Ayoola C T Drake et al ldquoUltrastructurallocalization of estrogen receptor 120573 immunoreactivity in the rathippocampal formationrdquo Journal of ComparativeNeurology vol491 no 2 pp 81ndash95 2005

[50] A E Herbison andD TTheodosis ldquoAbsence of estrogen recep-tor immunoreactivity in somatostatin (SRIF) neurons of theperiventricular nucleus but sexually dimorphic colocalizationof estrogen receptor and SRIF immunoreactivities in neuronsof the bed nucleus of the stria terminalisrdquo Endocrinology vol132 no 4 pp 1707ndash1714 1993

[51] K Kalita S Szymczak and L Kaczmarek ldquoNon-nuclear estro-gen receptor 120573 and 120572 in the hippocampus of male and femaleratsrdquo Hippocampus vol 15 no 3 pp 404ndash412 2005

[52] T Ivanova and C Beyer ldquoOntogenetic expression and sexdifferences of aromatase and estrogen receptor-120572120573 mRNA inthe mouse hippocampusrdquo Cell and Tissue Research vol 300 no2 pp 231ndash237 2000

[53] C Y Pau K-Y F Pau and H G Spies ldquoPutative estrogenreceptor 120573 and 120572 mRNA expression in male and female rhesusmacaquesrdquo Molecular and Cellular Endocrinology vol 146 no1-2 pp 59ndash68 1998

[54] A L Wijayaratne and D P McDonnell ldquoThe human estrogenreceptor-120572 is a ubiquitinated protein whose stability is affected

12 ISRN Endocrinology

differentially by agonists antagonists and selective estrogenreceptor modulatorsrdquo Journal of Biological Chemistry vol 276no 38 pp 35684ndash35692 2001

[55] V Bartella P Rizza I Barone et al ldquoEstrogen receptor betabinds Sp1 and recruits a corepressor complex to the estrogenreceptor alpha gene promoterrdquo Breast Cancer Research andTreatment vol 134 no 2 pp 569ndash581 2012

[56] L C Li C C Yeh D Nojima and R Dahiya ldquoCloning andcharacterization of human estrogen receptor beta promoterrdquoBiochemical and Biophysical Research Communications vol 275no 2 pp 682ndash689 2000

[57] E A Vladusic A E Hornby F K Guerra-Vladusic J Lakinsand R Lupu ldquoExpression and regulation of estrogen receptor szligin human breast tumors and cell linesrdquoOncology Reports vol 7no 1 pp 157ndash167 2000

[58] T Hatsumi and Y Yamamuro ldquoDownregulation of estrogenreceptor gene expression by exogenous 17120573-estradiol in themammary glands of lactating micerdquo Experimental Biology andMedicine vol 231 no 3 pp 311ndash316 2006

[59] H B Patisaul P L Whitten and L J Young ldquoRegulation ofestrogen receptor beta mRNA in the brain opposite effectsof 17120573-estradiol and the phytoestrogen coumestrolrdquoMolecularBrain Research vol 67 no 1 pp 165ndash171 1999

[60] T J Brown N J MacLusky M Shanabrough and F NaftolinldquoComparison of age- and sex-related changes in cell nuclearestrogen-binding capacity and progestin receptor induction inthe rat brainrdquo Endocrinology vol 126 no 6 pp 2965ndash29721990

[61] B S Rubin T O Fox and R S Bridges ldquoEstrogen bindingin nuclear and cytosolic extracts from brain and pituitary ofmiddle-aged female ratsrdquo Brain Research vol 383 no 1-2 pp60ndash67 1986

[62] T Funabashi S P Kleopoulos P J Brooks et al ldquoChangesin estrogenic regulation of estrogen receptor 120572 mRNA andprogesterone receptor mRNA in the female rat hypothalamusduring aging an in situ hybridization studyrdquo NeuroscienceResearch vol 38 no 1 pp 85ndash92 2000

[63] M E Wilson K L Rosewell M L Kashon P J Shughrue IMerchenthaler and P M Wise ldquoAge differentially influencesestrogen receptor-120572 (ER120572) and estrogen receptor-120573 (ER120573) geneexpression in specific regions of the rat brainrdquo Mechanisms ofAgeing and Development vol 123 no 6 pp 593ndash601 2002

[64] W S Post P J Goldschmidt-Clermont C C Wilhide etal ldquoMethylation of the estrogen receptor gene is associatedwith aging and atherosclerosis in the cardiovascular systemrdquoCardiovascular Research vol 43 no 4 pp 985ndash991 1999

[65] J-P J Issa Y L Ottaviano P Celano S R Hamilton NE Davidson and S B Baylin ldquoMethylation of the oestrogenreceptor CpG island links ageing and neoplasia in humancolonrdquo Nature Genetics vol 7 no 4 pp 536ndash540 1994

[66] T Funabashi and F Kimura ldquoEffects of estrogen and estrogenreceptor messenger RNA levels in young and middle-agedfemale rats comparison ofmedial preoptic area andmediobasalhypothalamusrdquo Acta Biologica Hungarica vol 45 no 2ndash4 pp223ndash231 1994

[67] M AMiller P E Kolb B Planas andM A Raskind ldquoEstrogenreceptor and neurotensinneuromedin-N gene expression inthe preoptic area are unaltered with age in Fischer 344 femaleratsrdquo Endocrinology vol 135 no 5 pp 1986ndash1995 1994

[68] T R Chakraborty P R Hof L Ng and A C Gore ldquoStereologicanalysis of estrogen receptor alpha (ER alpha) expression in rat

hypothalamus and its regulation by aging and estrogenrdquo Journalof Comparative Neurology vol 466 no 3 pp 409ndash421 2003

[69] J M Westberry A L Trout and M E Wilson ldquoEpigeneticregulation of estrogen receptor beta expression in the rat cortexduring agingrdquo NeuroReport vol 22 no 9 pp 428ndash432 2011

[70] T R Chakraborty L Ng and A C Gore ldquoAge-related changesin estrogen receptor 120573 in rat hypothalamus a quantitativeanalysisrdquo Endocrinology vol 144 no 9 pp 4164ndash4171 2003

[71] I Poola S Koduri S Chatra and R Clarke ldquoIdentificationof twenty alternatively spliced estrogen receptor alpha mRNAsin breast cancer cell lines and tumors using splice targetedprimer approachrdquo Journal of Steroid Biochemistry andMolecularBiology vol 72 no 5 pp 249ndash258 2000

[72] T A Ishunina and D F Swaab ldquoHippocampal estrogenreceptor-alpha splice variant TADDI in the human brain inaging and Alzheimerrsquos diseaserdquoNeuroendocrinology vol 89 no2 pp 187ndash199 2009

[73] T A Ishunina and D F Swaab ldquoEstrogen receptor-120572 splicevariants in the human brainrdquo Gynecological Endocrinology vol24 no 2 pp 93ndash98 2008

[74] T A Ishunina F P M Kruijver R Balesar and D FSwaab ldquoDifferential expression of estrogen receptor 120572 and 120573immunoreactivity in the human supraoptic nucleus in rela-tion to sex and agingrdquo Journal of Clinical Endocrinology andMetabolism vol 85 no 9 pp 3283ndash3291 2000

[75] T A Ishunina D F Fischer andD F Swaab ldquoEstrogen receptor120572 and its splice variants in the hippocampus in aging andAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 28 no 11 pp1670ndash1681 2007

[76] J R Tollervey Z Wang T Hortobagyi et al ldquoAnalysis of alter-native splicing associated with aging and neurodegeneration inthe human brainrdquo Genome Research vol 21 no 10 pp 1572ndash1582 2011

[77] N NMott and T R Pak ldquoCharacterisation of human oestrogenreceptor beta (ER120573) splice variants in neuronal cellsrdquo Journal ofNeuroendocrinology vol 24 no 10 pp 1311ndash1321 2012

[78] S Inoue S-J Hoshino H Miyoshi et al ldquoIdentification ofa ovel isoform of estrogen receptor a potential inhibitor ofestrogen action in vascular smooth muscle cellsrdquo Biochemicaland Biophysical Research Communications vol 219 no 3 pp766ndash772 1996

[79] J K Skipper L J Young J M Bergeron M T Tetzlaff CT Osborn and D Crews ldquoIdentification of an isoform ofthe estrogen receptor messenger RNA lacking exon four andpresent in the brainrdquo Proceedings of the National Academy ofSciences of the United States of America vol 90 no 15 pp 7172ndash7175 1993

[80] R H Price Jr N Lorenzon and R J Handa ldquoDifferentialexpression of estrogen receptor beta splice variants in rat brainidentification and characterization of a novel variant missingexon 4rdquo Brain Research Molecular Brain Research vol 80 no2 pp 260ndash268 2000

[81] S Chu and P J Fuller ldquoIdentification of a splice variantof the rat estrogen receptor 120573 generdquo Molecular and CellularEndocrinology vol 132 no 1-2 pp 195ndash199 1997

[82] B Lu E Leygue H Dotzlaw L J Murphy L C Murphy andP H Watson ldquoEstrogen receptor-120573 mRNA variants in humanand murine tissuesrdquoMolecular and Cellular Endocrinology vol138 no 1-2 pp 199ndash203 1998

[83] T R Pak W C J Chung J L Roberts and R J HandaldquoLigand-independent effects of estrogen receptor 120573 on

ISRN Endocrinology 13

mouse gonadotropin-releasing hormone promoter activityrdquoEndocrinology vol 147 no 4 pp 1924ndash1931 2006

[84] T R Pak W C J Chung L R Hinds and R J HandaldquoEstrogen receptor-120573 mediates dihydrotestosterone-inducedstimulation of the arginine vasopressin promoter in neuronalcellsrdquo Endocrinology vol 148 no 7 pp 3371ndash3382 2007

[85] Y K Leung PMak S Hassan and SMHo ldquoEstrogen receptor(ER)-120573 isoforms a key to understanding ER-120573 signalingrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 103 no 35 pp 13162ndash13167 2006

[86] J M Wang X Hou S Adeosun et al ldquoA dominant negativeER120573 splice variant determines the effectiveness of early or lateestrogen therapy after ovariectomy in ratsrdquo PLoS One vol 7 no3 Article ID e33493 2012

[87] W C J Chung T R Pak S Suzuki W A Pouliot M EAndersen and R J Handa ldquoDetection and localization of anestrogen receptor beta splice variant protein (ER1205732) in theadult female rat forebrain and midbrain regionsrdquo Journal ofComparative Neurology vol 505 no 3 pp 249ndash267 2007

[88] R H Price Jr C A Butler P Webb R Uht P Kushner andR J Handa ldquoA splice variant of estrogen receptor 120573 missingexon 3 displays altered subnuclear localization and capacity fortranscriptional activationrdquo Endocrinology vol 142 no 5 pp2039ndash2049 2001

[89] Y Wang and R J Miksicek ldquoIdentification of a dominantnegative form of the human estrogen receptorrdquo MolecularEndocrinology vol 5 no 11 pp 1707ndash1715 1991

[90] E Kuppers and C Beyer ldquoExpression of estrogen receptor-120572and 120573 mRNA in the developing and adult mouse striatumrdquoNeuroscience Letters vol 276 no 2 pp 95ndash98 1999

[91] C Gundlah S G Kohama S J Mirkes V T Garyfallou H FUrbanski and C L Bethea ldquoDistribution of estrogen receptorbeta (ER120573) mRNA in hypothalamus midbrain and temporallobe of spayed macaque continued expression with hormonereplacementrdquo Brain Research Molecular Brain Research vol 76no 2 pp 191ndash204 2000

[92] Y Morishima P J M Murphy D-P Li E R Sanchez and WB Pratt ldquoStepwise assembly of a glucocorticoid receptorsdothsp90heterocomplex resolves two sequential ATP-dependent eventsinvolving first hsp70 and then hsp90 in opening of the steroidbinding pocketrdquo Journal of Biological Chemistry vol 275 no 24pp 18054ndash18060 2000

[93] K D Dittmar and W B Pratt ldquoFolding of the glucocorticoidreceptor by the reconstituted hsp90-based chaperone machin-eryThe initial hsp90sdotp60sdothsp70-dependent step is sufficient forcreating the steroid binding conformationrdquo Journal of BiologicalChemistry vol 272 no 20 pp 13047ndash13054 1997

[94] K I Kang X Meng J Devin-Leclerc et al ldquoThe molecularchaperone Hsp90 can negatively regulate the activity of aglucocorticosteroid-dependent promoterrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 4 pp 1439ndash1444 1999

[95] K Unno H Asakura Y Shibuya M Kaiho S Okada and NOku Naoto ldquoIncrease in basal level of Hsp70 consisting chieflyof constitutively expressed hsp70 (Hsc70) in aged rat brainrdquoJournals of Gerontology Series A vol 55 no 7 pp B329ndashB3352000

[96] U E Olazabal D W Pfaff and C V Mobbs ldquoSex differences inthe regulation of heat shock protein 70 kDa and 90 kDa in therat ventromedial hypothalamus by estrogenrdquo Brain Researchvol 596 no 1-2 pp 311ndash314 1992

[97] M A Pahlavani M D Harris S A Moore and A RichardsonldquoExpression of heat shock protein 70 in rat spleen lymphocytesis affected by age but not by food restrictionrdquo Journal ofNutrition vol 126 no 9 pp 2069ndash2075 1996

[98] A R Heydari B Wu R Takahashi R Strong and A Richard-son ldquoExpression of heat shock protein 70 is altered by age anddiet at the level of transcriptionrdquoMolecular andCellular Biologyvol 13 no 5 pp 2909ndash2918 1993

[99] M Sabbah K-I I Kang L Tora and G Redeuilh ldquoOestro-gen receptor facilitates the formation of preinitiation com-plex assembly involvement of the general transcription factorTFIIBrdquo Biochemical Journal vol 336 part 3 pp 639ndash646 1998

[100] S-Y Wu M C Thomas S Y Hou V Likhite and C-MChiang ldquoIsolation of mouse TFIID and functional character-ization of TBP and TFIID in mediating estrogen receptor andchromatin transcriptionrdquo Journal of Biological Chemistry vol274 no 33 pp 23480ndash23490 1999

[101] S Ghosh and M K Thakur ldquoTissue-specific expression ofreceptor-interacting protein in aging mouserdquo Age vol 30 no4 pp 237ndash243 2008

[102] J Frasor JM Danes B Komm K C N Chang C Richard Lyt-tle and B S Katzenellenbogen ldquoProfiling of estrogen up- anddown-regulated gene expression in human breast cancer cellsinsights into gene networks and pathways underlying estrogeniccontrol of proliferation and cell phenotyperdquo Endocrinology vol144 no 10 pp 4562ndash4574 2003

[103] J Frasor J M Danes C C Funk and B S Katzenellen-bogen ldquoEstrogen down-regulation of the corepressor N-CoRmechanism and implications for estrogen derepression of N-CoR-regulated genesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 102 no 37 pp13153ndash13157 2005

[104] N J McKenna and B W OrsquoMalley ldquoCombinatorial control ofgene expression by nuclear receptors and coregulatorsrdquoCell vol108 no 4 pp 465ndash474 2002

[105] T-P Yao G Ku N Zhou R Scully and D M Livingston ldquoThenuclear hormone receptor coactivator SRC-1 is a specific targetof p300rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 93 no 20 pp 10626ndash10631 1996

[106] B Hanstein R Eckner J DiRenzo et al ldquop300 is a componentof an estrogen receptor coactivator complexrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 93 no 21 pp 11540ndash11545 1996

[107] S Halachmi E Marden G Martin H MacKay C Abbon-danza and M Brown ldquoEstrogen receptor-associated proteinspossible mediators of hormone-induced transcriptionsrdquo Sci-ence vol 264 no 5164 pp 1455ndash1458 1994

[108] A J Horlein AM Naar T Heinzel et al ldquoLigand-independentrepression by the thyroid hormone receptor mediated by anuclear receptor co-repressorrdquo Nature vol 377 no 6548 pp397ndash404 1995

[109] J D Chen and R M Evans ldquoA transcriptional co-repressor thatinteracts with nuclear hormone receptorsrdquo Nature vol 377 no6548 pp 454ndash457 1995

[110] A Malovannaya R B Lanz S Y Jung et al ldquoAnalysis of thehuman endogenous coregulator complexomerdquoCell vol 145 no5 pp 787ndash799 2011

[111] Z Nawaz D M Lonard C L Smith et al ldquoThe Angelmansyndrome-associated protein E6-AP is a coactivator for thenuclear hormone receptor superfamilyrdquoMolecular and CellularBiology vol 19 no 2 pp 1182ndash1189 1999

14 ISRN Endocrinology

[112] B Zheng M Han M Bernier and J-K Wen ldquoNuclear actinand actin-binding proteins in the regulation of transcriptionand gene expressionrdquo FEBS Journal vol 276 no 10 pp 2669ndash2685 2009

[113] W A Hofmann L Stojiljkovic B Fuchsova et al ldquoActin is partof pre-initiation complexes and is necessary for transcription byRNA polymerase IIrdquoNature Cell Biology vol 6 no 11 pp 1094ndash1101 2004

[114] K Tokunaga T Shibuya Y Ishihama et al ldquoNucleocytoplasmictransport of fluorescent mRNA in living mammalian cellsnuclear mRNA export is coupled to ongoing gene transcrip-tionrdquo Genes to Cells vol 11 no 3 pp 305ndash317 2006

[115] R Metivier G Penot M R Hubner et al ldquoEstrogen receptor-120572 directs ordered cyclical and combinatorial recruitment ofcofactors on a natural target promoterrdquo Cell vol 115 no 6 pp751ndash763 2003

[116] C Ambrosino R Tarallo A Bamundo et al ldquoIdentification of ahormone-regulated dynamic nuclear actin network associatedwith estrogen receptor 120572 in human breast cancer cell nucleirdquoMolecular and Cellular Proteomics vol 9 no 6 pp 1352ndash13672010

[117] F Shao R Zhang L Dong and K Ying ldquoOverexpression ofgelsolin-like actin-capping protein is associated with progres-sion of lung adenocarcinomardquo Tohoku Journal of ExperimentalMedicine vol 225 no 2 pp 95ndash101 2011

[118] K Nishimura H-J Ting Y Harada et al ldquoModulation ofandrogen receptor transactivation by gelsolin a newly identi-fied androgen receptor coregulatorrdquo Cancer Research vol 63no 16 pp 4888ndash4894 2003

[119] J S Ahn I S Jang D I Kim et al ldquoAging-associated increaseof gelsolin for apoptosis resistancerdquoBiochemical and BiophysicalResearch Communications vol 312 no 4 pp 1335ndash1341 2003

[120] I Nalvarte T Schwend and J-A Gustafsson ldquoProteomicsanalysis of the estrogen receptor 120572 receptosomerdquoMolecular andCellular Proteomics vol 9 no 7 pp 1411ndash1422 2010

[121] L-H Miau C-J Chang B-J Shen W-H Tsai and S-C LeeldquoIdentification of heterogeneous nuclear ribonucleoprotein K(hnRNPK) as a repressor ofCEBP120573-mediated gene activationrdquoJournal of Biological Chemistry vol 273 no 17 pp 10784ndash107911998

[122] A Ostareck-Lederer D H Ostareck C Cans et al ldquoc-Src-mediated phosphorylation of hnRNP K drives translationalactivation of specifically silenced mRNAsrdquo Molecular and Cel-lular Biology vol 22 no 13 pp 4535ndash4543 2002

[123] P S Bagga G K Arhin and J Wilusz ldquoDSEF-1 is a member ofthe hnRNP H family of RNA-binding proteins and stimulatespre-mRNAcleavage and polyadenylation in vitrordquoNucleic AcidsResearch vol 26 no 23 pp 5343ndash5350 1998

[124] V Markovtsov J M Nikolic J A Goldman C W Turck M-Y Chou and D L Black ldquoCooperative assembly of an hnRNPcomplex induced by a tissue-specific homolog of polypyrimi-dine tract binding proteinrdquoMolecular and Cellular Biology vol20 no 20 pp 7463ndash7479 2000

[125] S Y Jung A Malovannaya J Wei B W OrsquoMalley and J QinldquoProteomic analysis of steady-state nuclear hormone receptorcoactivator complexesrdquoMolecular Endocrinology vol 19 no 10pp 2451ndash2465 2005

[126] W Hong R J Resnick C Rakowski D Shalloway S J Taylorand G A Blobel ldquoPhysical and functional interaction betweenthe transcriptional cofactor CBP and the KH domain proteinSam68rdquoMolecular Cancer Research vol 1 no 1 pp 48ndash55 2002

[127] R ShaoXWang BWeijdegard et al ldquoCoordinate regulation ofheterogeneous nuclear ribonucleoprotein dynamics by steroidhormones in the human fallopian tube and endometrium invivo and in vitrordquo American Journal of Physiology vol 302 no10 pp E1269ndashE1282 2012

[128] C SWoolley and B SMcEwen ldquoEstradiolmediates fluctuationin hippocampal synapse density during the estrous cycle in theadult ratrdquo Journal of Neuroscience vol 12 no 7 pp 2549ndash25541992

[129] C S Woolley H J Wenzel and P A Schwartzkroin ldquoEstradiolincreases the frequency of multiple synapse boutons in thehippocampal CA1 region of the adult female ratrdquo The Journalof Comparative Neurology vol 373 no 1 pp 108ndash117 1996

[130] C S Woolley ldquoEstrogen-mediated structural and functionalsynaptic plasticity in the female rat hippocampusrdquo Hormonesand Behavior vol 34 no 2 pp 140ndash148 1998

[131] D P Srivastava K M Woolfrey K A Jones et al ldquoRapidenhancement of two-step wiring plasticity by estrogen andNMDA receptor activityrdquo Proceedings of the National Academyof Sciences of the United States of America vol 105 no 38 pp14650ndash14655 2008

[132] M Ogiue-Ikeda N Tanabe H Mukai et al ldquoRapid modu-lation of synaptic plasticity by estrogens as well as endocrinedisrupters in hippocampal neuronsrdquo Brain Research Reviewsvol 57 no 2 pp 363ndash375 2008

[133] N J Sandstrom and C L Williams ldquoSpatial memory retentionis enhanced by acute and continuous estradiol replacementrdquoHormones and Behavior vol 45 no 2 pp 128ndash135 2004

[134] E Hogervorst J Williams M Budge W Riedel and JJolles ldquoThe nature of the effect of female gonadal hormonereplacement therapy on cognitive function in post-menopausalwomen a meta-analysisrdquo Neuroscience vol 101 no 3 pp 485ndash512 2000

[135] M E Bailey A C J Wang J Hao et al ldquoInteractive effects ofage and estrogen on cortical neurons implications for cognitiveagingrdquo Neuroscience vol 191 pp 148ndash158 2011

[136] A A Walf M E Rhodes and C A Frye ldquoOvarian steroidsenhance object recognition in naturally cycling and ovariec-tomized hormone-primed ratsrdquo Neurobiology of Learning andMemory vol 86 no 1 pp 35ndash46 2006

[137] V N Luine L F Jacome and N J Maclusky ldquoRapid enhance-ment of visual and place memory by estrogens in ratsrdquoEndocrinology vol 144 no 7 pp 2836ndash2844 2003

[138] L Fan Z Zhao P T Orr C H Chambers M C Lewis and KM Frick ldquoEstradiol-induced object memory consolidation inmiddle-aged femalemice requires dorsal hippocampal extracel-lular signal-regulated kinase and phosphatidylinositol 3-kinaseactivationrdquo Journal of Neuroscience vol 30 no 12 pp 4390ndash4400 2010

[139] D B Dubal and PMWise ldquoNeuroprotective effects of estradiolin middle-aged female ratsrdquo Endocrinology vol 142 no 1 pp43ndash48 2001

[140] S-H Yang J Shi A L Day and J W Simpkins ldquoEstradiolexerts neuroprotective effects when administered after ischemicinsultrdquo Stroke vol 31 no 3 pp 745ndash750 2000

[141] J W Simpkins G Rajakumar Y-Q Zhang et al ldquoEstrogensmay reduce mortality and ischemic damage caused by middlecerebral artery occlusion in the female ratrdquo Journal of Neuro-surgery vol 87 no 5 pp 724ndash730 1997

[142] J Shi K S Panickar S-H Yang O Rabbani A L Day and JWSimpkins ldquoEstrogen attenuates over-expression of 120573-amyloid

ISRN Endocrinology 15

precursor protein messager RNA in an animal model of focalischemiardquo Brain Research vol 810 no 1-2 pp 87ndash92 1998

[143] Q-H Zhang Y-H Huang Y-Z Hu et al ldquoDisruption ofestrogen receptor beta in mice brain results in pathologicalalterations resemblingAlzheimer diseaserdquoActa PharmacologicaSinica vol 25 no 4 pp 452ndash457 2004

[144] E F Rissman A L Heck J E Leonard M A Shupnik and J-A Gustafsson ldquoDisruption of estrogen receptor 120573 gene impairsspatial learning in female micerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no6 pp 3996ndash4001 2002

[145] M Day A Sung S Logue M Bowlby and R Arias ldquoBetaestrogen receptor knockout (BERKO) mice present attenuatedhippocampal CA1 long-term potentiation and related memorydeficits in contextual fear conditioningrdquo Behavioural BrainResearch vol 164 no 1 pp 128ndash131 2005

[146] R Vierk G Glassmeier L Zhou et al ldquoAromatase inhibitionabolishes LTP generation in female but not in male micerdquo TheJournal of Neuroscience vol 32 no 24 pp 8116ndash8126 2012

[147] R-M Vouimba M R Foy J G Foy and R FThompson ldquo17120573-estradiol suppresses expression of long-term depression in agedratsrdquo Brain Research Bulletin vol 53 no 6 pp 783ndash787 2000

[148] C E Andreescu B A Milojkovic E D Haasdijk et alldquoEstradiol improves cerebellar memory formation by activatingestrogen receptor 120573rdquo Journal of Neuroscience vol 27 no 40 pp10832ndash10839 2007

[149] Y-Y Huang P V Nguyen T Abel and E R Kandel ldquoLong-lasting forms of synaptic potentiation in the mammalian hip-pocampusrdquo Learning Memory vol 3 no 2-3 pp 74ndash85 1996

[150] H Mukai T Tsurugizawa G Murakami et al ldquoRapid mod-ulation of long-term depression and spinogenesis via synapticestrogen receptors in hippocampal principal neuronsrdquo Journalof Neurochemistry vol 100 no 4 pp 950ndash967 2007

[151] L Liu T P Wong M F Pozza et al ldquoRole of NMDA receptorsubtypes in governing the direction of hippocampal synapticplasticityrdquo Science vol 304 no 5673 pp 1021ndash1024 2004

[152] M Cyr O Ghribi C Thibault M Morissette M Landry andT di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[153] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[154] C C Smith and L L McMahon ldquoEstradiol-induced increasein the magnitude of long-term potentiation is prevented byblocking NR2B-containing receptorsrdquo Journal of Neurosciencevol 26 no 33 pp 8517ndash8522 2006

[155] Y Zhou J J Watters and D M Dorsa ldquoEstrogen rapidlyinduces the phosphorylation of the cAMP response elementbinding protein in rat brainrdquo Endocrinology vol 137 no 5 pp2163ndash2166 1996

[156] XGonda T TelekG Juhasz J Lazary AVargha andG BagdyldquoPatterns of mood changes throughout the reproductive cyclein healthy women without premenstrual dysphoric disordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 32 no 8 pp 1782ndash1788 2008

[157] E W Freeman ldquoPremenstrual syndrome and premenstrualdysphoric disorder definitions and diagnosisrdquo Psychoneuroen-docrinology vol 28 supplement 3 pp 25ndash37 2003

[158] T D Lund T Rovis W C J Chung and R J Handa ldquoNovelactions of estrogen receptor-120573 on anxiety-related behaviorsrdquoEndocrinology vol 146 no 2 pp 797ndash807 2005

[159] N Breslau L Schultz and E Peterson ldquoSex differences indepression a role for preexisting anxietyrdquo Psychiatry Researchvol 58 no 1 pp 1ndash12 1995

[160] P E Bebbington G Dunn R Jenkins et al ldquoThe influenceof age and sex on the prevalence of depressive conditionsreport from the National Survey of Psychiatric MorbidityrdquoPsychological Medicine vol 28 no 1 pp 9ndash19 1998

[161] G Aguilera J P Harwood and J X Wilson ldquoMechanisms ofaction of corticotropin-releasing factor and other regulators ofcorticotropin release in rat pituitary cellsrdquo Journal of BiologicalChemistry vol 258 no 13 pp 8039ndash8045 1983

[162] A Papadimitriou and K N Priftis ldquoRegulation of thehypothalamic-pituitary-adrenal axisrdquo NeuroImmunoModula-tion vol 16 no 5 pp 265ndash271 2009

[163] S Suzuki and R J Handa ldquoRegulation of estrogen receptor-120573expression in the female rat hypothalamus differential effectsof dexamethasone and estradiolrdquo Endocrinology vol 145 no 8pp 3658ndash3670 2004

[164] W J S Miller S Suzuki L K Miller R Handa and R M UhtldquoEstrogen receptor (ER)120573 isoforms rather than ER120572 regulatecorticotropin-releasing hormone promoter activity through analternate pathwayrdquo Journal of Neuroscience vol 24 no 47 pp10628ndash10635 2004

[165] C IsgorM CecchiM Kabbaj H Akil and S JWatson ldquoEstro-gen receptor 120573 in the paraventricular nucleus of hypothalamusregulates the neuroendocrine response to stress and is regulatedby corticosteronerdquo Neuroscience vol 121 no 4 pp 837ndash8452003

[166] M L Forsling I Kallo D E Hartley et al ldquoOestrogen receptor-120573 and neurohypophysial hormones functional interaction andneuroanatomical localisationrdquo Pharmacology Biochemistry andBehavior vol 76 no 3-4 pp 535ndash542 2003

[167] A S Lalmansingh and R M Uht ldquoEstradiol regulatescorticotropin-releasing hormone gene (crh) expression in arapid and phasic manner that parallels estrogen receptor-120572 and-120573 recruitment to a 3101584051015840-cyclic adenosine 51015840- monophosphateregulatory region of the proximal crh promoterrdquo Endocrinologyvol 149 no 1 pp 346ndash357 2008

[168] B N Roy R L Reid and D A van Vugt ldquoThe effects ofestrogen and progesterone on corticotropin-releasing hormoneand arginine vasopressin messenger ribonucleic acid levelsin the paraventricular nucleus and supraoptic nucleus of therhesus monkeyrdquo Endocrinology vol 140 no 5 pp 2191ndash21981999

[169] X Ni R C Nicholson B R King E-C Chan M A Read andR Smith ldquoEstrogen represses whereas the estrogen-antagonistICI 182780 stimulates placental CRH gene expressionrdquo Journalof Clinical Endocrinology and Metabolism vol 87 no 8 pp3774ndash3778 2002

[170] N C Vamvakopoulos and G P Chrousos ldquoEvidence of directestrogenic regulation of human corticotropin-releasing hor-mone gene expression Potential implications for the sexualdimophism of the stress response and immuneinflammatoryreactionrdquo Journal of Clinical Investigation vol 92 no 4 pp1896ndash1902 1993

[171] Y Hu D L Wu C X Luo et al ldquoHippocampal nitric oxidecontributes to sex difference in affective behaviorsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 35 pp 14224ndash14229 2012

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

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Diabetes ResearchJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

8 ISRN Endocrinology

Factor BER structureand function

Factor Ccoregulatory and

transcriptional interactions

120573

120573120573

120573

120572

120572

120572 120572

V

V

V

V

V

V

V

V

ESR1

ESR2

Age and E2

++

Context-dependentER-regulated

gene expression

Factor Atissue-specific

ER gene expression

Figure 3 Age and hormonalmilieu exponentially increase the potential diversity of estrogen receptor signaling leading to context-dependentgene regulation Age and E

2influence ER gene expression alternative splicing coregulatory protein expression and interaction which

ultimately direct ER-target gene transcription

For example long-term E2deprivation diminished aged

female rhesus macaquesrsquo performance in a delayed responsetask a PFC- dependent task [135] E

2also enhanced object

recognition under a number of different paradigms [136ndash138] and there are also multiple lines of evidence supportingE2-mediated neuroprotection which may be important for

cognition especially after stroke [139ndash142]Pharmacological targeting of the receptors with ER selec-

tive ligands has been a standard method for investigating thebehavioral physiological and cellular actions of E

2mediated

distinctly throughER120572 andor ER120573 however valuable insighthas also come from the ER120573-null (120573ERKO) mice 120573ERKOmice have significantly fewer neurons in the cortex hypotha-lamus amygdala and ventral tegmental area compared toWTThey also exhibit neuronal shrinkage and hyperprolifer-ation of glia by 3 months of age as well as having high levelsof apoE and apoE-dependent deposition of amyloid plaquesthroughout the CNS by 12 months of age [143] These micealso demonstrate spatial learning deficits in the Morris watermaze [144] and a decrease in hippocampal- and amygdala-dependent memory in a fear-conditioning paradigm that isaccompanied by decreased synaptic plasticity in hippocampalslice preparations [145] The critical role of ER120573 in higher-level brain functions has been deduced from these studiesand others warranting a full investigation of the wide-spreadmolecular actions of E

2known to contribute to cellular

processes on at least two levels at the synapse and on thegenome

Long-term potentiation (LTP) is an important compo-nent of learning and memory It represents an increasein synaptic transmission and plasticity that underlies cog-nitive behaviors and it is readily altered by E

2in many

circumstances In fact application of an aromatase inhibitoreliminates CA LTP generated by theta-burst stimulation inintact female neurons but not male or OVX animals posinga potentially serious concern for women using aromataseinhibitors for therapeutic treatment of breast cancer [146] E

2

can also enhance or suppress long-term depression (LTD)reducing synaptic transmission which may be dependentupon the specific receptors involved In aged male CA1cells E

2decreased LTD [147] however E

2enhanced LTP in

the cerebellum where ER120573 is the predominately expressedcognate receptor [148]

Although the majority of studies on cognitive processfocus on the rapid effects of E

2 late-phase long-term potenti-

ation (L-LTP) depends upon transcription and translation ofnewmRNA [149] to sustain an increase in synaptic transmis-sion E

2has been shown to regulate LTP in CA1 pyramidal

cells [150] over the span of 48 hours and this regulationappears to be dependent upon a higher ratio of NMDARrelative to AMPAR LTP induction requires activation ofNR2A-containing NMDARs however increased expressionof NR2B potentiates LTP magnitude [151] Notably E

2

increased expression of NR2B mRNA and NR2B expressionat the synapse [152 153] and the E

2-induced increase in

LTP can be abolished by blocking NR2B receptors [154]

ISRN Endocrinology 9

suggesting a transcriptional role for ERs in synaptic plasticityMoreover E

2application may increase CREB expression and

the amount of phosphorylated CREB in regions such as theamygdala [155] and BNST [117 155] which may be critical inthe formation of long-term memories Taken together thesedata demonstrate that E

2regulates neuronal plasticity and

memory through its original role as a transcription factor andalso by acting as a general intracellular signaling moleculethrough regulation of NMDARs and CREB However todate there are little data on the mechanisms by which ER120573regulates these processes or how the same principles ofplasticity may apply to other neurological issues

12 Estrogens and Mood Regulation

A range of behavioral experiments indicate that E2mod-

ulation of stress mood and affect is a complex storywith considerable conflicting data that may as in otherprocesses be explained in part by distinct roles for ER120572 andER120573 Anecdotally many women report mood fluctuationsas corresponding to changes in circulating estrogen levelssuch as what occurs during the menstrual cycle peripubertypostpartum and peripostmenopause Incidence of anxietyand depression are observed at perimenopause and whenhormone levels are fluctuating [156 157] However E

2can

also exhibit anxiogenic properties and often anxiety anddepression present in a comorbid fashion especially inwomen [158 159] Interestingly after the age of 55 bouts ofdepression and anxiety appear to decrease in women [160]As previously mentioned perimenopausal women receivingCEE in the KEEPs study reported an improvement in moodand the primary actions of CEE tend to be mediated throughER120573 [20] A plethora of behavioral studies has mountedin response to observational reports and at first glance itappears that ER120573 has an anxiolytic and antidepressive rolehowever there is still an immense void to be filled withrespect to biochemical and molecular mechanisms of ER120573and affective disorders Elucidating the precise molecularmechanisms that require ER120573 in plasticity and neurotrans-mitter processing in brain regions regulating these behaviorswill help clarify the role of E

2in stress- and mood-related

processesContemporary hypotheses concerning the onset of affec-

tive disorders revolve around perturbations to the cen-tral processing of environmental stress The hypothalamic-pituitary-adrenal (HPA) axis is the 3-tiered hierarchicalbiological system that mediates physical or psychologicalresponse to stressors The primary steroid regulating theHPA axis is cortisolcorticosterone (humansrats CORT) aglucocorticoid receptor (GR) ligand that is produced fromthe adrenals to exert negative feedback upon the HPAsystem to effectively modulate response to stressors Theparaventricular nucleus of hypothalamus (PVN) producestwo neuropeptides corticotropin-releasing hormone (CRH)and arginine vasopressin (AVP) to activate the HPA axisCRF and AVP synergistically stimulate release of adreno-corticotropic hormone (ACTH) from the anterior pituitarywhich acts on the adrenal cortex to produce CORT CORT

binds GR and negatively regulates CRF and AVP expressionsand releases through classical negative feedback mechanisms[161 162] ER120573 is themain ER expressed in the PVN [158 163ndash165] and regulation of AVP is an interesting example of howER action can vary AVP expression fluctuates during themenstrual cycle and is usually highest when E

2is low In fact

oral contraceptives appear to decrease AVP expression andE2is thought to inhibit AVP in the human SON [166] In

the rodent system ER120573 and its splice variants activate therodent AVP promoter independent of ligand [84] howeverthe human promoter is repressed by ER120573 and splice variantsThis discrepancy between the human and rat wasmediated byan AP-1 response element on the human AVP promoter thatis not present in the rat Importantly ER120573 acted similarly inthe two systems when the AP-1 sequence was deleted fromthe human promoter underscoring the striking alterationsthat small changes in DNA sequence can invoke in E

2

signaling pathways and the importance of understanding theexperimental context upon which such conclusions are based[77] On the contrary rat and human CRF expression wasincreased in response to E

2in rodent monkey and human

hypothalamus but it was inhibited in the placenta [167ndash170]In addition to AVP and CRF glutamatergic and GABAer-

gic projects from regions like the BNST AMY PFC andhippocampus all express ER120573 [45 46] and are likely targetsfor E2to exert effects on the HPA axis Moreover decreased

ER120573 mRNA in postmortem locus coeruleus has been foundto correlate with suicide [13] and even more recentlyER120573-mediated hippocampal nitric oxide levels have beenimplicated in affective behaviors in females but not males[171] Neurotransmitter release from these regions influencesmood affect and stress responses and E

2increases the rate

of monoamine oxidase degradation and serotonin transportwhich enhances serotonin at the synapse E

2also increases

serotonin receptor expression [172 173] Dopamine andserotonin [174] are diminished in the BNST POA and hip-pocampus and caudate putamen (dopamine) of 120573ERKOmice[174] further implicating an important role for ER120573 in theregulation of emotion and mood 120573ERKO mice also displayserious morphological and functional abnormalities in thebrain that correlate to increased depression and anxiety [12175ndash178] In addition to 120573ERKO studies administration ofER120573 selective agonists (diarylpoprionitrile DPN) decreasesboth stress markers and anxiety-related behaviors in rats[158] In fact there have been several studies implicatingER120573 and its variants in affective behaviors but the molecularmechanisms remain poorly understood

13 Summary

Estrogen-receptor-mediated signaling in the brain regulatesneurological processes many of which translate to cog-nitive and affective behavioral outputs When estrogen isdeclining and becomes replete as in menopause a num-ber of neurophysiological changes occur producing someunwanted changes The most common and logical remedyis replacement of bioidentical hormone E

2 however this

treatment can be problematic depending upon the length

10 ISRN Endocrinology

of time a woman has been in a postmenopausal estrogen-deprived state This suggests that there is a molecular switchin estrogen-mediated signaling that may allow for drasticchange in ER signaling not to mention the interaction of E

2

signaling components and the natural aging process Thesechanges are likely to include alterations to receptor profilesincluding expression of alternatively spliced variants thatrespond differently to E

2 changes in the cellular microenvi-

ronment that can alter the proteinprotein associations whichultimately leads to changes in ER-mediated gene transcrip-tion and synaptic transmission ER120573 in particular is widelyexpressed and implicated positively in the regulation ofmemory and mood fluctuations two of the most commonlyreported neurological issues in postmenopausal women Itis important to understand the actions of ER120573 in the areasregulating these processes to identify what when how andfor whom hormone therapy may be a useful treatment torectify cognitive and affective issues

Acknowledgments

This work was supported by NIA RO1 AG033605-01 andNIH T32 AG031780 The authors N N Mott and T R Pakhave nothing to disclose

References

[1] C Bengtsson O Lindquist and L Redvall ldquoIs the menopausalage rapidly changingrdquoMaturitas vol 1 no 3 pp 159ndash164 1979

[2] A Singh S Kaur and I Walia ldquoA historical perspective onmenopause andmenopausal agerdquo Bulletin of the Indian Instituteof History of Medicine (Hyderabad) vol 32 no 2 pp 121ndash1352002

[3] P Verhaeghen and J Cerella ldquoAging executive control andattention a review of meta-analysesrdquo Neuroscience and Biobe-havioral Reviews vol 26 no 7 pp 849ndash857 2002

[4] T E Wroolie H A Kenna K E Williams et al ldquoDifferencesin verbal memory performance in postmenopausal womenreceiving hormone therapy 17120573-estradiol versus conjugatedequine estrogensrdquoAmerican Journal of Geriatric Psychiatry vol19 no 9 pp 792ndash802 2011

[5] B B Sherwin ldquoEstrogenic effects on memory in womenrdquoAnnals of the New York Academy of Sciences vol 743 pp 213ndash230 1994

[6] B B Sherwin ldquoHormones mood and cognitive functioning inpostmenopausal womenrdquoObstetrics andGynecology vol 87 no2 supplement pp 20Sndash26S 1996

[7] B B Sherwin ldquoSex hormones and psychological functioning inpostmenopausalwomenrdquoExperimentalGerontology vol 29 no3-4 pp 423ndash430 1994

[8] SM Phillips and B B Sherwin ldquoEffects of estrogen onmemoryfunction in surgically menopausal womenrdquo Psychoneuroen-docrinology vol 17 no 5 pp 485ndash495 1992

[9] R Lindsay J M Aitken and J B Anderson ldquoLong term pre-vention of postmenopausal osteoporosis by oestrogen Evidencefor an increased bone mass after delayed onset of oestrogentreatmentrdquoThe Lancet vol 1 no 7968 pp 1038ndash1040 1976

[10] J E Rossouw R L Prentice J E Manson et al ldquoPost-menopausal hormone therapy and risk of cardiovascular dis-ease by age and years since menopauserdquo The Journal of the

American Medical Association vol 297 no 13 pp 1465ndash14772007

[11] Q-G Zhang D Han R-M Wang et al ldquoC terminusof Hsc70-interacting protein (CHIP)-mediated degradationof hippocampal estrogen receptor-120572 and the critical periodhypothesis of estrogen neuroprotectionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 108 no 35 pp E617ndashE624 2011

[12] W Krezel S Dupont A Krust P Chambon and P F ChapmanldquoIncreased anxiety and synaptic plasticity in estrogen receptor120573-deficient micerdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 21 pp 12278ndash12282 2001

[13] H Ostlund E Keller and Y L Hurd ldquoEstrogen receptor geneexpression in relation to neuropsychiatric disordersrdquo Annals ofthe New York Academy of Sciences vol 1007 pp 54ndash63 2003

[14] S A Shumaker C Legault S R Rapp et al ldquoEstrogen plusprogestin and the incidence of dementia and mild cognitiveimpairment in postmenopausal women the Womenrsquos HealthInitiative Memory Study a randomized controlled trialrdquo Jour-nal of the American Medical Association vol 289 no 20 pp2651ndash2662 2003

[15] S A Shumaker C Legault L Kuller et al ldquoConjugated equineestrogens and incidence of probable dementia and mild cog-nitive impairment in postmenopausal women womenrsquos HealthInitiative Memory Studyrdquo Journal of the American MedicalAssociation vol 291 no 24 pp 2947ndash2958 2004

[16] S R Rapp M A Espeland S A Shumaker et al ldquoEffect ofestrogen plus progestin on global cognitive function in post-menopausal women the Womenrsquos Health Initiative MemoryStudy a randomized controlled trialrdquo Journal of the AmericanMedical Association vol 289 no 20 pp 2663ndash2672 2003

[17] VWHenderson K S Benke R C Green L A Cupples and LA Farrer ldquoPostmenopausal hormone therapy and Alzheimerrsquosdisease risk interaction with agerdquo Journal of Neurology Neuro-surgery and Psychiatry vol 76 no 1 pp 103ndash105 2005

[18] E Garbe and S Suissa ldquoHormone replacement therapy andacute coronary syndromes methodological issues betweenrandomized and observational studiesrdquo Human Reproductionvol 19 no 1 pp 8ndash13 2004

[19] B B Braden A N Garcia S E Mennenga et al ldquoCognitive-impairing effects of medroxyprogesterone acetate in the ratindependent and interactive effects across timerdquo Psychophar-macology vol 218 no 2 pp 405ndash418 2011

[20] B R Bhavnani S-P Tam and X Lu ldquoStructure activity rela-tionships and differential interactions and functional activity ofvarious equine estrogens mediated via estrogen receptors (ERs)ER120572 and ER120573rdquo Endocrinology vol 149 no 10 pp 4857ndash48702008

[21] E Hogervorst and S Bandelow ldquoSex steroids to maintaincognitive function in women after the menopause a meta-analyses of treatment trialsrdquoMaturitas vol 66 no 1 pp 56ndash712010

[22] D J Mangelsdorf C Thummel M Beato et al ldquoThe nuclearreceptor super-family the second decaderdquo Cell vol 83 no 6pp 835ndash839 1995

[23] E V Jensen T Suzuki T Kawashima W E Stumpf P WJungblut and E R DeSombre ldquoA two-step mechanism forthe interaction of estradiol with rat uterusrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 59 no 2 pp 632ndash638 1968

ISRN Endocrinology 11

[24] F Naftolin T L Horvath R L Jakab C Leranth N Haradaand J Balthazart ldquoAromatase immunoreactivity in axon termi-nals of the vertebrate brain an immunocytochemical study onquail rat monkey and human tissuesrdquoNeuroendocrinology vol63 no 2 pp 149ndash155 1996

[25] C E Roselli S E Abdelgadir O K Roslashnnekleiv and S AKlosterman ldquoAnatomic distribution and regulation of aro-matase gene expression in the rat brainrdquo Biology of Reproduc-tion vol 58 no 1 pp 79ndash87 1998

[26] J Balthazart and G F Ball ldquoIs brain estradiol a hormone or aneurotransmitterrdquo Trends in Neurosciences vol 29 no 5 pp241ndash249 2006

[27] T R Pak Y S Rao S A Prins and N N Mott ldquoAn emergingrole for microRNAs in sexually dimorphic neurobiologicalsystemsrdquo Pflugers Archiv vol 465 no 5 pp 655ndash667 2013

[28] K Yamagata S Fujiyama S Ito et al ldquoMaturation ofmicroRNAis hormonally regulated by a nuclear receptorrdquo Molecular Cellvol 36 no 2 pp 340ndash347 2009

[29] Y Masuhiro Y Mezaki M Sakari et al ldquoSplicing potentiationby growth factor signals via estrogen receptor phosphorylationrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 23 pp 8126ndash8131 2005

[30] A Tremblay G B Tremblay F Labrie and V Giguere ldquoLigand-Independent recruitment of SRC-1 to estrogen receptor 120573through phosphorylation of activation function AF-1rdquo Molec-ular Cell vol 3 no 4 pp 513ndash519 1999

[31] S H Meijsing M A Pufall A Y So D L Bates L Chenand K R Yamamoto ldquoDNA binding site sequence directsglucocorticoid receptor structure and activityrdquo Science vol 324no 5925 pp 407ndash410 2009

[32] W Bourguet P Germain and H Gronemeyer ldquoNuclearreceptor ligand-binding domains three-dimensional struc-tures molecular interactions and pharmacological implica-tionsrdquo Trends in Pharmacological Sciences vol 21 no 10 pp381ndash388 2000

[33] A Koide C Zhao M Naganuma et al ldquoIdentification ofregions within the F domain of the human estrogen receptor 120572that are important for modulating transactivation and protein-protein interactionsrdquoMolecular Endocrinology vol 21 no 4 pp829ndash842 2007

[34] D F Skafar and S Koide ldquoUnderstanding the human estrogenreceptor-alpha using targeted mutagenesisrdquoMolecular and Cel-lular Endocrinology vol 246 no 1-2 pp 83ndash90 2006

[35] E C Chang J Frasor B Komm and B S KatzenellenbogenldquoImpact of estrogen receptor 120573 on gene networks regulated byestrogen receptor 120572 in breast cancer cellsrdquo Endocrinology vol147 no 10 pp 4831ndash4842 2006

[36] X Zhu I Leav Y-K Leung et al ldquoDynamic regulation ofestrogen receptor-120573 expression by DNA methylation duringprostate cancer development andmetastasisrdquoAmerican Journalof Pathology vol 164 no 6 pp 2003ndash2012 2004

[37] D N Petersen G T Tkalcevic P H Koza-Taylor T G Turiand T A Brown ldquoIdentification of estrogen receptor 1205732 afunctional variant of estrogen receptor 120573 expressed in normalrat tissuesrdquo Endocrinology vol 139 no 3 pp 1082ndash1092 1998

[38] L A Helguero M H Faulds J-A Gustafsson and L-AHaldosen ldquoEstrogen receptors alfa (ER120572) and beta (ER120573)differentially regulate proliferation and apoptosis of the normalmurine mammary epithelial cell line HC11rdquo Oncogene vol 24no 44 pp 6605ndash6616 2005

[39] P C Kulakosky M A McCarty S C Jernigan K E Risingerand C M Klinge ldquoResponse element sequence modulates

estrogen receptor 120572 and 120573 affinity and activityrdquo Journal ofMolecular Endocrinology vol 29 no 1 pp 137ndash152 2002

[40] OM V Grober MMutarelli G Giurato et al ldquoGlobal analysisof estrogen receptor beta binding to breast cancer cell genomereveals an extensive interplay with estrogen receptor alpha fortarget gene regulationrdquo BMC Genomics vol 12 article 36 2011

[41] O I Vivar X Zhao E F Saunier et al ldquoEstrogen receptor 120573binds to and regulates three distinct classes of target genesrdquoJournal of Biological Chemistry vol 285 no 29 pp 22059ndash22066 2010

[42] G G J M Kuiper E Enmark M Pelto-Huikko S Nilssonand J-A Gustafsson ldquoCloning of a novel estrogen receptorexpressed in rat prostate and ovaryrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 93 no12 pp 5925ndash5930 1996

[43] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and 120572 and 120573rdquo Endocrinology vol 138no 3 pp 863ndash870 1997

[44] D B Dubal H Zhu J Yu et al ldquoEstrogen receptor alpha notbeta is a critical link in estradiol-mediated protection againstbrain injuryrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 98 no 4 pp 1952ndash1957 2001

[45] P J Shughrue P J Scrimo and I Merchenthaler ldquoEvidence forthe colocalization of estrogen receptor-120573 mRNA and estrogenreceptor-120572 immunoreactivity in neurons of the rat forebrainrdquoEndocrinology vol 139 no 12 pp 5267ndash5270 1998

[46] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in therat central nervous systemrdquo Journal of Comparative Neurologyvol 388 no 4 pp 507ndash525 1997

[47] T AMilner B SMcEwen S Hayashi C J Li L P Reagan andS E Alves ldquoUltrastructural evidence that hippocampal alphaestrogen receptors are located at extranuclear sitesrdquoThe Journalof Comparative Neurology vol 429 no 3 pp 355ndash371 2001

[48] T A Milner L S Lubbers S E Alves and B S McEwenldquoNuclear and extranuclear estrogen binding sites in the ratforebrain and autonomic medullary areasrdquo Endocrinology vol149 no 7 pp 3306ndash3312 2008

[49] T A Milner K Ayoola C T Drake et al ldquoUltrastructurallocalization of estrogen receptor 120573 immunoreactivity in the rathippocampal formationrdquo Journal of ComparativeNeurology vol491 no 2 pp 81ndash95 2005

[50] A E Herbison andD TTheodosis ldquoAbsence of estrogen recep-tor immunoreactivity in somatostatin (SRIF) neurons of theperiventricular nucleus but sexually dimorphic colocalizationof estrogen receptor and SRIF immunoreactivities in neuronsof the bed nucleus of the stria terminalisrdquo Endocrinology vol132 no 4 pp 1707ndash1714 1993

[51] K Kalita S Szymczak and L Kaczmarek ldquoNon-nuclear estro-gen receptor 120573 and 120572 in the hippocampus of male and femaleratsrdquo Hippocampus vol 15 no 3 pp 404ndash412 2005

[52] T Ivanova and C Beyer ldquoOntogenetic expression and sexdifferences of aromatase and estrogen receptor-120572120573 mRNA inthe mouse hippocampusrdquo Cell and Tissue Research vol 300 no2 pp 231ndash237 2000

[53] C Y Pau K-Y F Pau and H G Spies ldquoPutative estrogenreceptor 120573 and 120572 mRNA expression in male and female rhesusmacaquesrdquo Molecular and Cellular Endocrinology vol 146 no1-2 pp 59ndash68 1998

[54] A L Wijayaratne and D P McDonnell ldquoThe human estrogenreceptor-120572 is a ubiquitinated protein whose stability is affected

12 ISRN Endocrinology

differentially by agonists antagonists and selective estrogenreceptor modulatorsrdquo Journal of Biological Chemistry vol 276no 38 pp 35684ndash35692 2001

[55] V Bartella P Rizza I Barone et al ldquoEstrogen receptor betabinds Sp1 and recruits a corepressor complex to the estrogenreceptor alpha gene promoterrdquo Breast Cancer Research andTreatment vol 134 no 2 pp 569ndash581 2012

[56] L C Li C C Yeh D Nojima and R Dahiya ldquoCloning andcharacterization of human estrogen receptor beta promoterrdquoBiochemical and Biophysical Research Communications vol 275no 2 pp 682ndash689 2000

[57] E A Vladusic A E Hornby F K Guerra-Vladusic J Lakinsand R Lupu ldquoExpression and regulation of estrogen receptor szligin human breast tumors and cell linesrdquoOncology Reports vol 7no 1 pp 157ndash167 2000

[58] T Hatsumi and Y Yamamuro ldquoDownregulation of estrogenreceptor gene expression by exogenous 17120573-estradiol in themammary glands of lactating micerdquo Experimental Biology andMedicine vol 231 no 3 pp 311ndash316 2006

[59] H B Patisaul P L Whitten and L J Young ldquoRegulation ofestrogen receptor beta mRNA in the brain opposite effectsof 17120573-estradiol and the phytoestrogen coumestrolrdquoMolecularBrain Research vol 67 no 1 pp 165ndash171 1999

[60] T J Brown N J MacLusky M Shanabrough and F NaftolinldquoComparison of age- and sex-related changes in cell nuclearestrogen-binding capacity and progestin receptor induction inthe rat brainrdquo Endocrinology vol 126 no 6 pp 2965ndash29721990

[61] B S Rubin T O Fox and R S Bridges ldquoEstrogen bindingin nuclear and cytosolic extracts from brain and pituitary ofmiddle-aged female ratsrdquo Brain Research vol 383 no 1-2 pp60ndash67 1986

[62] T Funabashi S P Kleopoulos P J Brooks et al ldquoChangesin estrogenic regulation of estrogen receptor 120572 mRNA andprogesterone receptor mRNA in the female rat hypothalamusduring aging an in situ hybridization studyrdquo NeuroscienceResearch vol 38 no 1 pp 85ndash92 2000

[63] M E Wilson K L Rosewell M L Kashon P J Shughrue IMerchenthaler and P M Wise ldquoAge differentially influencesestrogen receptor-120572 (ER120572) and estrogen receptor-120573 (ER120573) geneexpression in specific regions of the rat brainrdquo Mechanisms ofAgeing and Development vol 123 no 6 pp 593ndash601 2002

[64] W S Post P J Goldschmidt-Clermont C C Wilhide etal ldquoMethylation of the estrogen receptor gene is associatedwith aging and atherosclerosis in the cardiovascular systemrdquoCardiovascular Research vol 43 no 4 pp 985ndash991 1999

[65] J-P J Issa Y L Ottaviano P Celano S R Hamilton NE Davidson and S B Baylin ldquoMethylation of the oestrogenreceptor CpG island links ageing and neoplasia in humancolonrdquo Nature Genetics vol 7 no 4 pp 536ndash540 1994

[66] T Funabashi and F Kimura ldquoEffects of estrogen and estrogenreceptor messenger RNA levels in young and middle-agedfemale rats comparison ofmedial preoptic area andmediobasalhypothalamusrdquo Acta Biologica Hungarica vol 45 no 2ndash4 pp223ndash231 1994

[67] M AMiller P E Kolb B Planas andM A Raskind ldquoEstrogenreceptor and neurotensinneuromedin-N gene expression inthe preoptic area are unaltered with age in Fischer 344 femaleratsrdquo Endocrinology vol 135 no 5 pp 1986ndash1995 1994

[68] T R Chakraborty P R Hof L Ng and A C Gore ldquoStereologicanalysis of estrogen receptor alpha (ER alpha) expression in rat

hypothalamus and its regulation by aging and estrogenrdquo Journalof Comparative Neurology vol 466 no 3 pp 409ndash421 2003

[69] J M Westberry A L Trout and M E Wilson ldquoEpigeneticregulation of estrogen receptor beta expression in the rat cortexduring agingrdquo NeuroReport vol 22 no 9 pp 428ndash432 2011

[70] T R Chakraborty L Ng and A C Gore ldquoAge-related changesin estrogen receptor 120573 in rat hypothalamus a quantitativeanalysisrdquo Endocrinology vol 144 no 9 pp 4164ndash4171 2003

[71] I Poola S Koduri S Chatra and R Clarke ldquoIdentificationof twenty alternatively spliced estrogen receptor alpha mRNAsin breast cancer cell lines and tumors using splice targetedprimer approachrdquo Journal of Steroid Biochemistry andMolecularBiology vol 72 no 5 pp 249ndash258 2000

[72] T A Ishunina and D F Swaab ldquoHippocampal estrogenreceptor-alpha splice variant TADDI in the human brain inaging and Alzheimerrsquos diseaserdquoNeuroendocrinology vol 89 no2 pp 187ndash199 2009

[73] T A Ishunina and D F Swaab ldquoEstrogen receptor-120572 splicevariants in the human brainrdquo Gynecological Endocrinology vol24 no 2 pp 93ndash98 2008

[74] T A Ishunina F P M Kruijver R Balesar and D FSwaab ldquoDifferential expression of estrogen receptor 120572 and 120573immunoreactivity in the human supraoptic nucleus in rela-tion to sex and agingrdquo Journal of Clinical Endocrinology andMetabolism vol 85 no 9 pp 3283ndash3291 2000

[75] T A Ishunina D F Fischer andD F Swaab ldquoEstrogen receptor120572 and its splice variants in the hippocampus in aging andAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 28 no 11 pp1670ndash1681 2007

[76] J R Tollervey Z Wang T Hortobagyi et al ldquoAnalysis of alter-native splicing associated with aging and neurodegeneration inthe human brainrdquo Genome Research vol 21 no 10 pp 1572ndash1582 2011

[77] N NMott and T R Pak ldquoCharacterisation of human oestrogenreceptor beta (ER120573) splice variants in neuronal cellsrdquo Journal ofNeuroendocrinology vol 24 no 10 pp 1311ndash1321 2012

[78] S Inoue S-J Hoshino H Miyoshi et al ldquoIdentification ofa ovel isoform of estrogen receptor a potential inhibitor ofestrogen action in vascular smooth muscle cellsrdquo Biochemicaland Biophysical Research Communications vol 219 no 3 pp766ndash772 1996

[79] J K Skipper L J Young J M Bergeron M T Tetzlaff CT Osborn and D Crews ldquoIdentification of an isoform ofthe estrogen receptor messenger RNA lacking exon four andpresent in the brainrdquo Proceedings of the National Academy ofSciences of the United States of America vol 90 no 15 pp 7172ndash7175 1993

[80] R H Price Jr N Lorenzon and R J Handa ldquoDifferentialexpression of estrogen receptor beta splice variants in rat brainidentification and characterization of a novel variant missingexon 4rdquo Brain Research Molecular Brain Research vol 80 no2 pp 260ndash268 2000

[81] S Chu and P J Fuller ldquoIdentification of a splice variantof the rat estrogen receptor 120573 generdquo Molecular and CellularEndocrinology vol 132 no 1-2 pp 195ndash199 1997

[82] B Lu E Leygue H Dotzlaw L J Murphy L C Murphy andP H Watson ldquoEstrogen receptor-120573 mRNA variants in humanand murine tissuesrdquoMolecular and Cellular Endocrinology vol138 no 1-2 pp 199ndash203 1998

[83] T R Pak W C J Chung J L Roberts and R J HandaldquoLigand-independent effects of estrogen receptor 120573 on

ISRN Endocrinology 13

mouse gonadotropin-releasing hormone promoter activityrdquoEndocrinology vol 147 no 4 pp 1924ndash1931 2006

[84] T R Pak W C J Chung L R Hinds and R J HandaldquoEstrogen receptor-120573 mediates dihydrotestosterone-inducedstimulation of the arginine vasopressin promoter in neuronalcellsrdquo Endocrinology vol 148 no 7 pp 3371ndash3382 2007

[85] Y K Leung PMak S Hassan and SMHo ldquoEstrogen receptor(ER)-120573 isoforms a key to understanding ER-120573 signalingrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 103 no 35 pp 13162ndash13167 2006

[86] J M Wang X Hou S Adeosun et al ldquoA dominant negativeER120573 splice variant determines the effectiveness of early or lateestrogen therapy after ovariectomy in ratsrdquo PLoS One vol 7 no3 Article ID e33493 2012

[87] W C J Chung T R Pak S Suzuki W A Pouliot M EAndersen and R J Handa ldquoDetection and localization of anestrogen receptor beta splice variant protein (ER1205732) in theadult female rat forebrain and midbrain regionsrdquo Journal ofComparative Neurology vol 505 no 3 pp 249ndash267 2007

[88] R H Price Jr C A Butler P Webb R Uht P Kushner andR J Handa ldquoA splice variant of estrogen receptor 120573 missingexon 3 displays altered subnuclear localization and capacity fortranscriptional activationrdquo Endocrinology vol 142 no 5 pp2039ndash2049 2001

[89] Y Wang and R J Miksicek ldquoIdentification of a dominantnegative form of the human estrogen receptorrdquo MolecularEndocrinology vol 5 no 11 pp 1707ndash1715 1991

[90] E Kuppers and C Beyer ldquoExpression of estrogen receptor-120572and 120573 mRNA in the developing and adult mouse striatumrdquoNeuroscience Letters vol 276 no 2 pp 95ndash98 1999

[91] C Gundlah S G Kohama S J Mirkes V T Garyfallou H FUrbanski and C L Bethea ldquoDistribution of estrogen receptorbeta (ER120573) mRNA in hypothalamus midbrain and temporallobe of spayed macaque continued expression with hormonereplacementrdquo Brain Research Molecular Brain Research vol 76no 2 pp 191ndash204 2000

[92] Y Morishima P J M Murphy D-P Li E R Sanchez and WB Pratt ldquoStepwise assembly of a glucocorticoid receptorsdothsp90heterocomplex resolves two sequential ATP-dependent eventsinvolving first hsp70 and then hsp90 in opening of the steroidbinding pocketrdquo Journal of Biological Chemistry vol 275 no 24pp 18054ndash18060 2000

[93] K D Dittmar and W B Pratt ldquoFolding of the glucocorticoidreceptor by the reconstituted hsp90-based chaperone machin-eryThe initial hsp90sdotp60sdothsp70-dependent step is sufficient forcreating the steroid binding conformationrdquo Journal of BiologicalChemistry vol 272 no 20 pp 13047ndash13054 1997

[94] K I Kang X Meng J Devin-Leclerc et al ldquoThe molecularchaperone Hsp90 can negatively regulate the activity of aglucocorticosteroid-dependent promoterrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 4 pp 1439ndash1444 1999

[95] K Unno H Asakura Y Shibuya M Kaiho S Okada and NOku Naoto ldquoIncrease in basal level of Hsp70 consisting chieflyof constitutively expressed hsp70 (Hsc70) in aged rat brainrdquoJournals of Gerontology Series A vol 55 no 7 pp B329ndashB3352000

[96] U E Olazabal D W Pfaff and C V Mobbs ldquoSex differences inthe regulation of heat shock protein 70 kDa and 90 kDa in therat ventromedial hypothalamus by estrogenrdquo Brain Researchvol 596 no 1-2 pp 311ndash314 1992

[97] M A Pahlavani M D Harris S A Moore and A RichardsonldquoExpression of heat shock protein 70 in rat spleen lymphocytesis affected by age but not by food restrictionrdquo Journal ofNutrition vol 126 no 9 pp 2069ndash2075 1996

[98] A R Heydari B Wu R Takahashi R Strong and A Richard-son ldquoExpression of heat shock protein 70 is altered by age anddiet at the level of transcriptionrdquoMolecular andCellular Biologyvol 13 no 5 pp 2909ndash2918 1993

[99] M Sabbah K-I I Kang L Tora and G Redeuilh ldquoOestro-gen receptor facilitates the formation of preinitiation com-plex assembly involvement of the general transcription factorTFIIBrdquo Biochemical Journal vol 336 part 3 pp 639ndash646 1998

[100] S-Y Wu M C Thomas S Y Hou V Likhite and C-MChiang ldquoIsolation of mouse TFIID and functional character-ization of TBP and TFIID in mediating estrogen receptor andchromatin transcriptionrdquo Journal of Biological Chemistry vol274 no 33 pp 23480ndash23490 1999

[101] S Ghosh and M K Thakur ldquoTissue-specific expression ofreceptor-interacting protein in aging mouserdquo Age vol 30 no4 pp 237ndash243 2008

[102] J Frasor JM Danes B Komm K C N Chang C Richard Lyt-tle and B S Katzenellenbogen ldquoProfiling of estrogen up- anddown-regulated gene expression in human breast cancer cellsinsights into gene networks and pathways underlying estrogeniccontrol of proliferation and cell phenotyperdquo Endocrinology vol144 no 10 pp 4562ndash4574 2003

[103] J Frasor J M Danes C C Funk and B S Katzenellen-bogen ldquoEstrogen down-regulation of the corepressor N-CoRmechanism and implications for estrogen derepression of N-CoR-regulated genesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 102 no 37 pp13153ndash13157 2005

[104] N J McKenna and B W OrsquoMalley ldquoCombinatorial control ofgene expression by nuclear receptors and coregulatorsrdquoCell vol108 no 4 pp 465ndash474 2002

[105] T-P Yao G Ku N Zhou R Scully and D M Livingston ldquoThenuclear hormone receptor coactivator SRC-1 is a specific targetof p300rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 93 no 20 pp 10626ndash10631 1996

[106] B Hanstein R Eckner J DiRenzo et al ldquop300 is a componentof an estrogen receptor coactivator complexrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 93 no 21 pp 11540ndash11545 1996

[107] S Halachmi E Marden G Martin H MacKay C Abbon-danza and M Brown ldquoEstrogen receptor-associated proteinspossible mediators of hormone-induced transcriptionsrdquo Sci-ence vol 264 no 5164 pp 1455ndash1458 1994

[108] A J Horlein AM Naar T Heinzel et al ldquoLigand-independentrepression by the thyroid hormone receptor mediated by anuclear receptor co-repressorrdquo Nature vol 377 no 6548 pp397ndash404 1995

[109] J D Chen and R M Evans ldquoA transcriptional co-repressor thatinteracts with nuclear hormone receptorsrdquo Nature vol 377 no6548 pp 454ndash457 1995

[110] A Malovannaya R B Lanz S Y Jung et al ldquoAnalysis of thehuman endogenous coregulator complexomerdquoCell vol 145 no5 pp 787ndash799 2011

[111] Z Nawaz D M Lonard C L Smith et al ldquoThe Angelmansyndrome-associated protein E6-AP is a coactivator for thenuclear hormone receptor superfamilyrdquoMolecular and CellularBiology vol 19 no 2 pp 1182ndash1189 1999

14 ISRN Endocrinology

[112] B Zheng M Han M Bernier and J-K Wen ldquoNuclear actinand actin-binding proteins in the regulation of transcriptionand gene expressionrdquo FEBS Journal vol 276 no 10 pp 2669ndash2685 2009

[113] W A Hofmann L Stojiljkovic B Fuchsova et al ldquoActin is partof pre-initiation complexes and is necessary for transcription byRNA polymerase IIrdquoNature Cell Biology vol 6 no 11 pp 1094ndash1101 2004

[114] K Tokunaga T Shibuya Y Ishihama et al ldquoNucleocytoplasmictransport of fluorescent mRNA in living mammalian cellsnuclear mRNA export is coupled to ongoing gene transcrip-tionrdquo Genes to Cells vol 11 no 3 pp 305ndash317 2006

[115] R Metivier G Penot M R Hubner et al ldquoEstrogen receptor-120572 directs ordered cyclical and combinatorial recruitment ofcofactors on a natural target promoterrdquo Cell vol 115 no 6 pp751ndash763 2003

[116] C Ambrosino R Tarallo A Bamundo et al ldquoIdentification of ahormone-regulated dynamic nuclear actin network associatedwith estrogen receptor 120572 in human breast cancer cell nucleirdquoMolecular and Cellular Proteomics vol 9 no 6 pp 1352ndash13672010

[117] F Shao R Zhang L Dong and K Ying ldquoOverexpression ofgelsolin-like actin-capping protein is associated with progres-sion of lung adenocarcinomardquo Tohoku Journal of ExperimentalMedicine vol 225 no 2 pp 95ndash101 2011

[118] K Nishimura H-J Ting Y Harada et al ldquoModulation ofandrogen receptor transactivation by gelsolin a newly identi-fied androgen receptor coregulatorrdquo Cancer Research vol 63no 16 pp 4888ndash4894 2003

[119] J S Ahn I S Jang D I Kim et al ldquoAging-associated increaseof gelsolin for apoptosis resistancerdquoBiochemical and BiophysicalResearch Communications vol 312 no 4 pp 1335ndash1341 2003

[120] I Nalvarte T Schwend and J-A Gustafsson ldquoProteomicsanalysis of the estrogen receptor 120572 receptosomerdquoMolecular andCellular Proteomics vol 9 no 7 pp 1411ndash1422 2010

[121] L-H Miau C-J Chang B-J Shen W-H Tsai and S-C LeeldquoIdentification of heterogeneous nuclear ribonucleoprotein K(hnRNPK) as a repressor ofCEBP120573-mediated gene activationrdquoJournal of Biological Chemistry vol 273 no 17 pp 10784ndash107911998

[122] A Ostareck-Lederer D H Ostareck C Cans et al ldquoc-Src-mediated phosphorylation of hnRNP K drives translationalactivation of specifically silenced mRNAsrdquo Molecular and Cel-lular Biology vol 22 no 13 pp 4535ndash4543 2002

[123] P S Bagga G K Arhin and J Wilusz ldquoDSEF-1 is a member ofthe hnRNP H family of RNA-binding proteins and stimulatespre-mRNAcleavage and polyadenylation in vitrordquoNucleic AcidsResearch vol 26 no 23 pp 5343ndash5350 1998

[124] V Markovtsov J M Nikolic J A Goldman C W Turck M-Y Chou and D L Black ldquoCooperative assembly of an hnRNPcomplex induced by a tissue-specific homolog of polypyrimi-dine tract binding proteinrdquoMolecular and Cellular Biology vol20 no 20 pp 7463ndash7479 2000

[125] S Y Jung A Malovannaya J Wei B W OrsquoMalley and J QinldquoProteomic analysis of steady-state nuclear hormone receptorcoactivator complexesrdquoMolecular Endocrinology vol 19 no 10pp 2451ndash2465 2005

[126] W Hong R J Resnick C Rakowski D Shalloway S J Taylorand G A Blobel ldquoPhysical and functional interaction betweenthe transcriptional cofactor CBP and the KH domain proteinSam68rdquoMolecular Cancer Research vol 1 no 1 pp 48ndash55 2002

[127] R ShaoXWang BWeijdegard et al ldquoCoordinate regulation ofheterogeneous nuclear ribonucleoprotein dynamics by steroidhormones in the human fallopian tube and endometrium invivo and in vitrordquo American Journal of Physiology vol 302 no10 pp E1269ndashE1282 2012

[128] C SWoolley and B SMcEwen ldquoEstradiolmediates fluctuationin hippocampal synapse density during the estrous cycle in theadult ratrdquo Journal of Neuroscience vol 12 no 7 pp 2549ndash25541992

[129] C S Woolley H J Wenzel and P A Schwartzkroin ldquoEstradiolincreases the frequency of multiple synapse boutons in thehippocampal CA1 region of the adult female ratrdquo The Journalof Comparative Neurology vol 373 no 1 pp 108ndash117 1996

[130] C S Woolley ldquoEstrogen-mediated structural and functionalsynaptic plasticity in the female rat hippocampusrdquo Hormonesand Behavior vol 34 no 2 pp 140ndash148 1998

[131] D P Srivastava K M Woolfrey K A Jones et al ldquoRapidenhancement of two-step wiring plasticity by estrogen andNMDA receptor activityrdquo Proceedings of the National Academyof Sciences of the United States of America vol 105 no 38 pp14650ndash14655 2008

[132] M Ogiue-Ikeda N Tanabe H Mukai et al ldquoRapid modu-lation of synaptic plasticity by estrogens as well as endocrinedisrupters in hippocampal neuronsrdquo Brain Research Reviewsvol 57 no 2 pp 363ndash375 2008

[133] N J Sandstrom and C L Williams ldquoSpatial memory retentionis enhanced by acute and continuous estradiol replacementrdquoHormones and Behavior vol 45 no 2 pp 128ndash135 2004

[134] E Hogervorst J Williams M Budge W Riedel and JJolles ldquoThe nature of the effect of female gonadal hormonereplacement therapy on cognitive function in post-menopausalwomen a meta-analysisrdquo Neuroscience vol 101 no 3 pp 485ndash512 2000

[135] M E Bailey A C J Wang J Hao et al ldquoInteractive effects ofage and estrogen on cortical neurons implications for cognitiveagingrdquo Neuroscience vol 191 pp 148ndash158 2011

[136] A A Walf M E Rhodes and C A Frye ldquoOvarian steroidsenhance object recognition in naturally cycling and ovariec-tomized hormone-primed ratsrdquo Neurobiology of Learning andMemory vol 86 no 1 pp 35ndash46 2006

[137] V N Luine L F Jacome and N J Maclusky ldquoRapid enhance-ment of visual and place memory by estrogens in ratsrdquoEndocrinology vol 144 no 7 pp 2836ndash2844 2003

[138] L Fan Z Zhao P T Orr C H Chambers M C Lewis and KM Frick ldquoEstradiol-induced object memory consolidation inmiddle-aged femalemice requires dorsal hippocampal extracel-lular signal-regulated kinase and phosphatidylinositol 3-kinaseactivationrdquo Journal of Neuroscience vol 30 no 12 pp 4390ndash4400 2010

[139] D B Dubal and PMWise ldquoNeuroprotective effects of estradiolin middle-aged female ratsrdquo Endocrinology vol 142 no 1 pp43ndash48 2001

[140] S-H Yang J Shi A L Day and J W Simpkins ldquoEstradiolexerts neuroprotective effects when administered after ischemicinsultrdquo Stroke vol 31 no 3 pp 745ndash750 2000

[141] J W Simpkins G Rajakumar Y-Q Zhang et al ldquoEstrogensmay reduce mortality and ischemic damage caused by middlecerebral artery occlusion in the female ratrdquo Journal of Neuro-surgery vol 87 no 5 pp 724ndash730 1997

[142] J Shi K S Panickar S-H Yang O Rabbani A L Day and JWSimpkins ldquoEstrogen attenuates over-expression of 120573-amyloid

ISRN Endocrinology 15

precursor protein messager RNA in an animal model of focalischemiardquo Brain Research vol 810 no 1-2 pp 87ndash92 1998

[143] Q-H Zhang Y-H Huang Y-Z Hu et al ldquoDisruption ofestrogen receptor beta in mice brain results in pathologicalalterations resemblingAlzheimer diseaserdquoActa PharmacologicaSinica vol 25 no 4 pp 452ndash457 2004

[144] E F Rissman A L Heck J E Leonard M A Shupnik and J-A Gustafsson ldquoDisruption of estrogen receptor 120573 gene impairsspatial learning in female micerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no6 pp 3996ndash4001 2002

[145] M Day A Sung S Logue M Bowlby and R Arias ldquoBetaestrogen receptor knockout (BERKO) mice present attenuatedhippocampal CA1 long-term potentiation and related memorydeficits in contextual fear conditioningrdquo Behavioural BrainResearch vol 164 no 1 pp 128ndash131 2005

[146] R Vierk G Glassmeier L Zhou et al ldquoAromatase inhibitionabolishes LTP generation in female but not in male micerdquo TheJournal of Neuroscience vol 32 no 24 pp 8116ndash8126 2012

[147] R-M Vouimba M R Foy J G Foy and R FThompson ldquo17120573-estradiol suppresses expression of long-term depression in agedratsrdquo Brain Research Bulletin vol 53 no 6 pp 783ndash787 2000

[148] C E Andreescu B A Milojkovic E D Haasdijk et alldquoEstradiol improves cerebellar memory formation by activatingestrogen receptor 120573rdquo Journal of Neuroscience vol 27 no 40 pp10832ndash10839 2007

[149] Y-Y Huang P V Nguyen T Abel and E R Kandel ldquoLong-lasting forms of synaptic potentiation in the mammalian hip-pocampusrdquo Learning Memory vol 3 no 2-3 pp 74ndash85 1996

[150] H Mukai T Tsurugizawa G Murakami et al ldquoRapid mod-ulation of long-term depression and spinogenesis via synapticestrogen receptors in hippocampal principal neuronsrdquo Journalof Neurochemistry vol 100 no 4 pp 950ndash967 2007

[151] L Liu T P Wong M F Pozza et al ldquoRole of NMDA receptorsubtypes in governing the direction of hippocampal synapticplasticityrdquo Science vol 304 no 5673 pp 1021ndash1024 2004

[152] M Cyr O Ghribi C Thibault M Morissette M Landry andT di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[153] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[154] C C Smith and L L McMahon ldquoEstradiol-induced increasein the magnitude of long-term potentiation is prevented byblocking NR2B-containing receptorsrdquo Journal of Neurosciencevol 26 no 33 pp 8517ndash8522 2006

[155] Y Zhou J J Watters and D M Dorsa ldquoEstrogen rapidlyinduces the phosphorylation of the cAMP response elementbinding protein in rat brainrdquo Endocrinology vol 137 no 5 pp2163ndash2166 1996

[156] XGonda T TelekG Juhasz J Lazary AVargha andG BagdyldquoPatterns of mood changes throughout the reproductive cyclein healthy women without premenstrual dysphoric disordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 32 no 8 pp 1782ndash1788 2008

[157] E W Freeman ldquoPremenstrual syndrome and premenstrualdysphoric disorder definitions and diagnosisrdquo Psychoneuroen-docrinology vol 28 supplement 3 pp 25ndash37 2003

[158] T D Lund T Rovis W C J Chung and R J Handa ldquoNovelactions of estrogen receptor-120573 on anxiety-related behaviorsrdquoEndocrinology vol 146 no 2 pp 797ndash807 2005

[159] N Breslau L Schultz and E Peterson ldquoSex differences indepression a role for preexisting anxietyrdquo Psychiatry Researchvol 58 no 1 pp 1ndash12 1995

[160] P E Bebbington G Dunn R Jenkins et al ldquoThe influenceof age and sex on the prevalence of depressive conditionsreport from the National Survey of Psychiatric MorbidityrdquoPsychological Medicine vol 28 no 1 pp 9ndash19 1998

[161] G Aguilera J P Harwood and J X Wilson ldquoMechanisms ofaction of corticotropin-releasing factor and other regulators ofcorticotropin release in rat pituitary cellsrdquo Journal of BiologicalChemistry vol 258 no 13 pp 8039ndash8045 1983

[162] A Papadimitriou and K N Priftis ldquoRegulation of thehypothalamic-pituitary-adrenal axisrdquo NeuroImmunoModula-tion vol 16 no 5 pp 265ndash271 2009

[163] S Suzuki and R J Handa ldquoRegulation of estrogen receptor-120573expression in the female rat hypothalamus differential effectsof dexamethasone and estradiolrdquo Endocrinology vol 145 no 8pp 3658ndash3670 2004

[164] W J S Miller S Suzuki L K Miller R Handa and R M UhtldquoEstrogen receptor (ER)120573 isoforms rather than ER120572 regulatecorticotropin-releasing hormone promoter activity through analternate pathwayrdquo Journal of Neuroscience vol 24 no 47 pp10628ndash10635 2004

[165] C IsgorM CecchiM Kabbaj H Akil and S JWatson ldquoEstro-gen receptor 120573 in the paraventricular nucleus of hypothalamusregulates the neuroendocrine response to stress and is regulatedby corticosteronerdquo Neuroscience vol 121 no 4 pp 837ndash8452003

[166] M L Forsling I Kallo D E Hartley et al ldquoOestrogen receptor-120573 and neurohypophysial hormones functional interaction andneuroanatomical localisationrdquo Pharmacology Biochemistry andBehavior vol 76 no 3-4 pp 535ndash542 2003

[167] A S Lalmansingh and R M Uht ldquoEstradiol regulatescorticotropin-releasing hormone gene (crh) expression in arapid and phasic manner that parallels estrogen receptor-120572 and-120573 recruitment to a 3101584051015840-cyclic adenosine 51015840- monophosphateregulatory region of the proximal crh promoterrdquo Endocrinologyvol 149 no 1 pp 346ndash357 2008

[168] B N Roy R L Reid and D A van Vugt ldquoThe effects ofestrogen and progesterone on corticotropin-releasing hormoneand arginine vasopressin messenger ribonucleic acid levelsin the paraventricular nucleus and supraoptic nucleus of therhesus monkeyrdquo Endocrinology vol 140 no 5 pp 2191ndash21981999

[169] X Ni R C Nicholson B R King E-C Chan M A Read andR Smith ldquoEstrogen represses whereas the estrogen-antagonistICI 182780 stimulates placental CRH gene expressionrdquo Journalof Clinical Endocrinology and Metabolism vol 87 no 8 pp3774ndash3778 2002

[170] N C Vamvakopoulos and G P Chrousos ldquoEvidence of directestrogenic regulation of human corticotropin-releasing hor-mone gene expression Potential implications for the sexualdimophism of the stress response and immuneinflammatoryreactionrdquo Journal of Clinical Investigation vol 92 no 4 pp1896ndash1902 1993

[171] Y Hu D L Wu C X Luo et al ldquoHippocampal nitric oxidecontributes to sex difference in affective behaviorsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 35 pp 14224ndash14229 2012

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

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Disease Markers

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Endocrinology 9

suggesting a transcriptional role for ERs in synaptic plasticityMoreover E

2application may increase CREB expression and

the amount of phosphorylated CREB in regions such as theamygdala [155] and BNST [117 155] which may be critical inthe formation of long-term memories Taken together thesedata demonstrate that E

2regulates neuronal plasticity and

memory through its original role as a transcription factor andalso by acting as a general intracellular signaling moleculethrough regulation of NMDARs and CREB However todate there are little data on the mechanisms by which ER120573regulates these processes or how the same principles ofplasticity may apply to other neurological issues

12 Estrogens and Mood Regulation

A range of behavioral experiments indicate that E2mod-

ulation of stress mood and affect is a complex storywith considerable conflicting data that may as in otherprocesses be explained in part by distinct roles for ER120572 andER120573 Anecdotally many women report mood fluctuationsas corresponding to changes in circulating estrogen levelssuch as what occurs during the menstrual cycle peripubertypostpartum and peripostmenopause Incidence of anxietyand depression are observed at perimenopause and whenhormone levels are fluctuating [156 157] However E

2can

also exhibit anxiogenic properties and often anxiety anddepression present in a comorbid fashion especially inwomen [158 159] Interestingly after the age of 55 bouts ofdepression and anxiety appear to decrease in women [160]As previously mentioned perimenopausal women receivingCEE in the KEEPs study reported an improvement in moodand the primary actions of CEE tend to be mediated throughER120573 [20] A plethora of behavioral studies has mountedin response to observational reports and at first glance itappears that ER120573 has an anxiolytic and antidepressive rolehowever there is still an immense void to be filled withrespect to biochemical and molecular mechanisms of ER120573and affective disorders Elucidating the precise molecularmechanisms that require ER120573 in plasticity and neurotrans-mitter processing in brain regions regulating these behaviorswill help clarify the role of E

2in stress- and mood-related

processesContemporary hypotheses concerning the onset of affec-

tive disorders revolve around perturbations to the cen-tral processing of environmental stress The hypothalamic-pituitary-adrenal (HPA) axis is the 3-tiered hierarchicalbiological system that mediates physical or psychologicalresponse to stressors The primary steroid regulating theHPA axis is cortisolcorticosterone (humansrats CORT) aglucocorticoid receptor (GR) ligand that is produced fromthe adrenals to exert negative feedback upon the HPAsystem to effectively modulate response to stressors Theparaventricular nucleus of hypothalamus (PVN) producestwo neuropeptides corticotropin-releasing hormone (CRH)and arginine vasopressin (AVP) to activate the HPA axisCRF and AVP synergistically stimulate release of adreno-corticotropic hormone (ACTH) from the anterior pituitarywhich acts on the adrenal cortex to produce CORT CORT

binds GR and negatively regulates CRF and AVP expressionsand releases through classical negative feedback mechanisms[161 162] ER120573 is themain ER expressed in the PVN [158 163ndash165] and regulation of AVP is an interesting example of howER action can vary AVP expression fluctuates during themenstrual cycle and is usually highest when E

2is low In fact

oral contraceptives appear to decrease AVP expression andE2is thought to inhibit AVP in the human SON [166] In

the rodent system ER120573 and its splice variants activate therodent AVP promoter independent of ligand [84] howeverthe human promoter is repressed by ER120573 and splice variantsThis discrepancy between the human and rat wasmediated byan AP-1 response element on the human AVP promoter thatis not present in the rat Importantly ER120573 acted similarly inthe two systems when the AP-1 sequence was deleted fromthe human promoter underscoring the striking alterationsthat small changes in DNA sequence can invoke in E

2

signaling pathways and the importance of understanding theexperimental context upon which such conclusions are based[77] On the contrary rat and human CRF expression wasincreased in response to E

2in rodent monkey and human

hypothalamus but it was inhibited in the placenta [167ndash170]In addition to AVP and CRF glutamatergic and GABAer-

gic projects from regions like the BNST AMY PFC andhippocampus all express ER120573 [45 46] and are likely targetsfor E2to exert effects on the HPA axis Moreover decreased

ER120573 mRNA in postmortem locus coeruleus has been foundto correlate with suicide [13] and even more recentlyER120573-mediated hippocampal nitric oxide levels have beenimplicated in affective behaviors in females but not males[171] Neurotransmitter release from these regions influencesmood affect and stress responses and E

2increases the rate

of monoamine oxidase degradation and serotonin transportwhich enhances serotonin at the synapse E

2also increases

serotonin receptor expression [172 173] Dopamine andserotonin [174] are diminished in the BNST POA and hip-pocampus and caudate putamen (dopamine) of 120573ERKOmice[174] further implicating an important role for ER120573 in theregulation of emotion and mood 120573ERKO mice also displayserious morphological and functional abnormalities in thebrain that correlate to increased depression and anxiety [12175ndash178] In addition to 120573ERKO studies administration ofER120573 selective agonists (diarylpoprionitrile DPN) decreasesboth stress markers and anxiety-related behaviors in rats[158] In fact there have been several studies implicatingER120573 and its variants in affective behaviors but the molecularmechanisms remain poorly understood

13 Summary

Estrogen-receptor-mediated signaling in the brain regulatesneurological processes many of which translate to cog-nitive and affective behavioral outputs When estrogen isdeclining and becomes replete as in menopause a num-ber of neurophysiological changes occur producing someunwanted changes The most common and logical remedyis replacement of bioidentical hormone E

2 however this

treatment can be problematic depending upon the length

10 ISRN Endocrinology

of time a woman has been in a postmenopausal estrogen-deprived state This suggests that there is a molecular switchin estrogen-mediated signaling that may allow for drasticchange in ER signaling not to mention the interaction of E

2

signaling components and the natural aging process Thesechanges are likely to include alterations to receptor profilesincluding expression of alternatively spliced variants thatrespond differently to E

2 changes in the cellular microenvi-

ronment that can alter the proteinprotein associations whichultimately leads to changes in ER-mediated gene transcrip-tion and synaptic transmission ER120573 in particular is widelyexpressed and implicated positively in the regulation ofmemory and mood fluctuations two of the most commonlyreported neurological issues in postmenopausal women Itis important to understand the actions of ER120573 in the areasregulating these processes to identify what when how andfor whom hormone therapy may be a useful treatment torectify cognitive and affective issues

Acknowledgments

This work was supported by NIA RO1 AG033605-01 andNIH T32 AG031780 The authors N N Mott and T R Pakhave nothing to disclose

References

[1] C Bengtsson O Lindquist and L Redvall ldquoIs the menopausalage rapidly changingrdquoMaturitas vol 1 no 3 pp 159ndash164 1979

[2] A Singh S Kaur and I Walia ldquoA historical perspective onmenopause andmenopausal agerdquo Bulletin of the Indian Instituteof History of Medicine (Hyderabad) vol 32 no 2 pp 121ndash1352002

[3] P Verhaeghen and J Cerella ldquoAging executive control andattention a review of meta-analysesrdquo Neuroscience and Biobe-havioral Reviews vol 26 no 7 pp 849ndash857 2002

[4] T E Wroolie H A Kenna K E Williams et al ldquoDifferencesin verbal memory performance in postmenopausal womenreceiving hormone therapy 17120573-estradiol versus conjugatedequine estrogensrdquoAmerican Journal of Geriatric Psychiatry vol19 no 9 pp 792ndash802 2011

[5] B B Sherwin ldquoEstrogenic effects on memory in womenrdquoAnnals of the New York Academy of Sciences vol 743 pp 213ndash230 1994

[6] B B Sherwin ldquoHormones mood and cognitive functioning inpostmenopausal womenrdquoObstetrics andGynecology vol 87 no2 supplement pp 20Sndash26S 1996

[7] B B Sherwin ldquoSex hormones and psychological functioning inpostmenopausalwomenrdquoExperimentalGerontology vol 29 no3-4 pp 423ndash430 1994

[8] SM Phillips and B B Sherwin ldquoEffects of estrogen onmemoryfunction in surgically menopausal womenrdquo Psychoneuroen-docrinology vol 17 no 5 pp 485ndash495 1992

[9] R Lindsay J M Aitken and J B Anderson ldquoLong term pre-vention of postmenopausal osteoporosis by oestrogen Evidencefor an increased bone mass after delayed onset of oestrogentreatmentrdquoThe Lancet vol 1 no 7968 pp 1038ndash1040 1976

[10] J E Rossouw R L Prentice J E Manson et al ldquoPost-menopausal hormone therapy and risk of cardiovascular dis-ease by age and years since menopauserdquo The Journal of the

American Medical Association vol 297 no 13 pp 1465ndash14772007

[11] Q-G Zhang D Han R-M Wang et al ldquoC terminusof Hsc70-interacting protein (CHIP)-mediated degradationof hippocampal estrogen receptor-120572 and the critical periodhypothesis of estrogen neuroprotectionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 108 no 35 pp E617ndashE624 2011

[12] W Krezel S Dupont A Krust P Chambon and P F ChapmanldquoIncreased anxiety and synaptic plasticity in estrogen receptor120573-deficient micerdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 21 pp 12278ndash12282 2001

[13] H Ostlund E Keller and Y L Hurd ldquoEstrogen receptor geneexpression in relation to neuropsychiatric disordersrdquo Annals ofthe New York Academy of Sciences vol 1007 pp 54ndash63 2003

[14] S A Shumaker C Legault S R Rapp et al ldquoEstrogen plusprogestin and the incidence of dementia and mild cognitiveimpairment in postmenopausal women the Womenrsquos HealthInitiative Memory Study a randomized controlled trialrdquo Jour-nal of the American Medical Association vol 289 no 20 pp2651ndash2662 2003

[15] S A Shumaker C Legault L Kuller et al ldquoConjugated equineestrogens and incidence of probable dementia and mild cog-nitive impairment in postmenopausal women womenrsquos HealthInitiative Memory Studyrdquo Journal of the American MedicalAssociation vol 291 no 24 pp 2947ndash2958 2004

[16] S R Rapp M A Espeland S A Shumaker et al ldquoEffect ofestrogen plus progestin on global cognitive function in post-menopausal women the Womenrsquos Health Initiative MemoryStudy a randomized controlled trialrdquo Journal of the AmericanMedical Association vol 289 no 20 pp 2663ndash2672 2003

[17] VWHenderson K S Benke R C Green L A Cupples and LA Farrer ldquoPostmenopausal hormone therapy and Alzheimerrsquosdisease risk interaction with agerdquo Journal of Neurology Neuro-surgery and Psychiatry vol 76 no 1 pp 103ndash105 2005

[18] E Garbe and S Suissa ldquoHormone replacement therapy andacute coronary syndromes methodological issues betweenrandomized and observational studiesrdquo Human Reproductionvol 19 no 1 pp 8ndash13 2004

[19] B B Braden A N Garcia S E Mennenga et al ldquoCognitive-impairing effects of medroxyprogesterone acetate in the ratindependent and interactive effects across timerdquo Psychophar-macology vol 218 no 2 pp 405ndash418 2011

[20] B R Bhavnani S-P Tam and X Lu ldquoStructure activity rela-tionships and differential interactions and functional activity ofvarious equine estrogens mediated via estrogen receptors (ERs)ER120572 and ER120573rdquo Endocrinology vol 149 no 10 pp 4857ndash48702008

[21] E Hogervorst and S Bandelow ldquoSex steroids to maintaincognitive function in women after the menopause a meta-analyses of treatment trialsrdquoMaturitas vol 66 no 1 pp 56ndash712010

[22] D J Mangelsdorf C Thummel M Beato et al ldquoThe nuclearreceptor super-family the second decaderdquo Cell vol 83 no 6pp 835ndash839 1995

[23] E V Jensen T Suzuki T Kawashima W E Stumpf P WJungblut and E R DeSombre ldquoA two-step mechanism forthe interaction of estradiol with rat uterusrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 59 no 2 pp 632ndash638 1968

ISRN Endocrinology 11

[24] F Naftolin T L Horvath R L Jakab C Leranth N Haradaand J Balthazart ldquoAromatase immunoreactivity in axon termi-nals of the vertebrate brain an immunocytochemical study onquail rat monkey and human tissuesrdquoNeuroendocrinology vol63 no 2 pp 149ndash155 1996

[25] C E Roselli S E Abdelgadir O K Roslashnnekleiv and S AKlosterman ldquoAnatomic distribution and regulation of aro-matase gene expression in the rat brainrdquo Biology of Reproduc-tion vol 58 no 1 pp 79ndash87 1998

[26] J Balthazart and G F Ball ldquoIs brain estradiol a hormone or aneurotransmitterrdquo Trends in Neurosciences vol 29 no 5 pp241ndash249 2006

[27] T R Pak Y S Rao S A Prins and N N Mott ldquoAn emergingrole for microRNAs in sexually dimorphic neurobiologicalsystemsrdquo Pflugers Archiv vol 465 no 5 pp 655ndash667 2013

[28] K Yamagata S Fujiyama S Ito et al ldquoMaturation ofmicroRNAis hormonally regulated by a nuclear receptorrdquo Molecular Cellvol 36 no 2 pp 340ndash347 2009

[29] Y Masuhiro Y Mezaki M Sakari et al ldquoSplicing potentiationby growth factor signals via estrogen receptor phosphorylationrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 23 pp 8126ndash8131 2005

[30] A Tremblay G B Tremblay F Labrie and V Giguere ldquoLigand-Independent recruitment of SRC-1 to estrogen receptor 120573through phosphorylation of activation function AF-1rdquo Molec-ular Cell vol 3 no 4 pp 513ndash519 1999

[31] S H Meijsing M A Pufall A Y So D L Bates L Chenand K R Yamamoto ldquoDNA binding site sequence directsglucocorticoid receptor structure and activityrdquo Science vol 324no 5925 pp 407ndash410 2009

[32] W Bourguet P Germain and H Gronemeyer ldquoNuclearreceptor ligand-binding domains three-dimensional struc-tures molecular interactions and pharmacological implica-tionsrdquo Trends in Pharmacological Sciences vol 21 no 10 pp381ndash388 2000

[33] A Koide C Zhao M Naganuma et al ldquoIdentification ofregions within the F domain of the human estrogen receptor 120572that are important for modulating transactivation and protein-protein interactionsrdquoMolecular Endocrinology vol 21 no 4 pp829ndash842 2007

[34] D F Skafar and S Koide ldquoUnderstanding the human estrogenreceptor-alpha using targeted mutagenesisrdquoMolecular and Cel-lular Endocrinology vol 246 no 1-2 pp 83ndash90 2006

[35] E C Chang J Frasor B Komm and B S KatzenellenbogenldquoImpact of estrogen receptor 120573 on gene networks regulated byestrogen receptor 120572 in breast cancer cellsrdquo Endocrinology vol147 no 10 pp 4831ndash4842 2006

[36] X Zhu I Leav Y-K Leung et al ldquoDynamic regulation ofestrogen receptor-120573 expression by DNA methylation duringprostate cancer development andmetastasisrdquoAmerican Journalof Pathology vol 164 no 6 pp 2003ndash2012 2004

[37] D N Petersen G T Tkalcevic P H Koza-Taylor T G Turiand T A Brown ldquoIdentification of estrogen receptor 1205732 afunctional variant of estrogen receptor 120573 expressed in normalrat tissuesrdquo Endocrinology vol 139 no 3 pp 1082ndash1092 1998

[38] L A Helguero M H Faulds J-A Gustafsson and L-AHaldosen ldquoEstrogen receptors alfa (ER120572) and beta (ER120573)differentially regulate proliferation and apoptosis of the normalmurine mammary epithelial cell line HC11rdquo Oncogene vol 24no 44 pp 6605ndash6616 2005

[39] P C Kulakosky M A McCarty S C Jernigan K E Risingerand C M Klinge ldquoResponse element sequence modulates

estrogen receptor 120572 and 120573 affinity and activityrdquo Journal ofMolecular Endocrinology vol 29 no 1 pp 137ndash152 2002

[40] OM V Grober MMutarelli G Giurato et al ldquoGlobal analysisof estrogen receptor beta binding to breast cancer cell genomereveals an extensive interplay with estrogen receptor alpha fortarget gene regulationrdquo BMC Genomics vol 12 article 36 2011

[41] O I Vivar X Zhao E F Saunier et al ldquoEstrogen receptor 120573binds to and regulates three distinct classes of target genesrdquoJournal of Biological Chemistry vol 285 no 29 pp 22059ndash22066 2010

[42] G G J M Kuiper E Enmark M Pelto-Huikko S Nilssonand J-A Gustafsson ldquoCloning of a novel estrogen receptorexpressed in rat prostate and ovaryrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 93 no12 pp 5925ndash5930 1996

[43] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and 120572 and 120573rdquo Endocrinology vol 138no 3 pp 863ndash870 1997

[44] D B Dubal H Zhu J Yu et al ldquoEstrogen receptor alpha notbeta is a critical link in estradiol-mediated protection againstbrain injuryrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 98 no 4 pp 1952ndash1957 2001

[45] P J Shughrue P J Scrimo and I Merchenthaler ldquoEvidence forthe colocalization of estrogen receptor-120573 mRNA and estrogenreceptor-120572 immunoreactivity in neurons of the rat forebrainrdquoEndocrinology vol 139 no 12 pp 5267ndash5270 1998

[46] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in therat central nervous systemrdquo Journal of Comparative Neurologyvol 388 no 4 pp 507ndash525 1997

[47] T AMilner B SMcEwen S Hayashi C J Li L P Reagan andS E Alves ldquoUltrastructural evidence that hippocampal alphaestrogen receptors are located at extranuclear sitesrdquoThe Journalof Comparative Neurology vol 429 no 3 pp 355ndash371 2001

[48] T A Milner L S Lubbers S E Alves and B S McEwenldquoNuclear and extranuclear estrogen binding sites in the ratforebrain and autonomic medullary areasrdquo Endocrinology vol149 no 7 pp 3306ndash3312 2008

[49] T A Milner K Ayoola C T Drake et al ldquoUltrastructurallocalization of estrogen receptor 120573 immunoreactivity in the rathippocampal formationrdquo Journal of ComparativeNeurology vol491 no 2 pp 81ndash95 2005

[50] A E Herbison andD TTheodosis ldquoAbsence of estrogen recep-tor immunoreactivity in somatostatin (SRIF) neurons of theperiventricular nucleus but sexually dimorphic colocalizationof estrogen receptor and SRIF immunoreactivities in neuronsof the bed nucleus of the stria terminalisrdquo Endocrinology vol132 no 4 pp 1707ndash1714 1993

[51] K Kalita S Szymczak and L Kaczmarek ldquoNon-nuclear estro-gen receptor 120573 and 120572 in the hippocampus of male and femaleratsrdquo Hippocampus vol 15 no 3 pp 404ndash412 2005

[52] T Ivanova and C Beyer ldquoOntogenetic expression and sexdifferences of aromatase and estrogen receptor-120572120573 mRNA inthe mouse hippocampusrdquo Cell and Tissue Research vol 300 no2 pp 231ndash237 2000

[53] C Y Pau K-Y F Pau and H G Spies ldquoPutative estrogenreceptor 120573 and 120572 mRNA expression in male and female rhesusmacaquesrdquo Molecular and Cellular Endocrinology vol 146 no1-2 pp 59ndash68 1998

[54] A L Wijayaratne and D P McDonnell ldquoThe human estrogenreceptor-120572 is a ubiquitinated protein whose stability is affected

12 ISRN Endocrinology

differentially by agonists antagonists and selective estrogenreceptor modulatorsrdquo Journal of Biological Chemistry vol 276no 38 pp 35684ndash35692 2001

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[56] L C Li C C Yeh D Nojima and R Dahiya ldquoCloning andcharacterization of human estrogen receptor beta promoterrdquoBiochemical and Biophysical Research Communications vol 275no 2 pp 682ndash689 2000

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[63] M E Wilson K L Rosewell M L Kashon P J Shughrue IMerchenthaler and P M Wise ldquoAge differentially influencesestrogen receptor-120572 (ER120572) and estrogen receptor-120573 (ER120573) geneexpression in specific regions of the rat brainrdquo Mechanisms ofAgeing and Development vol 123 no 6 pp 593ndash601 2002

[64] W S Post P J Goldschmidt-Clermont C C Wilhide etal ldquoMethylation of the estrogen receptor gene is associatedwith aging and atherosclerosis in the cardiovascular systemrdquoCardiovascular Research vol 43 no 4 pp 985ndash991 1999

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[68] T R Chakraborty P R Hof L Ng and A C Gore ldquoStereologicanalysis of estrogen receptor alpha (ER alpha) expression in rat

hypothalamus and its regulation by aging and estrogenrdquo Journalof Comparative Neurology vol 466 no 3 pp 409ndash421 2003

[69] J M Westberry A L Trout and M E Wilson ldquoEpigeneticregulation of estrogen receptor beta expression in the rat cortexduring agingrdquo NeuroReport vol 22 no 9 pp 428ndash432 2011

[70] T R Chakraborty L Ng and A C Gore ldquoAge-related changesin estrogen receptor 120573 in rat hypothalamus a quantitativeanalysisrdquo Endocrinology vol 144 no 9 pp 4164ndash4171 2003

[71] I Poola S Koduri S Chatra and R Clarke ldquoIdentificationof twenty alternatively spliced estrogen receptor alpha mRNAsin breast cancer cell lines and tumors using splice targetedprimer approachrdquo Journal of Steroid Biochemistry andMolecularBiology vol 72 no 5 pp 249ndash258 2000

[72] T A Ishunina and D F Swaab ldquoHippocampal estrogenreceptor-alpha splice variant TADDI in the human brain inaging and Alzheimerrsquos diseaserdquoNeuroendocrinology vol 89 no2 pp 187ndash199 2009

[73] T A Ishunina and D F Swaab ldquoEstrogen receptor-120572 splicevariants in the human brainrdquo Gynecological Endocrinology vol24 no 2 pp 93ndash98 2008

[74] T A Ishunina F P M Kruijver R Balesar and D FSwaab ldquoDifferential expression of estrogen receptor 120572 and 120573immunoreactivity in the human supraoptic nucleus in rela-tion to sex and agingrdquo Journal of Clinical Endocrinology andMetabolism vol 85 no 9 pp 3283ndash3291 2000

[75] T A Ishunina D F Fischer andD F Swaab ldquoEstrogen receptor120572 and its splice variants in the hippocampus in aging andAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 28 no 11 pp1670ndash1681 2007

[76] J R Tollervey Z Wang T Hortobagyi et al ldquoAnalysis of alter-native splicing associated with aging and neurodegeneration inthe human brainrdquo Genome Research vol 21 no 10 pp 1572ndash1582 2011

[77] N NMott and T R Pak ldquoCharacterisation of human oestrogenreceptor beta (ER120573) splice variants in neuronal cellsrdquo Journal ofNeuroendocrinology vol 24 no 10 pp 1311ndash1321 2012

[78] S Inoue S-J Hoshino H Miyoshi et al ldquoIdentification ofa ovel isoform of estrogen receptor a potential inhibitor ofestrogen action in vascular smooth muscle cellsrdquo Biochemicaland Biophysical Research Communications vol 219 no 3 pp766ndash772 1996

[79] J K Skipper L J Young J M Bergeron M T Tetzlaff CT Osborn and D Crews ldquoIdentification of an isoform ofthe estrogen receptor messenger RNA lacking exon four andpresent in the brainrdquo Proceedings of the National Academy ofSciences of the United States of America vol 90 no 15 pp 7172ndash7175 1993

[80] R H Price Jr N Lorenzon and R J Handa ldquoDifferentialexpression of estrogen receptor beta splice variants in rat brainidentification and characterization of a novel variant missingexon 4rdquo Brain Research Molecular Brain Research vol 80 no2 pp 260ndash268 2000

[81] S Chu and P J Fuller ldquoIdentification of a splice variantof the rat estrogen receptor 120573 generdquo Molecular and CellularEndocrinology vol 132 no 1-2 pp 195ndash199 1997

[82] B Lu E Leygue H Dotzlaw L J Murphy L C Murphy andP H Watson ldquoEstrogen receptor-120573 mRNA variants in humanand murine tissuesrdquoMolecular and Cellular Endocrinology vol138 no 1-2 pp 199ndash203 1998

[83] T R Pak W C J Chung J L Roberts and R J HandaldquoLigand-independent effects of estrogen receptor 120573 on

ISRN Endocrinology 13

mouse gonadotropin-releasing hormone promoter activityrdquoEndocrinology vol 147 no 4 pp 1924ndash1931 2006

[84] T R Pak W C J Chung L R Hinds and R J HandaldquoEstrogen receptor-120573 mediates dihydrotestosterone-inducedstimulation of the arginine vasopressin promoter in neuronalcellsrdquo Endocrinology vol 148 no 7 pp 3371ndash3382 2007

[85] Y K Leung PMak S Hassan and SMHo ldquoEstrogen receptor(ER)-120573 isoforms a key to understanding ER-120573 signalingrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 103 no 35 pp 13162ndash13167 2006

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[87] W C J Chung T R Pak S Suzuki W A Pouliot M EAndersen and R J Handa ldquoDetection and localization of anestrogen receptor beta splice variant protein (ER1205732) in theadult female rat forebrain and midbrain regionsrdquo Journal ofComparative Neurology vol 505 no 3 pp 249ndash267 2007

[88] R H Price Jr C A Butler P Webb R Uht P Kushner andR J Handa ldquoA splice variant of estrogen receptor 120573 missingexon 3 displays altered subnuclear localization and capacity fortranscriptional activationrdquo Endocrinology vol 142 no 5 pp2039ndash2049 2001

[89] Y Wang and R J Miksicek ldquoIdentification of a dominantnegative form of the human estrogen receptorrdquo MolecularEndocrinology vol 5 no 11 pp 1707ndash1715 1991

[90] E Kuppers and C Beyer ldquoExpression of estrogen receptor-120572and 120573 mRNA in the developing and adult mouse striatumrdquoNeuroscience Letters vol 276 no 2 pp 95ndash98 1999

[91] C Gundlah S G Kohama S J Mirkes V T Garyfallou H FUrbanski and C L Bethea ldquoDistribution of estrogen receptorbeta (ER120573) mRNA in hypothalamus midbrain and temporallobe of spayed macaque continued expression with hormonereplacementrdquo Brain Research Molecular Brain Research vol 76no 2 pp 191ndash204 2000

[92] Y Morishima P J M Murphy D-P Li E R Sanchez and WB Pratt ldquoStepwise assembly of a glucocorticoid receptorsdothsp90heterocomplex resolves two sequential ATP-dependent eventsinvolving first hsp70 and then hsp90 in opening of the steroidbinding pocketrdquo Journal of Biological Chemistry vol 275 no 24pp 18054ndash18060 2000

[93] K D Dittmar and W B Pratt ldquoFolding of the glucocorticoidreceptor by the reconstituted hsp90-based chaperone machin-eryThe initial hsp90sdotp60sdothsp70-dependent step is sufficient forcreating the steroid binding conformationrdquo Journal of BiologicalChemistry vol 272 no 20 pp 13047ndash13054 1997

[94] K I Kang X Meng J Devin-Leclerc et al ldquoThe molecularchaperone Hsp90 can negatively regulate the activity of aglucocorticosteroid-dependent promoterrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 4 pp 1439ndash1444 1999

[95] K Unno H Asakura Y Shibuya M Kaiho S Okada and NOku Naoto ldquoIncrease in basal level of Hsp70 consisting chieflyof constitutively expressed hsp70 (Hsc70) in aged rat brainrdquoJournals of Gerontology Series A vol 55 no 7 pp B329ndashB3352000

[96] U E Olazabal D W Pfaff and C V Mobbs ldquoSex differences inthe regulation of heat shock protein 70 kDa and 90 kDa in therat ventromedial hypothalamus by estrogenrdquo Brain Researchvol 596 no 1-2 pp 311ndash314 1992

[97] M A Pahlavani M D Harris S A Moore and A RichardsonldquoExpression of heat shock protein 70 in rat spleen lymphocytesis affected by age but not by food restrictionrdquo Journal ofNutrition vol 126 no 9 pp 2069ndash2075 1996

[98] A R Heydari B Wu R Takahashi R Strong and A Richard-son ldquoExpression of heat shock protein 70 is altered by age anddiet at the level of transcriptionrdquoMolecular andCellular Biologyvol 13 no 5 pp 2909ndash2918 1993

[99] M Sabbah K-I I Kang L Tora and G Redeuilh ldquoOestro-gen receptor facilitates the formation of preinitiation com-plex assembly involvement of the general transcription factorTFIIBrdquo Biochemical Journal vol 336 part 3 pp 639ndash646 1998

[100] S-Y Wu M C Thomas S Y Hou V Likhite and C-MChiang ldquoIsolation of mouse TFIID and functional character-ization of TBP and TFIID in mediating estrogen receptor andchromatin transcriptionrdquo Journal of Biological Chemistry vol274 no 33 pp 23480ndash23490 1999

[101] S Ghosh and M K Thakur ldquoTissue-specific expression ofreceptor-interacting protein in aging mouserdquo Age vol 30 no4 pp 237ndash243 2008

[102] J Frasor JM Danes B Komm K C N Chang C Richard Lyt-tle and B S Katzenellenbogen ldquoProfiling of estrogen up- anddown-regulated gene expression in human breast cancer cellsinsights into gene networks and pathways underlying estrogeniccontrol of proliferation and cell phenotyperdquo Endocrinology vol144 no 10 pp 4562ndash4574 2003

[103] J Frasor J M Danes C C Funk and B S Katzenellen-bogen ldquoEstrogen down-regulation of the corepressor N-CoRmechanism and implications for estrogen derepression of N-CoR-regulated genesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 102 no 37 pp13153ndash13157 2005

[104] N J McKenna and B W OrsquoMalley ldquoCombinatorial control ofgene expression by nuclear receptors and coregulatorsrdquoCell vol108 no 4 pp 465ndash474 2002

[105] T-P Yao G Ku N Zhou R Scully and D M Livingston ldquoThenuclear hormone receptor coactivator SRC-1 is a specific targetof p300rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 93 no 20 pp 10626ndash10631 1996

[106] B Hanstein R Eckner J DiRenzo et al ldquop300 is a componentof an estrogen receptor coactivator complexrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 93 no 21 pp 11540ndash11545 1996

[107] S Halachmi E Marden G Martin H MacKay C Abbon-danza and M Brown ldquoEstrogen receptor-associated proteinspossible mediators of hormone-induced transcriptionsrdquo Sci-ence vol 264 no 5164 pp 1455ndash1458 1994

[108] A J Horlein AM Naar T Heinzel et al ldquoLigand-independentrepression by the thyroid hormone receptor mediated by anuclear receptor co-repressorrdquo Nature vol 377 no 6548 pp397ndash404 1995

[109] J D Chen and R M Evans ldquoA transcriptional co-repressor thatinteracts with nuclear hormone receptorsrdquo Nature vol 377 no6548 pp 454ndash457 1995

[110] A Malovannaya R B Lanz S Y Jung et al ldquoAnalysis of thehuman endogenous coregulator complexomerdquoCell vol 145 no5 pp 787ndash799 2011

[111] Z Nawaz D M Lonard C L Smith et al ldquoThe Angelmansyndrome-associated protein E6-AP is a coactivator for thenuclear hormone receptor superfamilyrdquoMolecular and CellularBiology vol 19 no 2 pp 1182ndash1189 1999

14 ISRN Endocrinology

[112] B Zheng M Han M Bernier and J-K Wen ldquoNuclear actinand actin-binding proteins in the regulation of transcriptionand gene expressionrdquo FEBS Journal vol 276 no 10 pp 2669ndash2685 2009

[113] W A Hofmann L Stojiljkovic B Fuchsova et al ldquoActin is partof pre-initiation complexes and is necessary for transcription byRNA polymerase IIrdquoNature Cell Biology vol 6 no 11 pp 1094ndash1101 2004

[114] K Tokunaga T Shibuya Y Ishihama et al ldquoNucleocytoplasmictransport of fluorescent mRNA in living mammalian cellsnuclear mRNA export is coupled to ongoing gene transcrip-tionrdquo Genes to Cells vol 11 no 3 pp 305ndash317 2006

[115] R Metivier G Penot M R Hubner et al ldquoEstrogen receptor-120572 directs ordered cyclical and combinatorial recruitment ofcofactors on a natural target promoterrdquo Cell vol 115 no 6 pp751ndash763 2003

[116] C Ambrosino R Tarallo A Bamundo et al ldquoIdentification of ahormone-regulated dynamic nuclear actin network associatedwith estrogen receptor 120572 in human breast cancer cell nucleirdquoMolecular and Cellular Proteomics vol 9 no 6 pp 1352ndash13672010

[117] F Shao R Zhang L Dong and K Ying ldquoOverexpression ofgelsolin-like actin-capping protein is associated with progres-sion of lung adenocarcinomardquo Tohoku Journal of ExperimentalMedicine vol 225 no 2 pp 95ndash101 2011

[118] K Nishimura H-J Ting Y Harada et al ldquoModulation ofandrogen receptor transactivation by gelsolin a newly identi-fied androgen receptor coregulatorrdquo Cancer Research vol 63no 16 pp 4888ndash4894 2003

[119] J S Ahn I S Jang D I Kim et al ldquoAging-associated increaseof gelsolin for apoptosis resistancerdquoBiochemical and BiophysicalResearch Communications vol 312 no 4 pp 1335ndash1341 2003

[120] I Nalvarte T Schwend and J-A Gustafsson ldquoProteomicsanalysis of the estrogen receptor 120572 receptosomerdquoMolecular andCellular Proteomics vol 9 no 7 pp 1411ndash1422 2010

[121] L-H Miau C-J Chang B-J Shen W-H Tsai and S-C LeeldquoIdentification of heterogeneous nuclear ribonucleoprotein K(hnRNPK) as a repressor ofCEBP120573-mediated gene activationrdquoJournal of Biological Chemistry vol 273 no 17 pp 10784ndash107911998

[122] A Ostareck-Lederer D H Ostareck C Cans et al ldquoc-Src-mediated phosphorylation of hnRNP K drives translationalactivation of specifically silenced mRNAsrdquo Molecular and Cel-lular Biology vol 22 no 13 pp 4535ndash4543 2002

[123] P S Bagga G K Arhin and J Wilusz ldquoDSEF-1 is a member ofthe hnRNP H family of RNA-binding proteins and stimulatespre-mRNAcleavage and polyadenylation in vitrordquoNucleic AcidsResearch vol 26 no 23 pp 5343ndash5350 1998

[124] V Markovtsov J M Nikolic J A Goldman C W Turck M-Y Chou and D L Black ldquoCooperative assembly of an hnRNPcomplex induced by a tissue-specific homolog of polypyrimi-dine tract binding proteinrdquoMolecular and Cellular Biology vol20 no 20 pp 7463ndash7479 2000

[125] S Y Jung A Malovannaya J Wei B W OrsquoMalley and J QinldquoProteomic analysis of steady-state nuclear hormone receptorcoactivator complexesrdquoMolecular Endocrinology vol 19 no 10pp 2451ndash2465 2005

[126] W Hong R J Resnick C Rakowski D Shalloway S J Taylorand G A Blobel ldquoPhysical and functional interaction betweenthe transcriptional cofactor CBP and the KH domain proteinSam68rdquoMolecular Cancer Research vol 1 no 1 pp 48ndash55 2002

[127] R ShaoXWang BWeijdegard et al ldquoCoordinate regulation ofheterogeneous nuclear ribonucleoprotein dynamics by steroidhormones in the human fallopian tube and endometrium invivo and in vitrordquo American Journal of Physiology vol 302 no10 pp E1269ndashE1282 2012

[128] C SWoolley and B SMcEwen ldquoEstradiolmediates fluctuationin hippocampal synapse density during the estrous cycle in theadult ratrdquo Journal of Neuroscience vol 12 no 7 pp 2549ndash25541992

[129] C S Woolley H J Wenzel and P A Schwartzkroin ldquoEstradiolincreases the frequency of multiple synapse boutons in thehippocampal CA1 region of the adult female ratrdquo The Journalof Comparative Neurology vol 373 no 1 pp 108ndash117 1996

[130] C S Woolley ldquoEstrogen-mediated structural and functionalsynaptic plasticity in the female rat hippocampusrdquo Hormonesand Behavior vol 34 no 2 pp 140ndash148 1998

[131] D P Srivastava K M Woolfrey K A Jones et al ldquoRapidenhancement of two-step wiring plasticity by estrogen andNMDA receptor activityrdquo Proceedings of the National Academyof Sciences of the United States of America vol 105 no 38 pp14650ndash14655 2008

[132] M Ogiue-Ikeda N Tanabe H Mukai et al ldquoRapid modu-lation of synaptic plasticity by estrogens as well as endocrinedisrupters in hippocampal neuronsrdquo Brain Research Reviewsvol 57 no 2 pp 363ndash375 2008

[133] N J Sandstrom and C L Williams ldquoSpatial memory retentionis enhanced by acute and continuous estradiol replacementrdquoHormones and Behavior vol 45 no 2 pp 128ndash135 2004

[134] E Hogervorst J Williams M Budge W Riedel and JJolles ldquoThe nature of the effect of female gonadal hormonereplacement therapy on cognitive function in post-menopausalwomen a meta-analysisrdquo Neuroscience vol 101 no 3 pp 485ndash512 2000

[135] M E Bailey A C J Wang J Hao et al ldquoInteractive effects ofage and estrogen on cortical neurons implications for cognitiveagingrdquo Neuroscience vol 191 pp 148ndash158 2011

[136] A A Walf M E Rhodes and C A Frye ldquoOvarian steroidsenhance object recognition in naturally cycling and ovariec-tomized hormone-primed ratsrdquo Neurobiology of Learning andMemory vol 86 no 1 pp 35ndash46 2006

[137] V N Luine L F Jacome and N J Maclusky ldquoRapid enhance-ment of visual and place memory by estrogens in ratsrdquoEndocrinology vol 144 no 7 pp 2836ndash2844 2003

[138] L Fan Z Zhao P T Orr C H Chambers M C Lewis and KM Frick ldquoEstradiol-induced object memory consolidation inmiddle-aged femalemice requires dorsal hippocampal extracel-lular signal-regulated kinase and phosphatidylinositol 3-kinaseactivationrdquo Journal of Neuroscience vol 30 no 12 pp 4390ndash4400 2010

[139] D B Dubal and PMWise ldquoNeuroprotective effects of estradiolin middle-aged female ratsrdquo Endocrinology vol 142 no 1 pp43ndash48 2001

[140] S-H Yang J Shi A L Day and J W Simpkins ldquoEstradiolexerts neuroprotective effects when administered after ischemicinsultrdquo Stroke vol 31 no 3 pp 745ndash750 2000

[141] J W Simpkins G Rajakumar Y-Q Zhang et al ldquoEstrogensmay reduce mortality and ischemic damage caused by middlecerebral artery occlusion in the female ratrdquo Journal of Neuro-surgery vol 87 no 5 pp 724ndash730 1997

[142] J Shi K S Panickar S-H Yang O Rabbani A L Day and JWSimpkins ldquoEstrogen attenuates over-expression of 120573-amyloid

ISRN Endocrinology 15

precursor protein messager RNA in an animal model of focalischemiardquo Brain Research vol 810 no 1-2 pp 87ndash92 1998

[143] Q-H Zhang Y-H Huang Y-Z Hu et al ldquoDisruption ofestrogen receptor beta in mice brain results in pathologicalalterations resemblingAlzheimer diseaserdquoActa PharmacologicaSinica vol 25 no 4 pp 452ndash457 2004

[144] E F Rissman A L Heck J E Leonard M A Shupnik and J-A Gustafsson ldquoDisruption of estrogen receptor 120573 gene impairsspatial learning in female micerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no6 pp 3996ndash4001 2002

[145] M Day A Sung S Logue M Bowlby and R Arias ldquoBetaestrogen receptor knockout (BERKO) mice present attenuatedhippocampal CA1 long-term potentiation and related memorydeficits in contextual fear conditioningrdquo Behavioural BrainResearch vol 164 no 1 pp 128ndash131 2005

[146] R Vierk G Glassmeier L Zhou et al ldquoAromatase inhibitionabolishes LTP generation in female but not in male micerdquo TheJournal of Neuroscience vol 32 no 24 pp 8116ndash8126 2012

[147] R-M Vouimba M R Foy J G Foy and R FThompson ldquo17120573-estradiol suppresses expression of long-term depression in agedratsrdquo Brain Research Bulletin vol 53 no 6 pp 783ndash787 2000

[148] C E Andreescu B A Milojkovic E D Haasdijk et alldquoEstradiol improves cerebellar memory formation by activatingestrogen receptor 120573rdquo Journal of Neuroscience vol 27 no 40 pp10832ndash10839 2007

[149] Y-Y Huang P V Nguyen T Abel and E R Kandel ldquoLong-lasting forms of synaptic potentiation in the mammalian hip-pocampusrdquo Learning Memory vol 3 no 2-3 pp 74ndash85 1996

[150] H Mukai T Tsurugizawa G Murakami et al ldquoRapid mod-ulation of long-term depression and spinogenesis via synapticestrogen receptors in hippocampal principal neuronsrdquo Journalof Neurochemistry vol 100 no 4 pp 950ndash967 2007

[151] L Liu T P Wong M F Pozza et al ldquoRole of NMDA receptorsubtypes in governing the direction of hippocampal synapticplasticityrdquo Science vol 304 no 5673 pp 1021ndash1024 2004

[152] M Cyr O Ghribi C Thibault M Morissette M Landry andT di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[153] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[154] C C Smith and L L McMahon ldquoEstradiol-induced increasein the magnitude of long-term potentiation is prevented byblocking NR2B-containing receptorsrdquo Journal of Neurosciencevol 26 no 33 pp 8517ndash8522 2006

[155] Y Zhou J J Watters and D M Dorsa ldquoEstrogen rapidlyinduces the phosphorylation of the cAMP response elementbinding protein in rat brainrdquo Endocrinology vol 137 no 5 pp2163ndash2166 1996

[156] XGonda T TelekG Juhasz J Lazary AVargha andG BagdyldquoPatterns of mood changes throughout the reproductive cyclein healthy women without premenstrual dysphoric disordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 32 no 8 pp 1782ndash1788 2008

[157] E W Freeman ldquoPremenstrual syndrome and premenstrualdysphoric disorder definitions and diagnosisrdquo Psychoneuroen-docrinology vol 28 supplement 3 pp 25ndash37 2003

[158] T D Lund T Rovis W C J Chung and R J Handa ldquoNovelactions of estrogen receptor-120573 on anxiety-related behaviorsrdquoEndocrinology vol 146 no 2 pp 797ndash807 2005

[159] N Breslau L Schultz and E Peterson ldquoSex differences indepression a role for preexisting anxietyrdquo Psychiatry Researchvol 58 no 1 pp 1ndash12 1995

[160] P E Bebbington G Dunn R Jenkins et al ldquoThe influenceof age and sex on the prevalence of depressive conditionsreport from the National Survey of Psychiatric MorbidityrdquoPsychological Medicine vol 28 no 1 pp 9ndash19 1998

[161] G Aguilera J P Harwood and J X Wilson ldquoMechanisms ofaction of corticotropin-releasing factor and other regulators ofcorticotropin release in rat pituitary cellsrdquo Journal of BiologicalChemistry vol 258 no 13 pp 8039ndash8045 1983

[162] A Papadimitriou and K N Priftis ldquoRegulation of thehypothalamic-pituitary-adrenal axisrdquo NeuroImmunoModula-tion vol 16 no 5 pp 265ndash271 2009

[163] S Suzuki and R J Handa ldquoRegulation of estrogen receptor-120573expression in the female rat hypothalamus differential effectsof dexamethasone and estradiolrdquo Endocrinology vol 145 no 8pp 3658ndash3670 2004

[164] W J S Miller S Suzuki L K Miller R Handa and R M UhtldquoEstrogen receptor (ER)120573 isoforms rather than ER120572 regulatecorticotropin-releasing hormone promoter activity through analternate pathwayrdquo Journal of Neuroscience vol 24 no 47 pp10628ndash10635 2004

[165] C IsgorM CecchiM Kabbaj H Akil and S JWatson ldquoEstro-gen receptor 120573 in the paraventricular nucleus of hypothalamusregulates the neuroendocrine response to stress and is regulatedby corticosteronerdquo Neuroscience vol 121 no 4 pp 837ndash8452003

[166] M L Forsling I Kallo D E Hartley et al ldquoOestrogen receptor-120573 and neurohypophysial hormones functional interaction andneuroanatomical localisationrdquo Pharmacology Biochemistry andBehavior vol 76 no 3-4 pp 535ndash542 2003

[167] A S Lalmansingh and R M Uht ldquoEstradiol regulatescorticotropin-releasing hormone gene (crh) expression in arapid and phasic manner that parallels estrogen receptor-120572 and-120573 recruitment to a 3101584051015840-cyclic adenosine 51015840- monophosphateregulatory region of the proximal crh promoterrdquo Endocrinologyvol 149 no 1 pp 346ndash357 2008

[168] B N Roy R L Reid and D A van Vugt ldquoThe effects ofestrogen and progesterone on corticotropin-releasing hormoneand arginine vasopressin messenger ribonucleic acid levelsin the paraventricular nucleus and supraoptic nucleus of therhesus monkeyrdquo Endocrinology vol 140 no 5 pp 2191ndash21981999

[169] X Ni R C Nicholson B R King E-C Chan M A Read andR Smith ldquoEstrogen represses whereas the estrogen-antagonistICI 182780 stimulates placental CRH gene expressionrdquo Journalof Clinical Endocrinology and Metabolism vol 87 no 8 pp3774ndash3778 2002

[170] N C Vamvakopoulos and G P Chrousos ldquoEvidence of directestrogenic regulation of human corticotropin-releasing hor-mone gene expression Potential implications for the sexualdimophism of the stress response and immuneinflammatoryreactionrdquo Journal of Clinical Investigation vol 92 no 4 pp1896ndash1902 1993

[171] Y Hu D L Wu C X Luo et al ldquoHippocampal nitric oxidecontributes to sex difference in affective behaviorsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 35 pp 14224ndash14229 2012

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

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Disease Markers

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

10 ISRN Endocrinology

of time a woman has been in a postmenopausal estrogen-deprived state This suggests that there is a molecular switchin estrogen-mediated signaling that may allow for drasticchange in ER signaling not to mention the interaction of E

2

signaling components and the natural aging process Thesechanges are likely to include alterations to receptor profilesincluding expression of alternatively spliced variants thatrespond differently to E

2 changes in the cellular microenvi-

ronment that can alter the proteinprotein associations whichultimately leads to changes in ER-mediated gene transcrip-tion and synaptic transmission ER120573 in particular is widelyexpressed and implicated positively in the regulation ofmemory and mood fluctuations two of the most commonlyreported neurological issues in postmenopausal women Itis important to understand the actions of ER120573 in the areasregulating these processes to identify what when how andfor whom hormone therapy may be a useful treatment torectify cognitive and affective issues

Acknowledgments

This work was supported by NIA RO1 AG033605-01 andNIH T32 AG031780 The authors N N Mott and T R Pakhave nothing to disclose

References

[1] C Bengtsson O Lindquist and L Redvall ldquoIs the menopausalage rapidly changingrdquoMaturitas vol 1 no 3 pp 159ndash164 1979

[2] A Singh S Kaur and I Walia ldquoA historical perspective onmenopause andmenopausal agerdquo Bulletin of the Indian Instituteof History of Medicine (Hyderabad) vol 32 no 2 pp 121ndash1352002

[3] P Verhaeghen and J Cerella ldquoAging executive control andattention a review of meta-analysesrdquo Neuroscience and Biobe-havioral Reviews vol 26 no 7 pp 849ndash857 2002

[4] T E Wroolie H A Kenna K E Williams et al ldquoDifferencesin verbal memory performance in postmenopausal womenreceiving hormone therapy 17120573-estradiol versus conjugatedequine estrogensrdquoAmerican Journal of Geriatric Psychiatry vol19 no 9 pp 792ndash802 2011

[5] B B Sherwin ldquoEstrogenic effects on memory in womenrdquoAnnals of the New York Academy of Sciences vol 743 pp 213ndash230 1994

[6] B B Sherwin ldquoHormones mood and cognitive functioning inpostmenopausal womenrdquoObstetrics andGynecology vol 87 no2 supplement pp 20Sndash26S 1996

[7] B B Sherwin ldquoSex hormones and psychological functioning inpostmenopausalwomenrdquoExperimentalGerontology vol 29 no3-4 pp 423ndash430 1994

[8] SM Phillips and B B Sherwin ldquoEffects of estrogen onmemoryfunction in surgically menopausal womenrdquo Psychoneuroen-docrinology vol 17 no 5 pp 485ndash495 1992

[9] R Lindsay J M Aitken and J B Anderson ldquoLong term pre-vention of postmenopausal osteoporosis by oestrogen Evidencefor an increased bone mass after delayed onset of oestrogentreatmentrdquoThe Lancet vol 1 no 7968 pp 1038ndash1040 1976

[10] J E Rossouw R L Prentice J E Manson et al ldquoPost-menopausal hormone therapy and risk of cardiovascular dis-ease by age and years since menopauserdquo The Journal of the

American Medical Association vol 297 no 13 pp 1465ndash14772007

[11] Q-G Zhang D Han R-M Wang et al ldquoC terminusof Hsc70-interacting protein (CHIP)-mediated degradationof hippocampal estrogen receptor-120572 and the critical periodhypothesis of estrogen neuroprotectionrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 108 no 35 pp E617ndashE624 2011

[12] W Krezel S Dupont A Krust P Chambon and P F ChapmanldquoIncreased anxiety and synaptic plasticity in estrogen receptor120573-deficient micerdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 21 pp 12278ndash12282 2001

[13] H Ostlund E Keller and Y L Hurd ldquoEstrogen receptor geneexpression in relation to neuropsychiatric disordersrdquo Annals ofthe New York Academy of Sciences vol 1007 pp 54ndash63 2003

[14] S A Shumaker C Legault S R Rapp et al ldquoEstrogen plusprogestin and the incidence of dementia and mild cognitiveimpairment in postmenopausal women the Womenrsquos HealthInitiative Memory Study a randomized controlled trialrdquo Jour-nal of the American Medical Association vol 289 no 20 pp2651ndash2662 2003

[15] S A Shumaker C Legault L Kuller et al ldquoConjugated equineestrogens and incidence of probable dementia and mild cog-nitive impairment in postmenopausal women womenrsquos HealthInitiative Memory Studyrdquo Journal of the American MedicalAssociation vol 291 no 24 pp 2947ndash2958 2004

[16] S R Rapp M A Espeland S A Shumaker et al ldquoEffect ofestrogen plus progestin on global cognitive function in post-menopausal women the Womenrsquos Health Initiative MemoryStudy a randomized controlled trialrdquo Journal of the AmericanMedical Association vol 289 no 20 pp 2663ndash2672 2003

[17] VWHenderson K S Benke R C Green L A Cupples and LA Farrer ldquoPostmenopausal hormone therapy and Alzheimerrsquosdisease risk interaction with agerdquo Journal of Neurology Neuro-surgery and Psychiatry vol 76 no 1 pp 103ndash105 2005

[18] E Garbe and S Suissa ldquoHormone replacement therapy andacute coronary syndromes methodological issues betweenrandomized and observational studiesrdquo Human Reproductionvol 19 no 1 pp 8ndash13 2004

[19] B B Braden A N Garcia S E Mennenga et al ldquoCognitive-impairing effects of medroxyprogesterone acetate in the ratindependent and interactive effects across timerdquo Psychophar-macology vol 218 no 2 pp 405ndash418 2011

[20] B R Bhavnani S-P Tam and X Lu ldquoStructure activity rela-tionships and differential interactions and functional activity ofvarious equine estrogens mediated via estrogen receptors (ERs)ER120572 and ER120573rdquo Endocrinology vol 149 no 10 pp 4857ndash48702008

[21] E Hogervorst and S Bandelow ldquoSex steroids to maintaincognitive function in women after the menopause a meta-analyses of treatment trialsrdquoMaturitas vol 66 no 1 pp 56ndash712010

[22] D J Mangelsdorf C Thummel M Beato et al ldquoThe nuclearreceptor super-family the second decaderdquo Cell vol 83 no 6pp 835ndash839 1995

[23] E V Jensen T Suzuki T Kawashima W E Stumpf P WJungblut and E R DeSombre ldquoA two-step mechanism forthe interaction of estradiol with rat uterusrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 59 no 2 pp 632ndash638 1968

ISRN Endocrinology 11

[24] F Naftolin T L Horvath R L Jakab C Leranth N Haradaand J Balthazart ldquoAromatase immunoreactivity in axon termi-nals of the vertebrate brain an immunocytochemical study onquail rat monkey and human tissuesrdquoNeuroendocrinology vol63 no 2 pp 149ndash155 1996

[25] C E Roselli S E Abdelgadir O K Roslashnnekleiv and S AKlosterman ldquoAnatomic distribution and regulation of aro-matase gene expression in the rat brainrdquo Biology of Reproduc-tion vol 58 no 1 pp 79ndash87 1998

[26] J Balthazart and G F Ball ldquoIs brain estradiol a hormone or aneurotransmitterrdquo Trends in Neurosciences vol 29 no 5 pp241ndash249 2006

[27] T R Pak Y S Rao S A Prins and N N Mott ldquoAn emergingrole for microRNAs in sexually dimorphic neurobiologicalsystemsrdquo Pflugers Archiv vol 465 no 5 pp 655ndash667 2013

[28] K Yamagata S Fujiyama S Ito et al ldquoMaturation ofmicroRNAis hormonally regulated by a nuclear receptorrdquo Molecular Cellvol 36 no 2 pp 340ndash347 2009

[29] Y Masuhiro Y Mezaki M Sakari et al ldquoSplicing potentiationby growth factor signals via estrogen receptor phosphorylationrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 23 pp 8126ndash8131 2005

[30] A Tremblay G B Tremblay F Labrie and V Giguere ldquoLigand-Independent recruitment of SRC-1 to estrogen receptor 120573through phosphorylation of activation function AF-1rdquo Molec-ular Cell vol 3 no 4 pp 513ndash519 1999

[31] S H Meijsing M A Pufall A Y So D L Bates L Chenand K R Yamamoto ldquoDNA binding site sequence directsglucocorticoid receptor structure and activityrdquo Science vol 324no 5925 pp 407ndash410 2009

[32] W Bourguet P Germain and H Gronemeyer ldquoNuclearreceptor ligand-binding domains three-dimensional struc-tures molecular interactions and pharmacological implica-tionsrdquo Trends in Pharmacological Sciences vol 21 no 10 pp381ndash388 2000

[33] A Koide C Zhao M Naganuma et al ldquoIdentification ofregions within the F domain of the human estrogen receptor 120572that are important for modulating transactivation and protein-protein interactionsrdquoMolecular Endocrinology vol 21 no 4 pp829ndash842 2007

[34] D F Skafar and S Koide ldquoUnderstanding the human estrogenreceptor-alpha using targeted mutagenesisrdquoMolecular and Cel-lular Endocrinology vol 246 no 1-2 pp 83ndash90 2006

[35] E C Chang J Frasor B Komm and B S KatzenellenbogenldquoImpact of estrogen receptor 120573 on gene networks regulated byestrogen receptor 120572 in breast cancer cellsrdquo Endocrinology vol147 no 10 pp 4831ndash4842 2006

[36] X Zhu I Leav Y-K Leung et al ldquoDynamic regulation ofestrogen receptor-120573 expression by DNA methylation duringprostate cancer development andmetastasisrdquoAmerican Journalof Pathology vol 164 no 6 pp 2003ndash2012 2004

[37] D N Petersen G T Tkalcevic P H Koza-Taylor T G Turiand T A Brown ldquoIdentification of estrogen receptor 1205732 afunctional variant of estrogen receptor 120573 expressed in normalrat tissuesrdquo Endocrinology vol 139 no 3 pp 1082ndash1092 1998

[38] L A Helguero M H Faulds J-A Gustafsson and L-AHaldosen ldquoEstrogen receptors alfa (ER120572) and beta (ER120573)differentially regulate proliferation and apoptosis of the normalmurine mammary epithelial cell line HC11rdquo Oncogene vol 24no 44 pp 6605ndash6616 2005

[39] P C Kulakosky M A McCarty S C Jernigan K E Risingerand C M Klinge ldquoResponse element sequence modulates

estrogen receptor 120572 and 120573 affinity and activityrdquo Journal ofMolecular Endocrinology vol 29 no 1 pp 137ndash152 2002

[40] OM V Grober MMutarelli G Giurato et al ldquoGlobal analysisof estrogen receptor beta binding to breast cancer cell genomereveals an extensive interplay with estrogen receptor alpha fortarget gene regulationrdquo BMC Genomics vol 12 article 36 2011

[41] O I Vivar X Zhao E F Saunier et al ldquoEstrogen receptor 120573binds to and regulates three distinct classes of target genesrdquoJournal of Biological Chemistry vol 285 no 29 pp 22059ndash22066 2010

[42] G G J M Kuiper E Enmark M Pelto-Huikko S Nilssonand J-A Gustafsson ldquoCloning of a novel estrogen receptorexpressed in rat prostate and ovaryrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 93 no12 pp 5925ndash5930 1996

[43] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and 120572 and 120573rdquo Endocrinology vol 138no 3 pp 863ndash870 1997

[44] D B Dubal H Zhu J Yu et al ldquoEstrogen receptor alpha notbeta is a critical link in estradiol-mediated protection againstbrain injuryrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 98 no 4 pp 1952ndash1957 2001

[45] P J Shughrue P J Scrimo and I Merchenthaler ldquoEvidence forthe colocalization of estrogen receptor-120573 mRNA and estrogenreceptor-120572 immunoreactivity in neurons of the rat forebrainrdquoEndocrinology vol 139 no 12 pp 5267ndash5270 1998

[46] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in therat central nervous systemrdquo Journal of Comparative Neurologyvol 388 no 4 pp 507ndash525 1997

[47] T AMilner B SMcEwen S Hayashi C J Li L P Reagan andS E Alves ldquoUltrastructural evidence that hippocampal alphaestrogen receptors are located at extranuclear sitesrdquoThe Journalof Comparative Neurology vol 429 no 3 pp 355ndash371 2001

[48] T A Milner L S Lubbers S E Alves and B S McEwenldquoNuclear and extranuclear estrogen binding sites in the ratforebrain and autonomic medullary areasrdquo Endocrinology vol149 no 7 pp 3306ndash3312 2008

[49] T A Milner K Ayoola C T Drake et al ldquoUltrastructurallocalization of estrogen receptor 120573 immunoreactivity in the rathippocampal formationrdquo Journal of ComparativeNeurology vol491 no 2 pp 81ndash95 2005

[50] A E Herbison andD TTheodosis ldquoAbsence of estrogen recep-tor immunoreactivity in somatostatin (SRIF) neurons of theperiventricular nucleus but sexually dimorphic colocalizationof estrogen receptor and SRIF immunoreactivities in neuronsof the bed nucleus of the stria terminalisrdquo Endocrinology vol132 no 4 pp 1707ndash1714 1993

[51] K Kalita S Szymczak and L Kaczmarek ldquoNon-nuclear estro-gen receptor 120573 and 120572 in the hippocampus of male and femaleratsrdquo Hippocampus vol 15 no 3 pp 404ndash412 2005

[52] T Ivanova and C Beyer ldquoOntogenetic expression and sexdifferences of aromatase and estrogen receptor-120572120573 mRNA inthe mouse hippocampusrdquo Cell and Tissue Research vol 300 no2 pp 231ndash237 2000

[53] C Y Pau K-Y F Pau and H G Spies ldquoPutative estrogenreceptor 120573 and 120572 mRNA expression in male and female rhesusmacaquesrdquo Molecular and Cellular Endocrinology vol 146 no1-2 pp 59ndash68 1998

[54] A L Wijayaratne and D P McDonnell ldquoThe human estrogenreceptor-120572 is a ubiquitinated protein whose stability is affected

12 ISRN Endocrinology

differentially by agonists antagonists and selective estrogenreceptor modulatorsrdquo Journal of Biological Chemistry vol 276no 38 pp 35684ndash35692 2001

[55] V Bartella P Rizza I Barone et al ldquoEstrogen receptor betabinds Sp1 and recruits a corepressor complex to the estrogenreceptor alpha gene promoterrdquo Breast Cancer Research andTreatment vol 134 no 2 pp 569ndash581 2012

[56] L C Li C C Yeh D Nojima and R Dahiya ldquoCloning andcharacterization of human estrogen receptor beta promoterrdquoBiochemical and Biophysical Research Communications vol 275no 2 pp 682ndash689 2000

[57] E A Vladusic A E Hornby F K Guerra-Vladusic J Lakinsand R Lupu ldquoExpression and regulation of estrogen receptor szligin human breast tumors and cell linesrdquoOncology Reports vol 7no 1 pp 157ndash167 2000

[58] T Hatsumi and Y Yamamuro ldquoDownregulation of estrogenreceptor gene expression by exogenous 17120573-estradiol in themammary glands of lactating micerdquo Experimental Biology andMedicine vol 231 no 3 pp 311ndash316 2006

[59] H B Patisaul P L Whitten and L J Young ldquoRegulation ofestrogen receptor beta mRNA in the brain opposite effectsof 17120573-estradiol and the phytoestrogen coumestrolrdquoMolecularBrain Research vol 67 no 1 pp 165ndash171 1999

[60] T J Brown N J MacLusky M Shanabrough and F NaftolinldquoComparison of age- and sex-related changes in cell nuclearestrogen-binding capacity and progestin receptor induction inthe rat brainrdquo Endocrinology vol 126 no 6 pp 2965ndash29721990

[61] B S Rubin T O Fox and R S Bridges ldquoEstrogen bindingin nuclear and cytosolic extracts from brain and pituitary ofmiddle-aged female ratsrdquo Brain Research vol 383 no 1-2 pp60ndash67 1986

[62] T Funabashi S P Kleopoulos P J Brooks et al ldquoChangesin estrogenic regulation of estrogen receptor 120572 mRNA andprogesterone receptor mRNA in the female rat hypothalamusduring aging an in situ hybridization studyrdquo NeuroscienceResearch vol 38 no 1 pp 85ndash92 2000

[63] M E Wilson K L Rosewell M L Kashon P J Shughrue IMerchenthaler and P M Wise ldquoAge differentially influencesestrogen receptor-120572 (ER120572) and estrogen receptor-120573 (ER120573) geneexpression in specific regions of the rat brainrdquo Mechanisms ofAgeing and Development vol 123 no 6 pp 593ndash601 2002

[64] W S Post P J Goldschmidt-Clermont C C Wilhide etal ldquoMethylation of the estrogen receptor gene is associatedwith aging and atherosclerosis in the cardiovascular systemrdquoCardiovascular Research vol 43 no 4 pp 985ndash991 1999

[65] J-P J Issa Y L Ottaviano P Celano S R Hamilton NE Davidson and S B Baylin ldquoMethylation of the oestrogenreceptor CpG island links ageing and neoplasia in humancolonrdquo Nature Genetics vol 7 no 4 pp 536ndash540 1994

[66] T Funabashi and F Kimura ldquoEffects of estrogen and estrogenreceptor messenger RNA levels in young and middle-agedfemale rats comparison ofmedial preoptic area andmediobasalhypothalamusrdquo Acta Biologica Hungarica vol 45 no 2ndash4 pp223ndash231 1994

[67] M AMiller P E Kolb B Planas andM A Raskind ldquoEstrogenreceptor and neurotensinneuromedin-N gene expression inthe preoptic area are unaltered with age in Fischer 344 femaleratsrdquo Endocrinology vol 135 no 5 pp 1986ndash1995 1994

[68] T R Chakraborty P R Hof L Ng and A C Gore ldquoStereologicanalysis of estrogen receptor alpha (ER alpha) expression in rat

hypothalamus and its regulation by aging and estrogenrdquo Journalof Comparative Neurology vol 466 no 3 pp 409ndash421 2003

[69] J M Westberry A L Trout and M E Wilson ldquoEpigeneticregulation of estrogen receptor beta expression in the rat cortexduring agingrdquo NeuroReport vol 22 no 9 pp 428ndash432 2011

[70] T R Chakraborty L Ng and A C Gore ldquoAge-related changesin estrogen receptor 120573 in rat hypothalamus a quantitativeanalysisrdquo Endocrinology vol 144 no 9 pp 4164ndash4171 2003

[71] I Poola S Koduri S Chatra and R Clarke ldquoIdentificationof twenty alternatively spliced estrogen receptor alpha mRNAsin breast cancer cell lines and tumors using splice targetedprimer approachrdquo Journal of Steroid Biochemistry andMolecularBiology vol 72 no 5 pp 249ndash258 2000

[72] T A Ishunina and D F Swaab ldquoHippocampal estrogenreceptor-alpha splice variant TADDI in the human brain inaging and Alzheimerrsquos diseaserdquoNeuroendocrinology vol 89 no2 pp 187ndash199 2009

[73] T A Ishunina and D F Swaab ldquoEstrogen receptor-120572 splicevariants in the human brainrdquo Gynecological Endocrinology vol24 no 2 pp 93ndash98 2008

[74] T A Ishunina F P M Kruijver R Balesar and D FSwaab ldquoDifferential expression of estrogen receptor 120572 and 120573immunoreactivity in the human supraoptic nucleus in rela-tion to sex and agingrdquo Journal of Clinical Endocrinology andMetabolism vol 85 no 9 pp 3283ndash3291 2000

[75] T A Ishunina D F Fischer andD F Swaab ldquoEstrogen receptor120572 and its splice variants in the hippocampus in aging andAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 28 no 11 pp1670ndash1681 2007

[76] J R Tollervey Z Wang T Hortobagyi et al ldquoAnalysis of alter-native splicing associated with aging and neurodegeneration inthe human brainrdquo Genome Research vol 21 no 10 pp 1572ndash1582 2011

[77] N NMott and T R Pak ldquoCharacterisation of human oestrogenreceptor beta (ER120573) splice variants in neuronal cellsrdquo Journal ofNeuroendocrinology vol 24 no 10 pp 1311ndash1321 2012

[78] S Inoue S-J Hoshino H Miyoshi et al ldquoIdentification ofa ovel isoform of estrogen receptor a potential inhibitor ofestrogen action in vascular smooth muscle cellsrdquo Biochemicaland Biophysical Research Communications vol 219 no 3 pp766ndash772 1996

[79] J K Skipper L J Young J M Bergeron M T Tetzlaff CT Osborn and D Crews ldquoIdentification of an isoform ofthe estrogen receptor messenger RNA lacking exon four andpresent in the brainrdquo Proceedings of the National Academy ofSciences of the United States of America vol 90 no 15 pp 7172ndash7175 1993

[80] R H Price Jr N Lorenzon and R J Handa ldquoDifferentialexpression of estrogen receptor beta splice variants in rat brainidentification and characterization of a novel variant missingexon 4rdquo Brain Research Molecular Brain Research vol 80 no2 pp 260ndash268 2000

[81] S Chu and P J Fuller ldquoIdentification of a splice variantof the rat estrogen receptor 120573 generdquo Molecular and CellularEndocrinology vol 132 no 1-2 pp 195ndash199 1997

[82] B Lu E Leygue H Dotzlaw L J Murphy L C Murphy andP H Watson ldquoEstrogen receptor-120573 mRNA variants in humanand murine tissuesrdquoMolecular and Cellular Endocrinology vol138 no 1-2 pp 199ndash203 1998

[83] T R Pak W C J Chung J L Roberts and R J HandaldquoLigand-independent effects of estrogen receptor 120573 on

ISRN Endocrinology 13

mouse gonadotropin-releasing hormone promoter activityrdquoEndocrinology vol 147 no 4 pp 1924ndash1931 2006

[84] T R Pak W C J Chung L R Hinds and R J HandaldquoEstrogen receptor-120573 mediates dihydrotestosterone-inducedstimulation of the arginine vasopressin promoter in neuronalcellsrdquo Endocrinology vol 148 no 7 pp 3371ndash3382 2007

[85] Y K Leung PMak S Hassan and SMHo ldquoEstrogen receptor(ER)-120573 isoforms a key to understanding ER-120573 signalingrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 103 no 35 pp 13162ndash13167 2006

[86] J M Wang X Hou S Adeosun et al ldquoA dominant negativeER120573 splice variant determines the effectiveness of early or lateestrogen therapy after ovariectomy in ratsrdquo PLoS One vol 7 no3 Article ID e33493 2012

[87] W C J Chung T R Pak S Suzuki W A Pouliot M EAndersen and R J Handa ldquoDetection and localization of anestrogen receptor beta splice variant protein (ER1205732) in theadult female rat forebrain and midbrain regionsrdquo Journal ofComparative Neurology vol 505 no 3 pp 249ndash267 2007

[88] R H Price Jr C A Butler P Webb R Uht P Kushner andR J Handa ldquoA splice variant of estrogen receptor 120573 missingexon 3 displays altered subnuclear localization and capacity fortranscriptional activationrdquo Endocrinology vol 142 no 5 pp2039ndash2049 2001

[89] Y Wang and R J Miksicek ldquoIdentification of a dominantnegative form of the human estrogen receptorrdquo MolecularEndocrinology vol 5 no 11 pp 1707ndash1715 1991

[90] E Kuppers and C Beyer ldquoExpression of estrogen receptor-120572and 120573 mRNA in the developing and adult mouse striatumrdquoNeuroscience Letters vol 276 no 2 pp 95ndash98 1999

[91] C Gundlah S G Kohama S J Mirkes V T Garyfallou H FUrbanski and C L Bethea ldquoDistribution of estrogen receptorbeta (ER120573) mRNA in hypothalamus midbrain and temporallobe of spayed macaque continued expression with hormonereplacementrdquo Brain Research Molecular Brain Research vol 76no 2 pp 191ndash204 2000

[92] Y Morishima P J M Murphy D-P Li E R Sanchez and WB Pratt ldquoStepwise assembly of a glucocorticoid receptorsdothsp90heterocomplex resolves two sequential ATP-dependent eventsinvolving first hsp70 and then hsp90 in opening of the steroidbinding pocketrdquo Journal of Biological Chemistry vol 275 no 24pp 18054ndash18060 2000

[93] K D Dittmar and W B Pratt ldquoFolding of the glucocorticoidreceptor by the reconstituted hsp90-based chaperone machin-eryThe initial hsp90sdotp60sdothsp70-dependent step is sufficient forcreating the steroid binding conformationrdquo Journal of BiologicalChemistry vol 272 no 20 pp 13047ndash13054 1997

[94] K I Kang X Meng J Devin-Leclerc et al ldquoThe molecularchaperone Hsp90 can negatively regulate the activity of aglucocorticosteroid-dependent promoterrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 4 pp 1439ndash1444 1999

[95] K Unno H Asakura Y Shibuya M Kaiho S Okada and NOku Naoto ldquoIncrease in basal level of Hsp70 consisting chieflyof constitutively expressed hsp70 (Hsc70) in aged rat brainrdquoJournals of Gerontology Series A vol 55 no 7 pp B329ndashB3352000

[96] U E Olazabal D W Pfaff and C V Mobbs ldquoSex differences inthe regulation of heat shock protein 70 kDa and 90 kDa in therat ventromedial hypothalamus by estrogenrdquo Brain Researchvol 596 no 1-2 pp 311ndash314 1992

[97] M A Pahlavani M D Harris S A Moore and A RichardsonldquoExpression of heat shock protein 70 in rat spleen lymphocytesis affected by age but not by food restrictionrdquo Journal ofNutrition vol 126 no 9 pp 2069ndash2075 1996

[98] A R Heydari B Wu R Takahashi R Strong and A Richard-son ldquoExpression of heat shock protein 70 is altered by age anddiet at the level of transcriptionrdquoMolecular andCellular Biologyvol 13 no 5 pp 2909ndash2918 1993

[99] M Sabbah K-I I Kang L Tora and G Redeuilh ldquoOestro-gen receptor facilitates the formation of preinitiation com-plex assembly involvement of the general transcription factorTFIIBrdquo Biochemical Journal vol 336 part 3 pp 639ndash646 1998

[100] S-Y Wu M C Thomas S Y Hou V Likhite and C-MChiang ldquoIsolation of mouse TFIID and functional character-ization of TBP and TFIID in mediating estrogen receptor andchromatin transcriptionrdquo Journal of Biological Chemistry vol274 no 33 pp 23480ndash23490 1999

[101] S Ghosh and M K Thakur ldquoTissue-specific expression ofreceptor-interacting protein in aging mouserdquo Age vol 30 no4 pp 237ndash243 2008

[102] J Frasor JM Danes B Komm K C N Chang C Richard Lyt-tle and B S Katzenellenbogen ldquoProfiling of estrogen up- anddown-regulated gene expression in human breast cancer cellsinsights into gene networks and pathways underlying estrogeniccontrol of proliferation and cell phenotyperdquo Endocrinology vol144 no 10 pp 4562ndash4574 2003

[103] J Frasor J M Danes C C Funk and B S Katzenellen-bogen ldquoEstrogen down-regulation of the corepressor N-CoRmechanism and implications for estrogen derepression of N-CoR-regulated genesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 102 no 37 pp13153ndash13157 2005

[104] N J McKenna and B W OrsquoMalley ldquoCombinatorial control ofgene expression by nuclear receptors and coregulatorsrdquoCell vol108 no 4 pp 465ndash474 2002

[105] T-P Yao G Ku N Zhou R Scully and D M Livingston ldquoThenuclear hormone receptor coactivator SRC-1 is a specific targetof p300rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 93 no 20 pp 10626ndash10631 1996

[106] B Hanstein R Eckner J DiRenzo et al ldquop300 is a componentof an estrogen receptor coactivator complexrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 93 no 21 pp 11540ndash11545 1996

[107] S Halachmi E Marden G Martin H MacKay C Abbon-danza and M Brown ldquoEstrogen receptor-associated proteinspossible mediators of hormone-induced transcriptionsrdquo Sci-ence vol 264 no 5164 pp 1455ndash1458 1994

[108] A J Horlein AM Naar T Heinzel et al ldquoLigand-independentrepression by the thyroid hormone receptor mediated by anuclear receptor co-repressorrdquo Nature vol 377 no 6548 pp397ndash404 1995

[109] J D Chen and R M Evans ldquoA transcriptional co-repressor thatinteracts with nuclear hormone receptorsrdquo Nature vol 377 no6548 pp 454ndash457 1995

[110] A Malovannaya R B Lanz S Y Jung et al ldquoAnalysis of thehuman endogenous coregulator complexomerdquoCell vol 145 no5 pp 787ndash799 2011

[111] Z Nawaz D M Lonard C L Smith et al ldquoThe Angelmansyndrome-associated protein E6-AP is a coactivator for thenuclear hormone receptor superfamilyrdquoMolecular and CellularBiology vol 19 no 2 pp 1182ndash1189 1999

14 ISRN Endocrinology

[112] B Zheng M Han M Bernier and J-K Wen ldquoNuclear actinand actin-binding proteins in the regulation of transcriptionand gene expressionrdquo FEBS Journal vol 276 no 10 pp 2669ndash2685 2009

[113] W A Hofmann L Stojiljkovic B Fuchsova et al ldquoActin is partof pre-initiation complexes and is necessary for transcription byRNA polymerase IIrdquoNature Cell Biology vol 6 no 11 pp 1094ndash1101 2004

[114] K Tokunaga T Shibuya Y Ishihama et al ldquoNucleocytoplasmictransport of fluorescent mRNA in living mammalian cellsnuclear mRNA export is coupled to ongoing gene transcrip-tionrdquo Genes to Cells vol 11 no 3 pp 305ndash317 2006

[115] R Metivier G Penot M R Hubner et al ldquoEstrogen receptor-120572 directs ordered cyclical and combinatorial recruitment ofcofactors on a natural target promoterrdquo Cell vol 115 no 6 pp751ndash763 2003

[116] C Ambrosino R Tarallo A Bamundo et al ldquoIdentification of ahormone-regulated dynamic nuclear actin network associatedwith estrogen receptor 120572 in human breast cancer cell nucleirdquoMolecular and Cellular Proteomics vol 9 no 6 pp 1352ndash13672010

[117] F Shao R Zhang L Dong and K Ying ldquoOverexpression ofgelsolin-like actin-capping protein is associated with progres-sion of lung adenocarcinomardquo Tohoku Journal of ExperimentalMedicine vol 225 no 2 pp 95ndash101 2011

[118] K Nishimura H-J Ting Y Harada et al ldquoModulation ofandrogen receptor transactivation by gelsolin a newly identi-fied androgen receptor coregulatorrdquo Cancer Research vol 63no 16 pp 4888ndash4894 2003

[119] J S Ahn I S Jang D I Kim et al ldquoAging-associated increaseof gelsolin for apoptosis resistancerdquoBiochemical and BiophysicalResearch Communications vol 312 no 4 pp 1335ndash1341 2003

[120] I Nalvarte T Schwend and J-A Gustafsson ldquoProteomicsanalysis of the estrogen receptor 120572 receptosomerdquoMolecular andCellular Proteomics vol 9 no 7 pp 1411ndash1422 2010

[121] L-H Miau C-J Chang B-J Shen W-H Tsai and S-C LeeldquoIdentification of heterogeneous nuclear ribonucleoprotein K(hnRNPK) as a repressor ofCEBP120573-mediated gene activationrdquoJournal of Biological Chemistry vol 273 no 17 pp 10784ndash107911998

[122] A Ostareck-Lederer D H Ostareck C Cans et al ldquoc-Src-mediated phosphorylation of hnRNP K drives translationalactivation of specifically silenced mRNAsrdquo Molecular and Cel-lular Biology vol 22 no 13 pp 4535ndash4543 2002

[123] P S Bagga G K Arhin and J Wilusz ldquoDSEF-1 is a member ofthe hnRNP H family of RNA-binding proteins and stimulatespre-mRNAcleavage and polyadenylation in vitrordquoNucleic AcidsResearch vol 26 no 23 pp 5343ndash5350 1998

[124] V Markovtsov J M Nikolic J A Goldman C W Turck M-Y Chou and D L Black ldquoCooperative assembly of an hnRNPcomplex induced by a tissue-specific homolog of polypyrimi-dine tract binding proteinrdquoMolecular and Cellular Biology vol20 no 20 pp 7463ndash7479 2000

[125] S Y Jung A Malovannaya J Wei B W OrsquoMalley and J QinldquoProteomic analysis of steady-state nuclear hormone receptorcoactivator complexesrdquoMolecular Endocrinology vol 19 no 10pp 2451ndash2465 2005

[126] W Hong R J Resnick C Rakowski D Shalloway S J Taylorand G A Blobel ldquoPhysical and functional interaction betweenthe transcriptional cofactor CBP and the KH domain proteinSam68rdquoMolecular Cancer Research vol 1 no 1 pp 48ndash55 2002

[127] R ShaoXWang BWeijdegard et al ldquoCoordinate regulation ofheterogeneous nuclear ribonucleoprotein dynamics by steroidhormones in the human fallopian tube and endometrium invivo and in vitrordquo American Journal of Physiology vol 302 no10 pp E1269ndashE1282 2012

[128] C SWoolley and B SMcEwen ldquoEstradiolmediates fluctuationin hippocampal synapse density during the estrous cycle in theadult ratrdquo Journal of Neuroscience vol 12 no 7 pp 2549ndash25541992

[129] C S Woolley H J Wenzel and P A Schwartzkroin ldquoEstradiolincreases the frequency of multiple synapse boutons in thehippocampal CA1 region of the adult female ratrdquo The Journalof Comparative Neurology vol 373 no 1 pp 108ndash117 1996

[130] C S Woolley ldquoEstrogen-mediated structural and functionalsynaptic plasticity in the female rat hippocampusrdquo Hormonesand Behavior vol 34 no 2 pp 140ndash148 1998

[131] D P Srivastava K M Woolfrey K A Jones et al ldquoRapidenhancement of two-step wiring plasticity by estrogen andNMDA receptor activityrdquo Proceedings of the National Academyof Sciences of the United States of America vol 105 no 38 pp14650ndash14655 2008

[132] M Ogiue-Ikeda N Tanabe H Mukai et al ldquoRapid modu-lation of synaptic plasticity by estrogens as well as endocrinedisrupters in hippocampal neuronsrdquo Brain Research Reviewsvol 57 no 2 pp 363ndash375 2008

[133] N J Sandstrom and C L Williams ldquoSpatial memory retentionis enhanced by acute and continuous estradiol replacementrdquoHormones and Behavior vol 45 no 2 pp 128ndash135 2004

[134] E Hogervorst J Williams M Budge W Riedel and JJolles ldquoThe nature of the effect of female gonadal hormonereplacement therapy on cognitive function in post-menopausalwomen a meta-analysisrdquo Neuroscience vol 101 no 3 pp 485ndash512 2000

[135] M E Bailey A C J Wang J Hao et al ldquoInteractive effects ofage and estrogen on cortical neurons implications for cognitiveagingrdquo Neuroscience vol 191 pp 148ndash158 2011

[136] A A Walf M E Rhodes and C A Frye ldquoOvarian steroidsenhance object recognition in naturally cycling and ovariec-tomized hormone-primed ratsrdquo Neurobiology of Learning andMemory vol 86 no 1 pp 35ndash46 2006

[137] V N Luine L F Jacome and N J Maclusky ldquoRapid enhance-ment of visual and place memory by estrogens in ratsrdquoEndocrinology vol 144 no 7 pp 2836ndash2844 2003

[138] L Fan Z Zhao P T Orr C H Chambers M C Lewis and KM Frick ldquoEstradiol-induced object memory consolidation inmiddle-aged femalemice requires dorsal hippocampal extracel-lular signal-regulated kinase and phosphatidylinositol 3-kinaseactivationrdquo Journal of Neuroscience vol 30 no 12 pp 4390ndash4400 2010

[139] D B Dubal and PMWise ldquoNeuroprotective effects of estradiolin middle-aged female ratsrdquo Endocrinology vol 142 no 1 pp43ndash48 2001

[140] S-H Yang J Shi A L Day and J W Simpkins ldquoEstradiolexerts neuroprotective effects when administered after ischemicinsultrdquo Stroke vol 31 no 3 pp 745ndash750 2000

[141] J W Simpkins G Rajakumar Y-Q Zhang et al ldquoEstrogensmay reduce mortality and ischemic damage caused by middlecerebral artery occlusion in the female ratrdquo Journal of Neuro-surgery vol 87 no 5 pp 724ndash730 1997

[142] J Shi K S Panickar S-H Yang O Rabbani A L Day and JWSimpkins ldquoEstrogen attenuates over-expression of 120573-amyloid

ISRN Endocrinology 15

precursor protein messager RNA in an animal model of focalischemiardquo Brain Research vol 810 no 1-2 pp 87ndash92 1998

[143] Q-H Zhang Y-H Huang Y-Z Hu et al ldquoDisruption ofestrogen receptor beta in mice brain results in pathologicalalterations resemblingAlzheimer diseaserdquoActa PharmacologicaSinica vol 25 no 4 pp 452ndash457 2004

[144] E F Rissman A L Heck J E Leonard M A Shupnik and J-A Gustafsson ldquoDisruption of estrogen receptor 120573 gene impairsspatial learning in female micerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no6 pp 3996ndash4001 2002

[145] M Day A Sung S Logue M Bowlby and R Arias ldquoBetaestrogen receptor knockout (BERKO) mice present attenuatedhippocampal CA1 long-term potentiation and related memorydeficits in contextual fear conditioningrdquo Behavioural BrainResearch vol 164 no 1 pp 128ndash131 2005

[146] R Vierk G Glassmeier L Zhou et al ldquoAromatase inhibitionabolishes LTP generation in female but not in male micerdquo TheJournal of Neuroscience vol 32 no 24 pp 8116ndash8126 2012

[147] R-M Vouimba M R Foy J G Foy and R FThompson ldquo17120573-estradiol suppresses expression of long-term depression in agedratsrdquo Brain Research Bulletin vol 53 no 6 pp 783ndash787 2000

[148] C E Andreescu B A Milojkovic E D Haasdijk et alldquoEstradiol improves cerebellar memory formation by activatingestrogen receptor 120573rdquo Journal of Neuroscience vol 27 no 40 pp10832ndash10839 2007

[149] Y-Y Huang P V Nguyen T Abel and E R Kandel ldquoLong-lasting forms of synaptic potentiation in the mammalian hip-pocampusrdquo Learning Memory vol 3 no 2-3 pp 74ndash85 1996

[150] H Mukai T Tsurugizawa G Murakami et al ldquoRapid mod-ulation of long-term depression and spinogenesis via synapticestrogen receptors in hippocampal principal neuronsrdquo Journalof Neurochemistry vol 100 no 4 pp 950ndash967 2007

[151] L Liu T P Wong M F Pozza et al ldquoRole of NMDA receptorsubtypes in governing the direction of hippocampal synapticplasticityrdquo Science vol 304 no 5673 pp 1021ndash1024 2004

[152] M Cyr O Ghribi C Thibault M Morissette M Landry andT di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[153] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[154] C C Smith and L L McMahon ldquoEstradiol-induced increasein the magnitude of long-term potentiation is prevented byblocking NR2B-containing receptorsrdquo Journal of Neurosciencevol 26 no 33 pp 8517ndash8522 2006

[155] Y Zhou J J Watters and D M Dorsa ldquoEstrogen rapidlyinduces the phosphorylation of the cAMP response elementbinding protein in rat brainrdquo Endocrinology vol 137 no 5 pp2163ndash2166 1996

[156] XGonda T TelekG Juhasz J Lazary AVargha andG BagdyldquoPatterns of mood changes throughout the reproductive cyclein healthy women without premenstrual dysphoric disordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 32 no 8 pp 1782ndash1788 2008

[157] E W Freeman ldquoPremenstrual syndrome and premenstrualdysphoric disorder definitions and diagnosisrdquo Psychoneuroen-docrinology vol 28 supplement 3 pp 25ndash37 2003

[158] T D Lund T Rovis W C J Chung and R J Handa ldquoNovelactions of estrogen receptor-120573 on anxiety-related behaviorsrdquoEndocrinology vol 146 no 2 pp 797ndash807 2005

[159] N Breslau L Schultz and E Peterson ldquoSex differences indepression a role for preexisting anxietyrdquo Psychiatry Researchvol 58 no 1 pp 1ndash12 1995

[160] P E Bebbington G Dunn R Jenkins et al ldquoThe influenceof age and sex on the prevalence of depressive conditionsreport from the National Survey of Psychiatric MorbidityrdquoPsychological Medicine vol 28 no 1 pp 9ndash19 1998

[161] G Aguilera J P Harwood and J X Wilson ldquoMechanisms ofaction of corticotropin-releasing factor and other regulators ofcorticotropin release in rat pituitary cellsrdquo Journal of BiologicalChemistry vol 258 no 13 pp 8039ndash8045 1983

[162] A Papadimitriou and K N Priftis ldquoRegulation of thehypothalamic-pituitary-adrenal axisrdquo NeuroImmunoModula-tion vol 16 no 5 pp 265ndash271 2009

[163] S Suzuki and R J Handa ldquoRegulation of estrogen receptor-120573expression in the female rat hypothalamus differential effectsof dexamethasone and estradiolrdquo Endocrinology vol 145 no 8pp 3658ndash3670 2004

[164] W J S Miller S Suzuki L K Miller R Handa and R M UhtldquoEstrogen receptor (ER)120573 isoforms rather than ER120572 regulatecorticotropin-releasing hormone promoter activity through analternate pathwayrdquo Journal of Neuroscience vol 24 no 47 pp10628ndash10635 2004

[165] C IsgorM CecchiM Kabbaj H Akil and S JWatson ldquoEstro-gen receptor 120573 in the paraventricular nucleus of hypothalamusregulates the neuroendocrine response to stress and is regulatedby corticosteronerdquo Neuroscience vol 121 no 4 pp 837ndash8452003

[166] M L Forsling I Kallo D E Hartley et al ldquoOestrogen receptor-120573 and neurohypophysial hormones functional interaction andneuroanatomical localisationrdquo Pharmacology Biochemistry andBehavior vol 76 no 3-4 pp 535ndash542 2003

[167] A S Lalmansingh and R M Uht ldquoEstradiol regulatescorticotropin-releasing hormone gene (crh) expression in arapid and phasic manner that parallels estrogen receptor-120572 and-120573 recruitment to a 3101584051015840-cyclic adenosine 51015840- monophosphateregulatory region of the proximal crh promoterrdquo Endocrinologyvol 149 no 1 pp 346ndash357 2008

[168] B N Roy R L Reid and D A van Vugt ldquoThe effects ofestrogen and progesterone on corticotropin-releasing hormoneand arginine vasopressin messenger ribonucleic acid levelsin the paraventricular nucleus and supraoptic nucleus of therhesus monkeyrdquo Endocrinology vol 140 no 5 pp 2191ndash21981999

[169] X Ni R C Nicholson B R King E-C Chan M A Read andR Smith ldquoEstrogen represses whereas the estrogen-antagonistICI 182780 stimulates placental CRH gene expressionrdquo Journalof Clinical Endocrinology and Metabolism vol 87 no 8 pp3774ndash3778 2002

[170] N C Vamvakopoulos and G P Chrousos ldquoEvidence of directestrogenic regulation of human corticotropin-releasing hor-mone gene expression Potential implications for the sexualdimophism of the stress response and immuneinflammatoryreactionrdquo Journal of Clinical Investigation vol 92 no 4 pp1896ndash1902 1993

[171] Y Hu D L Wu C X Luo et al ldquoHippocampal nitric oxidecontributes to sex difference in affective behaviorsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 35 pp 14224ndash14229 2012

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

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Disease Markers

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OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ObesityJournal of

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Research and TreatmentAIDS

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Endocrinology 11

[24] F Naftolin T L Horvath R L Jakab C Leranth N Haradaand J Balthazart ldquoAromatase immunoreactivity in axon termi-nals of the vertebrate brain an immunocytochemical study onquail rat monkey and human tissuesrdquoNeuroendocrinology vol63 no 2 pp 149ndash155 1996

[25] C E Roselli S E Abdelgadir O K Roslashnnekleiv and S AKlosterman ldquoAnatomic distribution and regulation of aro-matase gene expression in the rat brainrdquo Biology of Reproduc-tion vol 58 no 1 pp 79ndash87 1998

[26] J Balthazart and G F Ball ldquoIs brain estradiol a hormone or aneurotransmitterrdquo Trends in Neurosciences vol 29 no 5 pp241ndash249 2006

[27] T R Pak Y S Rao S A Prins and N N Mott ldquoAn emergingrole for microRNAs in sexually dimorphic neurobiologicalsystemsrdquo Pflugers Archiv vol 465 no 5 pp 655ndash667 2013

[28] K Yamagata S Fujiyama S Ito et al ldquoMaturation ofmicroRNAis hormonally regulated by a nuclear receptorrdquo Molecular Cellvol 36 no 2 pp 340ndash347 2009

[29] Y Masuhiro Y Mezaki M Sakari et al ldquoSplicing potentiationby growth factor signals via estrogen receptor phosphorylationrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 23 pp 8126ndash8131 2005

[30] A Tremblay G B Tremblay F Labrie and V Giguere ldquoLigand-Independent recruitment of SRC-1 to estrogen receptor 120573through phosphorylation of activation function AF-1rdquo Molec-ular Cell vol 3 no 4 pp 513ndash519 1999

[31] S H Meijsing M A Pufall A Y So D L Bates L Chenand K R Yamamoto ldquoDNA binding site sequence directsglucocorticoid receptor structure and activityrdquo Science vol 324no 5925 pp 407ndash410 2009

[32] W Bourguet P Germain and H Gronemeyer ldquoNuclearreceptor ligand-binding domains three-dimensional struc-tures molecular interactions and pharmacological implica-tionsrdquo Trends in Pharmacological Sciences vol 21 no 10 pp381ndash388 2000

[33] A Koide C Zhao M Naganuma et al ldquoIdentification ofregions within the F domain of the human estrogen receptor 120572that are important for modulating transactivation and protein-protein interactionsrdquoMolecular Endocrinology vol 21 no 4 pp829ndash842 2007

[34] D F Skafar and S Koide ldquoUnderstanding the human estrogenreceptor-alpha using targeted mutagenesisrdquoMolecular and Cel-lular Endocrinology vol 246 no 1-2 pp 83ndash90 2006

[35] E C Chang J Frasor B Komm and B S KatzenellenbogenldquoImpact of estrogen receptor 120573 on gene networks regulated byestrogen receptor 120572 in breast cancer cellsrdquo Endocrinology vol147 no 10 pp 4831ndash4842 2006

[36] X Zhu I Leav Y-K Leung et al ldquoDynamic regulation ofestrogen receptor-120573 expression by DNA methylation duringprostate cancer development andmetastasisrdquoAmerican Journalof Pathology vol 164 no 6 pp 2003ndash2012 2004

[37] D N Petersen G T Tkalcevic P H Koza-Taylor T G Turiand T A Brown ldquoIdentification of estrogen receptor 1205732 afunctional variant of estrogen receptor 120573 expressed in normalrat tissuesrdquo Endocrinology vol 139 no 3 pp 1082ndash1092 1998

[38] L A Helguero M H Faulds J-A Gustafsson and L-AHaldosen ldquoEstrogen receptors alfa (ER120572) and beta (ER120573)differentially regulate proliferation and apoptosis of the normalmurine mammary epithelial cell line HC11rdquo Oncogene vol 24no 44 pp 6605ndash6616 2005

[39] P C Kulakosky M A McCarty S C Jernigan K E Risingerand C M Klinge ldquoResponse element sequence modulates

estrogen receptor 120572 and 120573 affinity and activityrdquo Journal ofMolecular Endocrinology vol 29 no 1 pp 137ndash152 2002

[40] OM V Grober MMutarelli G Giurato et al ldquoGlobal analysisof estrogen receptor beta binding to breast cancer cell genomereveals an extensive interplay with estrogen receptor alpha fortarget gene regulationrdquo BMC Genomics vol 12 article 36 2011

[41] O I Vivar X Zhao E F Saunier et al ldquoEstrogen receptor 120573binds to and regulates three distinct classes of target genesrdquoJournal of Biological Chemistry vol 285 no 29 pp 22059ndash22066 2010

[42] G G J M Kuiper E Enmark M Pelto-Huikko S Nilssonand J-A Gustafsson ldquoCloning of a novel estrogen receptorexpressed in rat prostate and ovaryrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 93 no12 pp 5925ndash5930 1996

[43] G G J M Kuiper B Carlsson K Grandien et al ldquoComparisonof the ligand binding specificity and transcript tissue distribu-tion of estrogen receptors and 120572 and 120573rdquo Endocrinology vol 138no 3 pp 863ndash870 1997

[44] D B Dubal H Zhu J Yu et al ldquoEstrogen receptor alpha notbeta is a critical link in estradiol-mediated protection againstbrain injuryrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 98 no 4 pp 1952ndash1957 2001

[45] P J Shughrue P J Scrimo and I Merchenthaler ldquoEvidence forthe colocalization of estrogen receptor-120573 mRNA and estrogenreceptor-120572 immunoreactivity in neurons of the rat forebrainrdquoEndocrinology vol 139 no 12 pp 5267ndash5270 1998

[46] P J Shughrue M V Lane and I Merchenthaler ldquoComparativedistribution of estrogen receptor-alpha and -beta mRNA in therat central nervous systemrdquo Journal of Comparative Neurologyvol 388 no 4 pp 507ndash525 1997

[47] T AMilner B SMcEwen S Hayashi C J Li L P Reagan andS E Alves ldquoUltrastructural evidence that hippocampal alphaestrogen receptors are located at extranuclear sitesrdquoThe Journalof Comparative Neurology vol 429 no 3 pp 355ndash371 2001

[48] T A Milner L S Lubbers S E Alves and B S McEwenldquoNuclear and extranuclear estrogen binding sites in the ratforebrain and autonomic medullary areasrdquo Endocrinology vol149 no 7 pp 3306ndash3312 2008

[49] T A Milner K Ayoola C T Drake et al ldquoUltrastructurallocalization of estrogen receptor 120573 immunoreactivity in the rathippocampal formationrdquo Journal of ComparativeNeurology vol491 no 2 pp 81ndash95 2005

[50] A E Herbison andD TTheodosis ldquoAbsence of estrogen recep-tor immunoreactivity in somatostatin (SRIF) neurons of theperiventricular nucleus but sexually dimorphic colocalizationof estrogen receptor and SRIF immunoreactivities in neuronsof the bed nucleus of the stria terminalisrdquo Endocrinology vol132 no 4 pp 1707ndash1714 1993

[51] K Kalita S Szymczak and L Kaczmarek ldquoNon-nuclear estro-gen receptor 120573 and 120572 in the hippocampus of male and femaleratsrdquo Hippocampus vol 15 no 3 pp 404ndash412 2005

[52] T Ivanova and C Beyer ldquoOntogenetic expression and sexdifferences of aromatase and estrogen receptor-120572120573 mRNA inthe mouse hippocampusrdquo Cell and Tissue Research vol 300 no2 pp 231ndash237 2000

[53] C Y Pau K-Y F Pau and H G Spies ldquoPutative estrogenreceptor 120573 and 120572 mRNA expression in male and female rhesusmacaquesrdquo Molecular and Cellular Endocrinology vol 146 no1-2 pp 59ndash68 1998

[54] A L Wijayaratne and D P McDonnell ldquoThe human estrogenreceptor-120572 is a ubiquitinated protein whose stability is affected

12 ISRN Endocrinology

differentially by agonists antagonists and selective estrogenreceptor modulatorsrdquo Journal of Biological Chemistry vol 276no 38 pp 35684ndash35692 2001

[55] V Bartella P Rizza I Barone et al ldquoEstrogen receptor betabinds Sp1 and recruits a corepressor complex to the estrogenreceptor alpha gene promoterrdquo Breast Cancer Research andTreatment vol 134 no 2 pp 569ndash581 2012

[56] L C Li C C Yeh D Nojima and R Dahiya ldquoCloning andcharacterization of human estrogen receptor beta promoterrdquoBiochemical and Biophysical Research Communications vol 275no 2 pp 682ndash689 2000

[57] E A Vladusic A E Hornby F K Guerra-Vladusic J Lakinsand R Lupu ldquoExpression and regulation of estrogen receptor szligin human breast tumors and cell linesrdquoOncology Reports vol 7no 1 pp 157ndash167 2000

[58] T Hatsumi and Y Yamamuro ldquoDownregulation of estrogenreceptor gene expression by exogenous 17120573-estradiol in themammary glands of lactating micerdquo Experimental Biology andMedicine vol 231 no 3 pp 311ndash316 2006

[59] H B Patisaul P L Whitten and L J Young ldquoRegulation ofestrogen receptor beta mRNA in the brain opposite effectsof 17120573-estradiol and the phytoestrogen coumestrolrdquoMolecularBrain Research vol 67 no 1 pp 165ndash171 1999

[60] T J Brown N J MacLusky M Shanabrough and F NaftolinldquoComparison of age- and sex-related changes in cell nuclearestrogen-binding capacity and progestin receptor induction inthe rat brainrdquo Endocrinology vol 126 no 6 pp 2965ndash29721990

[61] B S Rubin T O Fox and R S Bridges ldquoEstrogen bindingin nuclear and cytosolic extracts from brain and pituitary ofmiddle-aged female ratsrdquo Brain Research vol 383 no 1-2 pp60ndash67 1986

[62] T Funabashi S P Kleopoulos P J Brooks et al ldquoChangesin estrogenic regulation of estrogen receptor 120572 mRNA andprogesterone receptor mRNA in the female rat hypothalamusduring aging an in situ hybridization studyrdquo NeuroscienceResearch vol 38 no 1 pp 85ndash92 2000

[63] M E Wilson K L Rosewell M L Kashon P J Shughrue IMerchenthaler and P M Wise ldquoAge differentially influencesestrogen receptor-120572 (ER120572) and estrogen receptor-120573 (ER120573) geneexpression in specific regions of the rat brainrdquo Mechanisms ofAgeing and Development vol 123 no 6 pp 593ndash601 2002

[64] W S Post P J Goldschmidt-Clermont C C Wilhide etal ldquoMethylation of the estrogen receptor gene is associatedwith aging and atherosclerosis in the cardiovascular systemrdquoCardiovascular Research vol 43 no 4 pp 985ndash991 1999

[65] J-P J Issa Y L Ottaviano P Celano S R Hamilton NE Davidson and S B Baylin ldquoMethylation of the oestrogenreceptor CpG island links ageing and neoplasia in humancolonrdquo Nature Genetics vol 7 no 4 pp 536ndash540 1994

[66] T Funabashi and F Kimura ldquoEffects of estrogen and estrogenreceptor messenger RNA levels in young and middle-agedfemale rats comparison ofmedial preoptic area andmediobasalhypothalamusrdquo Acta Biologica Hungarica vol 45 no 2ndash4 pp223ndash231 1994

[67] M AMiller P E Kolb B Planas andM A Raskind ldquoEstrogenreceptor and neurotensinneuromedin-N gene expression inthe preoptic area are unaltered with age in Fischer 344 femaleratsrdquo Endocrinology vol 135 no 5 pp 1986ndash1995 1994

[68] T R Chakraborty P R Hof L Ng and A C Gore ldquoStereologicanalysis of estrogen receptor alpha (ER alpha) expression in rat

hypothalamus and its regulation by aging and estrogenrdquo Journalof Comparative Neurology vol 466 no 3 pp 409ndash421 2003

[69] J M Westberry A L Trout and M E Wilson ldquoEpigeneticregulation of estrogen receptor beta expression in the rat cortexduring agingrdquo NeuroReport vol 22 no 9 pp 428ndash432 2011

[70] T R Chakraborty L Ng and A C Gore ldquoAge-related changesin estrogen receptor 120573 in rat hypothalamus a quantitativeanalysisrdquo Endocrinology vol 144 no 9 pp 4164ndash4171 2003

[71] I Poola S Koduri S Chatra and R Clarke ldquoIdentificationof twenty alternatively spliced estrogen receptor alpha mRNAsin breast cancer cell lines and tumors using splice targetedprimer approachrdquo Journal of Steroid Biochemistry andMolecularBiology vol 72 no 5 pp 249ndash258 2000

[72] T A Ishunina and D F Swaab ldquoHippocampal estrogenreceptor-alpha splice variant TADDI in the human brain inaging and Alzheimerrsquos diseaserdquoNeuroendocrinology vol 89 no2 pp 187ndash199 2009

[73] T A Ishunina and D F Swaab ldquoEstrogen receptor-120572 splicevariants in the human brainrdquo Gynecological Endocrinology vol24 no 2 pp 93ndash98 2008

[74] T A Ishunina F P M Kruijver R Balesar and D FSwaab ldquoDifferential expression of estrogen receptor 120572 and 120573immunoreactivity in the human supraoptic nucleus in rela-tion to sex and agingrdquo Journal of Clinical Endocrinology andMetabolism vol 85 no 9 pp 3283ndash3291 2000

[75] T A Ishunina D F Fischer andD F Swaab ldquoEstrogen receptor120572 and its splice variants in the hippocampus in aging andAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 28 no 11 pp1670ndash1681 2007

[76] J R Tollervey Z Wang T Hortobagyi et al ldquoAnalysis of alter-native splicing associated with aging and neurodegeneration inthe human brainrdquo Genome Research vol 21 no 10 pp 1572ndash1582 2011

[77] N NMott and T R Pak ldquoCharacterisation of human oestrogenreceptor beta (ER120573) splice variants in neuronal cellsrdquo Journal ofNeuroendocrinology vol 24 no 10 pp 1311ndash1321 2012

[78] S Inoue S-J Hoshino H Miyoshi et al ldquoIdentification ofa ovel isoform of estrogen receptor a potential inhibitor ofestrogen action in vascular smooth muscle cellsrdquo Biochemicaland Biophysical Research Communications vol 219 no 3 pp766ndash772 1996

[79] J K Skipper L J Young J M Bergeron M T Tetzlaff CT Osborn and D Crews ldquoIdentification of an isoform ofthe estrogen receptor messenger RNA lacking exon four andpresent in the brainrdquo Proceedings of the National Academy ofSciences of the United States of America vol 90 no 15 pp 7172ndash7175 1993

[80] R H Price Jr N Lorenzon and R J Handa ldquoDifferentialexpression of estrogen receptor beta splice variants in rat brainidentification and characterization of a novel variant missingexon 4rdquo Brain Research Molecular Brain Research vol 80 no2 pp 260ndash268 2000

[81] S Chu and P J Fuller ldquoIdentification of a splice variantof the rat estrogen receptor 120573 generdquo Molecular and CellularEndocrinology vol 132 no 1-2 pp 195ndash199 1997

[82] B Lu E Leygue H Dotzlaw L J Murphy L C Murphy andP H Watson ldquoEstrogen receptor-120573 mRNA variants in humanand murine tissuesrdquoMolecular and Cellular Endocrinology vol138 no 1-2 pp 199ndash203 1998

[83] T R Pak W C J Chung J L Roberts and R J HandaldquoLigand-independent effects of estrogen receptor 120573 on

ISRN Endocrinology 13

mouse gonadotropin-releasing hormone promoter activityrdquoEndocrinology vol 147 no 4 pp 1924ndash1931 2006

[84] T R Pak W C J Chung L R Hinds and R J HandaldquoEstrogen receptor-120573 mediates dihydrotestosterone-inducedstimulation of the arginine vasopressin promoter in neuronalcellsrdquo Endocrinology vol 148 no 7 pp 3371ndash3382 2007

[85] Y K Leung PMak S Hassan and SMHo ldquoEstrogen receptor(ER)-120573 isoforms a key to understanding ER-120573 signalingrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 103 no 35 pp 13162ndash13167 2006

[86] J M Wang X Hou S Adeosun et al ldquoA dominant negativeER120573 splice variant determines the effectiveness of early or lateestrogen therapy after ovariectomy in ratsrdquo PLoS One vol 7 no3 Article ID e33493 2012

[87] W C J Chung T R Pak S Suzuki W A Pouliot M EAndersen and R J Handa ldquoDetection and localization of anestrogen receptor beta splice variant protein (ER1205732) in theadult female rat forebrain and midbrain regionsrdquo Journal ofComparative Neurology vol 505 no 3 pp 249ndash267 2007

[88] R H Price Jr C A Butler P Webb R Uht P Kushner andR J Handa ldquoA splice variant of estrogen receptor 120573 missingexon 3 displays altered subnuclear localization and capacity fortranscriptional activationrdquo Endocrinology vol 142 no 5 pp2039ndash2049 2001

[89] Y Wang and R J Miksicek ldquoIdentification of a dominantnegative form of the human estrogen receptorrdquo MolecularEndocrinology vol 5 no 11 pp 1707ndash1715 1991

[90] E Kuppers and C Beyer ldquoExpression of estrogen receptor-120572and 120573 mRNA in the developing and adult mouse striatumrdquoNeuroscience Letters vol 276 no 2 pp 95ndash98 1999

[91] C Gundlah S G Kohama S J Mirkes V T Garyfallou H FUrbanski and C L Bethea ldquoDistribution of estrogen receptorbeta (ER120573) mRNA in hypothalamus midbrain and temporallobe of spayed macaque continued expression with hormonereplacementrdquo Brain Research Molecular Brain Research vol 76no 2 pp 191ndash204 2000

[92] Y Morishima P J M Murphy D-P Li E R Sanchez and WB Pratt ldquoStepwise assembly of a glucocorticoid receptorsdothsp90heterocomplex resolves two sequential ATP-dependent eventsinvolving first hsp70 and then hsp90 in opening of the steroidbinding pocketrdquo Journal of Biological Chemistry vol 275 no 24pp 18054ndash18060 2000

[93] K D Dittmar and W B Pratt ldquoFolding of the glucocorticoidreceptor by the reconstituted hsp90-based chaperone machin-eryThe initial hsp90sdotp60sdothsp70-dependent step is sufficient forcreating the steroid binding conformationrdquo Journal of BiologicalChemistry vol 272 no 20 pp 13047ndash13054 1997

[94] K I Kang X Meng J Devin-Leclerc et al ldquoThe molecularchaperone Hsp90 can negatively regulate the activity of aglucocorticosteroid-dependent promoterrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 4 pp 1439ndash1444 1999

[95] K Unno H Asakura Y Shibuya M Kaiho S Okada and NOku Naoto ldquoIncrease in basal level of Hsp70 consisting chieflyof constitutively expressed hsp70 (Hsc70) in aged rat brainrdquoJournals of Gerontology Series A vol 55 no 7 pp B329ndashB3352000

[96] U E Olazabal D W Pfaff and C V Mobbs ldquoSex differences inthe regulation of heat shock protein 70 kDa and 90 kDa in therat ventromedial hypothalamus by estrogenrdquo Brain Researchvol 596 no 1-2 pp 311ndash314 1992

[97] M A Pahlavani M D Harris S A Moore and A RichardsonldquoExpression of heat shock protein 70 in rat spleen lymphocytesis affected by age but not by food restrictionrdquo Journal ofNutrition vol 126 no 9 pp 2069ndash2075 1996

[98] A R Heydari B Wu R Takahashi R Strong and A Richard-son ldquoExpression of heat shock protein 70 is altered by age anddiet at the level of transcriptionrdquoMolecular andCellular Biologyvol 13 no 5 pp 2909ndash2918 1993

[99] M Sabbah K-I I Kang L Tora and G Redeuilh ldquoOestro-gen receptor facilitates the formation of preinitiation com-plex assembly involvement of the general transcription factorTFIIBrdquo Biochemical Journal vol 336 part 3 pp 639ndash646 1998

[100] S-Y Wu M C Thomas S Y Hou V Likhite and C-MChiang ldquoIsolation of mouse TFIID and functional character-ization of TBP and TFIID in mediating estrogen receptor andchromatin transcriptionrdquo Journal of Biological Chemistry vol274 no 33 pp 23480ndash23490 1999

[101] S Ghosh and M K Thakur ldquoTissue-specific expression ofreceptor-interacting protein in aging mouserdquo Age vol 30 no4 pp 237ndash243 2008

[102] J Frasor JM Danes B Komm K C N Chang C Richard Lyt-tle and B S Katzenellenbogen ldquoProfiling of estrogen up- anddown-regulated gene expression in human breast cancer cellsinsights into gene networks and pathways underlying estrogeniccontrol of proliferation and cell phenotyperdquo Endocrinology vol144 no 10 pp 4562ndash4574 2003

[103] J Frasor J M Danes C C Funk and B S Katzenellen-bogen ldquoEstrogen down-regulation of the corepressor N-CoRmechanism and implications for estrogen derepression of N-CoR-regulated genesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 102 no 37 pp13153ndash13157 2005

[104] N J McKenna and B W OrsquoMalley ldquoCombinatorial control ofgene expression by nuclear receptors and coregulatorsrdquoCell vol108 no 4 pp 465ndash474 2002

[105] T-P Yao G Ku N Zhou R Scully and D M Livingston ldquoThenuclear hormone receptor coactivator SRC-1 is a specific targetof p300rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 93 no 20 pp 10626ndash10631 1996

[106] B Hanstein R Eckner J DiRenzo et al ldquop300 is a componentof an estrogen receptor coactivator complexrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 93 no 21 pp 11540ndash11545 1996

[107] S Halachmi E Marden G Martin H MacKay C Abbon-danza and M Brown ldquoEstrogen receptor-associated proteinspossible mediators of hormone-induced transcriptionsrdquo Sci-ence vol 264 no 5164 pp 1455ndash1458 1994

[108] A J Horlein AM Naar T Heinzel et al ldquoLigand-independentrepression by the thyroid hormone receptor mediated by anuclear receptor co-repressorrdquo Nature vol 377 no 6548 pp397ndash404 1995

[109] J D Chen and R M Evans ldquoA transcriptional co-repressor thatinteracts with nuclear hormone receptorsrdquo Nature vol 377 no6548 pp 454ndash457 1995

[110] A Malovannaya R B Lanz S Y Jung et al ldquoAnalysis of thehuman endogenous coregulator complexomerdquoCell vol 145 no5 pp 787ndash799 2011

[111] Z Nawaz D M Lonard C L Smith et al ldquoThe Angelmansyndrome-associated protein E6-AP is a coactivator for thenuclear hormone receptor superfamilyrdquoMolecular and CellularBiology vol 19 no 2 pp 1182ndash1189 1999

14 ISRN Endocrinology

[112] B Zheng M Han M Bernier and J-K Wen ldquoNuclear actinand actin-binding proteins in the regulation of transcriptionand gene expressionrdquo FEBS Journal vol 276 no 10 pp 2669ndash2685 2009

[113] W A Hofmann L Stojiljkovic B Fuchsova et al ldquoActin is partof pre-initiation complexes and is necessary for transcription byRNA polymerase IIrdquoNature Cell Biology vol 6 no 11 pp 1094ndash1101 2004

[114] K Tokunaga T Shibuya Y Ishihama et al ldquoNucleocytoplasmictransport of fluorescent mRNA in living mammalian cellsnuclear mRNA export is coupled to ongoing gene transcrip-tionrdquo Genes to Cells vol 11 no 3 pp 305ndash317 2006

[115] R Metivier G Penot M R Hubner et al ldquoEstrogen receptor-120572 directs ordered cyclical and combinatorial recruitment ofcofactors on a natural target promoterrdquo Cell vol 115 no 6 pp751ndash763 2003

[116] C Ambrosino R Tarallo A Bamundo et al ldquoIdentification of ahormone-regulated dynamic nuclear actin network associatedwith estrogen receptor 120572 in human breast cancer cell nucleirdquoMolecular and Cellular Proteomics vol 9 no 6 pp 1352ndash13672010

[117] F Shao R Zhang L Dong and K Ying ldquoOverexpression ofgelsolin-like actin-capping protein is associated with progres-sion of lung adenocarcinomardquo Tohoku Journal of ExperimentalMedicine vol 225 no 2 pp 95ndash101 2011

[118] K Nishimura H-J Ting Y Harada et al ldquoModulation ofandrogen receptor transactivation by gelsolin a newly identi-fied androgen receptor coregulatorrdquo Cancer Research vol 63no 16 pp 4888ndash4894 2003

[119] J S Ahn I S Jang D I Kim et al ldquoAging-associated increaseof gelsolin for apoptosis resistancerdquoBiochemical and BiophysicalResearch Communications vol 312 no 4 pp 1335ndash1341 2003

[120] I Nalvarte T Schwend and J-A Gustafsson ldquoProteomicsanalysis of the estrogen receptor 120572 receptosomerdquoMolecular andCellular Proteomics vol 9 no 7 pp 1411ndash1422 2010

[121] L-H Miau C-J Chang B-J Shen W-H Tsai and S-C LeeldquoIdentification of heterogeneous nuclear ribonucleoprotein K(hnRNPK) as a repressor ofCEBP120573-mediated gene activationrdquoJournal of Biological Chemistry vol 273 no 17 pp 10784ndash107911998

[122] A Ostareck-Lederer D H Ostareck C Cans et al ldquoc-Src-mediated phosphorylation of hnRNP K drives translationalactivation of specifically silenced mRNAsrdquo Molecular and Cel-lular Biology vol 22 no 13 pp 4535ndash4543 2002

[123] P S Bagga G K Arhin and J Wilusz ldquoDSEF-1 is a member ofthe hnRNP H family of RNA-binding proteins and stimulatespre-mRNAcleavage and polyadenylation in vitrordquoNucleic AcidsResearch vol 26 no 23 pp 5343ndash5350 1998

[124] V Markovtsov J M Nikolic J A Goldman C W Turck M-Y Chou and D L Black ldquoCooperative assembly of an hnRNPcomplex induced by a tissue-specific homolog of polypyrimi-dine tract binding proteinrdquoMolecular and Cellular Biology vol20 no 20 pp 7463ndash7479 2000

[125] S Y Jung A Malovannaya J Wei B W OrsquoMalley and J QinldquoProteomic analysis of steady-state nuclear hormone receptorcoactivator complexesrdquoMolecular Endocrinology vol 19 no 10pp 2451ndash2465 2005

[126] W Hong R J Resnick C Rakowski D Shalloway S J Taylorand G A Blobel ldquoPhysical and functional interaction betweenthe transcriptional cofactor CBP and the KH domain proteinSam68rdquoMolecular Cancer Research vol 1 no 1 pp 48ndash55 2002

[127] R ShaoXWang BWeijdegard et al ldquoCoordinate regulation ofheterogeneous nuclear ribonucleoprotein dynamics by steroidhormones in the human fallopian tube and endometrium invivo and in vitrordquo American Journal of Physiology vol 302 no10 pp E1269ndashE1282 2012

[128] C SWoolley and B SMcEwen ldquoEstradiolmediates fluctuationin hippocampal synapse density during the estrous cycle in theadult ratrdquo Journal of Neuroscience vol 12 no 7 pp 2549ndash25541992

[129] C S Woolley H J Wenzel and P A Schwartzkroin ldquoEstradiolincreases the frequency of multiple synapse boutons in thehippocampal CA1 region of the adult female ratrdquo The Journalof Comparative Neurology vol 373 no 1 pp 108ndash117 1996

[130] C S Woolley ldquoEstrogen-mediated structural and functionalsynaptic plasticity in the female rat hippocampusrdquo Hormonesand Behavior vol 34 no 2 pp 140ndash148 1998

[131] D P Srivastava K M Woolfrey K A Jones et al ldquoRapidenhancement of two-step wiring plasticity by estrogen andNMDA receptor activityrdquo Proceedings of the National Academyof Sciences of the United States of America vol 105 no 38 pp14650ndash14655 2008

[132] M Ogiue-Ikeda N Tanabe H Mukai et al ldquoRapid modu-lation of synaptic plasticity by estrogens as well as endocrinedisrupters in hippocampal neuronsrdquo Brain Research Reviewsvol 57 no 2 pp 363ndash375 2008

[133] N J Sandstrom and C L Williams ldquoSpatial memory retentionis enhanced by acute and continuous estradiol replacementrdquoHormones and Behavior vol 45 no 2 pp 128ndash135 2004

[134] E Hogervorst J Williams M Budge W Riedel and JJolles ldquoThe nature of the effect of female gonadal hormonereplacement therapy on cognitive function in post-menopausalwomen a meta-analysisrdquo Neuroscience vol 101 no 3 pp 485ndash512 2000

[135] M E Bailey A C J Wang J Hao et al ldquoInteractive effects ofage and estrogen on cortical neurons implications for cognitiveagingrdquo Neuroscience vol 191 pp 148ndash158 2011

[136] A A Walf M E Rhodes and C A Frye ldquoOvarian steroidsenhance object recognition in naturally cycling and ovariec-tomized hormone-primed ratsrdquo Neurobiology of Learning andMemory vol 86 no 1 pp 35ndash46 2006

[137] V N Luine L F Jacome and N J Maclusky ldquoRapid enhance-ment of visual and place memory by estrogens in ratsrdquoEndocrinology vol 144 no 7 pp 2836ndash2844 2003

[138] L Fan Z Zhao P T Orr C H Chambers M C Lewis and KM Frick ldquoEstradiol-induced object memory consolidation inmiddle-aged femalemice requires dorsal hippocampal extracel-lular signal-regulated kinase and phosphatidylinositol 3-kinaseactivationrdquo Journal of Neuroscience vol 30 no 12 pp 4390ndash4400 2010

[139] D B Dubal and PMWise ldquoNeuroprotective effects of estradiolin middle-aged female ratsrdquo Endocrinology vol 142 no 1 pp43ndash48 2001

[140] S-H Yang J Shi A L Day and J W Simpkins ldquoEstradiolexerts neuroprotective effects when administered after ischemicinsultrdquo Stroke vol 31 no 3 pp 745ndash750 2000

[141] J W Simpkins G Rajakumar Y-Q Zhang et al ldquoEstrogensmay reduce mortality and ischemic damage caused by middlecerebral artery occlusion in the female ratrdquo Journal of Neuro-surgery vol 87 no 5 pp 724ndash730 1997

[142] J Shi K S Panickar S-H Yang O Rabbani A L Day and JWSimpkins ldquoEstrogen attenuates over-expression of 120573-amyloid

ISRN Endocrinology 15

precursor protein messager RNA in an animal model of focalischemiardquo Brain Research vol 810 no 1-2 pp 87ndash92 1998

[143] Q-H Zhang Y-H Huang Y-Z Hu et al ldquoDisruption ofestrogen receptor beta in mice brain results in pathologicalalterations resemblingAlzheimer diseaserdquoActa PharmacologicaSinica vol 25 no 4 pp 452ndash457 2004

[144] E F Rissman A L Heck J E Leonard M A Shupnik and J-A Gustafsson ldquoDisruption of estrogen receptor 120573 gene impairsspatial learning in female micerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no6 pp 3996ndash4001 2002

[145] M Day A Sung S Logue M Bowlby and R Arias ldquoBetaestrogen receptor knockout (BERKO) mice present attenuatedhippocampal CA1 long-term potentiation and related memorydeficits in contextual fear conditioningrdquo Behavioural BrainResearch vol 164 no 1 pp 128ndash131 2005

[146] R Vierk G Glassmeier L Zhou et al ldquoAromatase inhibitionabolishes LTP generation in female but not in male micerdquo TheJournal of Neuroscience vol 32 no 24 pp 8116ndash8126 2012

[147] R-M Vouimba M R Foy J G Foy and R FThompson ldquo17120573-estradiol suppresses expression of long-term depression in agedratsrdquo Brain Research Bulletin vol 53 no 6 pp 783ndash787 2000

[148] C E Andreescu B A Milojkovic E D Haasdijk et alldquoEstradiol improves cerebellar memory formation by activatingestrogen receptor 120573rdquo Journal of Neuroscience vol 27 no 40 pp10832ndash10839 2007

[149] Y-Y Huang P V Nguyen T Abel and E R Kandel ldquoLong-lasting forms of synaptic potentiation in the mammalian hip-pocampusrdquo Learning Memory vol 3 no 2-3 pp 74ndash85 1996

[150] H Mukai T Tsurugizawa G Murakami et al ldquoRapid mod-ulation of long-term depression and spinogenesis via synapticestrogen receptors in hippocampal principal neuronsrdquo Journalof Neurochemistry vol 100 no 4 pp 950ndash967 2007

[151] L Liu T P Wong M F Pozza et al ldquoRole of NMDA receptorsubtypes in governing the direction of hippocampal synapticplasticityrdquo Science vol 304 no 5673 pp 1021ndash1024 2004

[152] M Cyr O Ghribi C Thibault M Morissette M Landry andT di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[153] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[154] C C Smith and L L McMahon ldquoEstradiol-induced increasein the magnitude of long-term potentiation is prevented byblocking NR2B-containing receptorsrdquo Journal of Neurosciencevol 26 no 33 pp 8517ndash8522 2006

[155] Y Zhou J J Watters and D M Dorsa ldquoEstrogen rapidlyinduces the phosphorylation of the cAMP response elementbinding protein in rat brainrdquo Endocrinology vol 137 no 5 pp2163ndash2166 1996

[156] XGonda T TelekG Juhasz J Lazary AVargha andG BagdyldquoPatterns of mood changes throughout the reproductive cyclein healthy women without premenstrual dysphoric disordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 32 no 8 pp 1782ndash1788 2008

[157] E W Freeman ldquoPremenstrual syndrome and premenstrualdysphoric disorder definitions and diagnosisrdquo Psychoneuroen-docrinology vol 28 supplement 3 pp 25ndash37 2003

[158] T D Lund T Rovis W C J Chung and R J Handa ldquoNovelactions of estrogen receptor-120573 on anxiety-related behaviorsrdquoEndocrinology vol 146 no 2 pp 797ndash807 2005

[159] N Breslau L Schultz and E Peterson ldquoSex differences indepression a role for preexisting anxietyrdquo Psychiatry Researchvol 58 no 1 pp 1ndash12 1995

[160] P E Bebbington G Dunn R Jenkins et al ldquoThe influenceof age and sex on the prevalence of depressive conditionsreport from the National Survey of Psychiatric MorbidityrdquoPsychological Medicine vol 28 no 1 pp 9ndash19 1998

[161] G Aguilera J P Harwood and J X Wilson ldquoMechanisms ofaction of corticotropin-releasing factor and other regulators ofcorticotropin release in rat pituitary cellsrdquo Journal of BiologicalChemistry vol 258 no 13 pp 8039ndash8045 1983

[162] A Papadimitriou and K N Priftis ldquoRegulation of thehypothalamic-pituitary-adrenal axisrdquo NeuroImmunoModula-tion vol 16 no 5 pp 265ndash271 2009

[163] S Suzuki and R J Handa ldquoRegulation of estrogen receptor-120573expression in the female rat hypothalamus differential effectsof dexamethasone and estradiolrdquo Endocrinology vol 145 no 8pp 3658ndash3670 2004

[164] W J S Miller S Suzuki L K Miller R Handa and R M UhtldquoEstrogen receptor (ER)120573 isoforms rather than ER120572 regulatecorticotropin-releasing hormone promoter activity through analternate pathwayrdquo Journal of Neuroscience vol 24 no 47 pp10628ndash10635 2004

[165] C IsgorM CecchiM Kabbaj H Akil and S JWatson ldquoEstro-gen receptor 120573 in the paraventricular nucleus of hypothalamusregulates the neuroendocrine response to stress and is regulatedby corticosteronerdquo Neuroscience vol 121 no 4 pp 837ndash8452003

[166] M L Forsling I Kallo D E Hartley et al ldquoOestrogen receptor-120573 and neurohypophysial hormones functional interaction andneuroanatomical localisationrdquo Pharmacology Biochemistry andBehavior vol 76 no 3-4 pp 535ndash542 2003

[167] A S Lalmansingh and R M Uht ldquoEstradiol regulatescorticotropin-releasing hormone gene (crh) expression in arapid and phasic manner that parallels estrogen receptor-120572 and-120573 recruitment to a 3101584051015840-cyclic adenosine 51015840- monophosphateregulatory region of the proximal crh promoterrdquo Endocrinologyvol 149 no 1 pp 346ndash357 2008

[168] B N Roy R L Reid and D A van Vugt ldquoThe effects ofestrogen and progesterone on corticotropin-releasing hormoneand arginine vasopressin messenger ribonucleic acid levelsin the paraventricular nucleus and supraoptic nucleus of therhesus monkeyrdquo Endocrinology vol 140 no 5 pp 2191ndash21981999

[169] X Ni R C Nicholson B R King E-C Chan M A Read andR Smith ldquoEstrogen represses whereas the estrogen-antagonistICI 182780 stimulates placental CRH gene expressionrdquo Journalof Clinical Endocrinology and Metabolism vol 87 no 8 pp3774ndash3778 2002

[170] N C Vamvakopoulos and G P Chrousos ldquoEvidence of directestrogenic regulation of human corticotropin-releasing hor-mone gene expression Potential implications for the sexualdimophism of the stress response and immuneinflammatoryreactionrdquo Journal of Clinical Investigation vol 92 no 4 pp1896ndash1902 1993

[171] Y Hu D L Wu C X Luo et al ldquoHippocampal nitric oxidecontributes to sex difference in affective behaviorsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 35 pp 14224ndash14229 2012

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

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Computational and Mathematical Methods in Medicine

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

12 ISRN Endocrinology

differentially by agonists antagonists and selective estrogenreceptor modulatorsrdquo Journal of Biological Chemistry vol 276no 38 pp 35684ndash35692 2001

[55] V Bartella P Rizza I Barone et al ldquoEstrogen receptor betabinds Sp1 and recruits a corepressor complex to the estrogenreceptor alpha gene promoterrdquo Breast Cancer Research andTreatment vol 134 no 2 pp 569ndash581 2012

[56] L C Li C C Yeh D Nojima and R Dahiya ldquoCloning andcharacterization of human estrogen receptor beta promoterrdquoBiochemical and Biophysical Research Communications vol 275no 2 pp 682ndash689 2000

[57] E A Vladusic A E Hornby F K Guerra-Vladusic J Lakinsand R Lupu ldquoExpression and regulation of estrogen receptor szligin human breast tumors and cell linesrdquoOncology Reports vol 7no 1 pp 157ndash167 2000

[58] T Hatsumi and Y Yamamuro ldquoDownregulation of estrogenreceptor gene expression by exogenous 17120573-estradiol in themammary glands of lactating micerdquo Experimental Biology andMedicine vol 231 no 3 pp 311ndash316 2006

[59] H B Patisaul P L Whitten and L J Young ldquoRegulation ofestrogen receptor beta mRNA in the brain opposite effectsof 17120573-estradiol and the phytoestrogen coumestrolrdquoMolecularBrain Research vol 67 no 1 pp 165ndash171 1999

[60] T J Brown N J MacLusky M Shanabrough and F NaftolinldquoComparison of age- and sex-related changes in cell nuclearestrogen-binding capacity and progestin receptor induction inthe rat brainrdquo Endocrinology vol 126 no 6 pp 2965ndash29721990

[61] B S Rubin T O Fox and R S Bridges ldquoEstrogen bindingin nuclear and cytosolic extracts from brain and pituitary ofmiddle-aged female ratsrdquo Brain Research vol 383 no 1-2 pp60ndash67 1986

[62] T Funabashi S P Kleopoulos P J Brooks et al ldquoChangesin estrogenic regulation of estrogen receptor 120572 mRNA andprogesterone receptor mRNA in the female rat hypothalamusduring aging an in situ hybridization studyrdquo NeuroscienceResearch vol 38 no 1 pp 85ndash92 2000

[63] M E Wilson K L Rosewell M L Kashon P J Shughrue IMerchenthaler and P M Wise ldquoAge differentially influencesestrogen receptor-120572 (ER120572) and estrogen receptor-120573 (ER120573) geneexpression in specific regions of the rat brainrdquo Mechanisms ofAgeing and Development vol 123 no 6 pp 593ndash601 2002

[64] W S Post P J Goldschmidt-Clermont C C Wilhide etal ldquoMethylation of the estrogen receptor gene is associatedwith aging and atherosclerosis in the cardiovascular systemrdquoCardiovascular Research vol 43 no 4 pp 985ndash991 1999

[65] J-P J Issa Y L Ottaviano P Celano S R Hamilton NE Davidson and S B Baylin ldquoMethylation of the oestrogenreceptor CpG island links ageing and neoplasia in humancolonrdquo Nature Genetics vol 7 no 4 pp 536ndash540 1994

[66] T Funabashi and F Kimura ldquoEffects of estrogen and estrogenreceptor messenger RNA levels in young and middle-agedfemale rats comparison ofmedial preoptic area andmediobasalhypothalamusrdquo Acta Biologica Hungarica vol 45 no 2ndash4 pp223ndash231 1994

[67] M AMiller P E Kolb B Planas andM A Raskind ldquoEstrogenreceptor and neurotensinneuromedin-N gene expression inthe preoptic area are unaltered with age in Fischer 344 femaleratsrdquo Endocrinology vol 135 no 5 pp 1986ndash1995 1994

[68] T R Chakraborty P R Hof L Ng and A C Gore ldquoStereologicanalysis of estrogen receptor alpha (ER alpha) expression in rat

hypothalamus and its regulation by aging and estrogenrdquo Journalof Comparative Neurology vol 466 no 3 pp 409ndash421 2003

[69] J M Westberry A L Trout and M E Wilson ldquoEpigeneticregulation of estrogen receptor beta expression in the rat cortexduring agingrdquo NeuroReport vol 22 no 9 pp 428ndash432 2011

[70] T R Chakraborty L Ng and A C Gore ldquoAge-related changesin estrogen receptor 120573 in rat hypothalamus a quantitativeanalysisrdquo Endocrinology vol 144 no 9 pp 4164ndash4171 2003

[71] I Poola S Koduri S Chatra and R Clarke ldquoIdentificationof twenty alternatively spliced estrogen receptor alpha mRNAsin breast cancer cell lines and tumors using splice targetedprimer approachrdquo Journal of Steroid Biochemistry andMolecularBiology vol 72 no 5 pp 249ndash258 2000

[72] T A Ishunina and D F Swaab ldquoHippocampal estrogenreceptor-alpha splice variant TADDI in the human brain inaging and Alzheimerrsquos diseaserdquoNeuroendocrinology vol 89 no2 pp 187ndash199 2009

[73] T A Ishunina and D F Swaab ldquoEstrogen receptor-120572 splicevariants in the human brainrdquo Gynecological Endocrinology vol24 no 2 pp 93ndash98 2008

[74] T A Ishunina F P M Kruijver R Balesar and D FSwaab ldquoDifferential expression of estrogen receptor 120572 and 120573immunoreactivity in the human supraoptic nucleus in rela-tion to sex and agingrdquo Journal of Clinical Endocrinology andMetabolism vol 85 no 9 pp 3283ndash3291 2000

[75] T A Ishunina D F Fischer andD F Swaab ldquoEstrogen receptor120572 and its splice variants in the hippocampus in aging andAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 28 no 11 pp1670ndash1681 2007

[76] J R Tollervey Z Wang T Hortobagyi et al ldquoAnalysis of alter-native splicing associated with aging and neurodegeneration inthe human brainrdquo Genome Research vol 21 no 10 pp 1572ndash1582 2011

[77] N NMott and T R Pak ldquoCharacterisation of human oestrogenreceptor beta (ER120573) splice variants in neuronal cellsrdquo Journal ofNeuroendocrinology vol 24 no 10 pp 1311ndash1321 2012

[78] S Inoue S-J Hoshino H Miyoshi et al ldquoIdentification ofa ovel isoform of estrogen receptor a potential inhibitor ofestrogen action in vascular smooth muscle cellsrdquo Biochemicaland Biophysical Research Communications vol 219 no 3 pp766ndash772 1996

[79] J K Skipper L J Young J M Bergeron M T Tetzlaff CT Osborn and D Crews ldquoIdentification of an isoform ofthe estrogen receptor messenger RNA lacking exon four andpresent in the brainrdquo Proceedings of the National Academy ofSciences of the United States of America vol 90 no 15 pp 7172ndash7175 1993

[80] R H Price Jr N Lorenzon and R J Handa ldquoDifferentialexpression of estrogen receptor beta splice variants in rat brainidentification and characterization of a novel variant missingexon 4rdquo Brain Research Molecular Brain Research vol 80 no2 pp 260ndash268 2000

[81] S Chu and P J Fuller ldquoIdentification of a splice variantof the rat estrogen receptor 120573 generdquo Molecular and CellularEndocrinology vol 132 no 1-2 pp 195ndash199 1997

[82] B Lu E Leygue H Dotzlaw L J Murphy L C Murphy andP H Watson ldquoEstrogen receptor-120573 mRNA variants in humanand murine tissuesrdquoMolecular and Cellular Endocrinology vol138 no 1-2 pp 199ndash203 1998

[83] T R Pak W C J Chung J L Roberts and R J HandaldquoLigand-independent effects of estrogen receptor 120573 on

ISRN Endocrinology 13

mouse gonadotropin-releasing hormone promoter activityrdquoEndocrinology vol 147 no 4 pp 1924ndash1931 2006

[84] T R Pak W C J Chung L R Hinds and R J HandaldquoEstrogen receptor-120573 mediates dihydrotestosterone-inducedstimulation of the arginine vasopressin promoter in neuronalcellsrdquo Endocrinology vol 148 no 7 pp 3371ndash3382 2007

[85] Y K Leung PMak S Hassan and SMHo ldquoEstrogen receptor(ER)-120573 isoforms a key to understanding ER-120573 signalingrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 103 no 35 pp 13162ndash13167 2006

[86] J M Wang X Hou S Adeosun et al ldquoA dominant negativeER120573 splice variant determines the effectiveness of early or lateestrogen therapy after ovariectomy in ratsrdquo PLoS One vol 7 no3 Article ID e33493 2012

[87] W C J Chung T R Pak S Suzuki W A Pouliot M EAndersen and R J Handa ldquoDetection and localization of anestrogen receptor beta splice variant protein (ER1205732) in theadult female rat forebrain and midbrain regionsrdquo Journal ofComparative Neurology vol 505 no 3 pp 249ndash267 2007

[88] R H Price Jr C A Butler P Webb R Uht P Kushner andR J Handa ldquoA splice variant of estrogen receptor 120573 missingexon 3 displays altered subnuclear localization and capacity fortranscriptional activationrdquo Endocrinology vol 142 no 5 pp2039ndash2049 2001

[89] Y Wang and R J Miksicek ldquoIdentification of a dominantnegative form of the human estrogen receptorrdquo MolecularEndocrinology vol 5 no 11 pp 1707ndash1715 1991

[90] E Kuppers and C Beyer ldquoExpression of estrogen receptor-120572and 120573 mRNA in the developing and adult mouse striatumrdquoNeuroscience Letters vol 276 no 2 pp 95ndash98 1999

[91] C Gundlah S G Kohama S J Mirkes V T Garyfallou H FUrbanski and C L Bethea ldquoDistribution of estrogen receptorbeta (ER120573) mRNA in hypothalamus midbrain and temporallobe of spayed macaque continued expression with hormonereplacementrdquo Brain Research Molecular Brain Research vol 76no 2 pp 191ndash204 2000

[92] Y Morishima P J M Murphy D-P Li E R Sanchez and WB Pratt ldquoStepwise assembly of a glucocorticoid receptorsdothsp90heterocomplex resolves two sequential ATP-dependent eventsinvolving first hsp70 and then hsp90 in opening of the steroidbinding pocketrdquo Journal of Biological Chemistry vol 275 no 24pp 18054ndash18060 2000

[93] K D Dittmar and W B Pratt ldquoFolding of the glucocorticoidreceptor by the reconstituted hsp90-based chaperone machin-eryThe initial hsp90sdotp60sdothsp70-dependent step is sufficient forcreating the steroid binding conformationrdquo Journal of BiologicalChemistry vol 272 no 20 pp 13047ndash13054 1997

[94] K I Kang X Meng J Devin-Leclerc et al ldquoThe molecularchaperone Hsp90 can negatively regulate the activity of aglucocorticosteroid-dependent promoterrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 4 pp 1439ndash1444 1999

[95] K Unno H Asakura Y Shibuya M Kaiho S Okada and NOku Naoto ldquoIncrease in basal level of Hsp70 consisting chieflyof constitutively expressed hsp70 (Hsc70) in aged rat brainrdquoJournals of Gerontology Series A vol 55 no 7 pp B329ndashB3352000

[96] U E Olazabal D W Pfaff and C V Mobbs ldquoSex differences inthe regulation of heat shock protein 70 kDa and 90 kDa in therat ventromedial hypothalamus by estrogenrdquo Brain Researchvol 596 no 1-2 pp 311ndash314 1992

[97] M A Pahlavani M D Harris S A Moore and A RichardsonldquoExpression of heat shock protein 70 in rat spleen lymphocytesis affected by age but not by food restrictionrdquo Journal ofNutrition vol 126 no 9 pp 2069ndash2075 1996

[98] A R Heydari B Wu R Takahashi R Strong and A Richard-son ldquoExpression of heat shock protein 70 is altered by age anddiet at the level of transcriptionrdquoMolecular andCellular Biologyvol 13 no 5 pp 2909ndash2918 1993

[99] M Sabbah K-I I Kang L Tora and G Redeuilh ldquoOestro-gen receptor facilitates the formation of preinitiation com-plex assembly involvement of the general transcription factorTFIIBrdquo Biochemical Journal vol 336 part 3 pp 639ndash646 1998

[100] S-Y Wu M C Thomas S Y Hou V Likhite and C-MChiang ldquoIsolation of mouse TFIID and functional character-ization of TBP and TFIID in mediating estrogen receptor andchromatin transcriptionrdquo Journal of Biological Chemistry vol274 no 33 pp 23480ndash23490 1999

[101] S Ghosh and M K Thakur ldquoTissue-specific expression ofreceptor-interacting protein in aging mouserdquo Age vol 30 no4 pp 237ndash243 2008

[102] J Frasor JM Danes B Komm K C N Chang C Richard Lyt-tle and B S Katzenellenbogen ldquoProfiling of estrogen up- anddown-regulated gene expression in human breast cancer cellsinsights into gene networks and pathways underlying estrogeniccontrol of proliferation and cell phenotyperdquo Endocrinology vol144 no 10 pp 4562ndash4574 2003

[103] J Frasor J M Danes C C Funk and B S Katzenellen-bogen ldquoEstrogen down-regulation of the corepressor N-CoRmechanism and implications for estrogen derepression of N-CoR-regulated genesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 102 no 37 pp13153ndash13157 2005

[104] N J McKenna and B W OrsquoMalley ldquoCombinatorial control ofgene expression by nuclear receptors and coregulatorsrdquoCell vol108 no 4 pp 465ndash474 2002

[105] T-P Yao G Ku N Zhou R Scully and D M Livingston ldquoThenuclear hormone receptor coactivator SRC-1 is a specific targetof p300rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 93 no 20 pp 10626ndash10631 1996

[106] B Hanstein R Eckner J DiRenzo et al ldquop300 is a componentof an estrogen receptor coactivator complexrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 93 no 21 pp 11540ndash11545 1996

[107] S Halachmi E Marden G Martin H MacKay C Abbon-danza and M Brown ldquoEstrogen receptor-associated proteinspossible mediators of hormone-induced transcriptionsrdquo Sci-ence vol 264 no 5164 pp 1455ndash1458 1994

[108] A J Horlein AM Naar T Heinzel et al ldquoLigand-independentrepression by the thyroid hormone receptor mediated by anuclear receptor co-repressorrdquo Nature vol 377 no 6548 pp397ndash404 1995

[109] J D Chen and R M Evans ldquoA transcriptional co-repressor thatinteracts with nuclear hormone receptorsrdquo Nature vol 377 no6548 pp 454ndash457 1995

[110] A Malovannaya R B Lanz S Y Jung et al ldquoAnalysis of thehuman endogenous coregulator complexomerdquoCell vol 145 no5 pp 787ndash799 2011

[111] Z Nawaz D M Lonard C L Smith et al ldquoThe Angelmansyndrome-associated protein E6-AP is a coactivator for thenuclear hormone receptor superfamilyrdquoMolecular and CellularBiology vol 19 no 2 pp 1182ndash1189 1999

14 ISRN Endocrinology

[112] B Zheng M Han M Bernier and J-K Wen ldquoNuclear actinand actin-binding proteins in the regulation of transcriptionand gene expressionrdquo FEBS Journal vol 276 no 10 pp 2669ndash2685 2009

[113] W A Hofmann L Stojiljkovic B Fuchsova et al ldquoActin is partof pre-initiation complexes and is necessary for transcription byRNA polymerase IIrdquoNature Cell Biology vol 6 no 11 pp 1094ndash1101 2004

[114] K Tokunaga T Shibuya Y Ishihama et al ldquoNucleocytoplasmictransport of fluorescent mRNA in living mammalian cellsnuclear mRNA export is coupled to ongoing gene transcrip-tionrdquo Genes to Cells vol 11 no 3 pp 305ndash317 2006

[115] R Metivier G Penot M R Hubner et al ldquoEstrogen receptor-120572 directs ordered cyclical and combinatorial recruitment ofcofactors on a natural target promoterrdquo Cell vol 115 no 6 pp751ndash763 2003

[116] C Ambrosino R Tarallo A Bamundo et al ldquoIdentification of ahormone-regulated dynamic nuclear actin network associatedwith estrogen receptor 120572 in human breast cancer cell nucleirdquoMolecular and Cellular Proteomics vol 9 no 6 pp 1352ndash13672010

[117] F Shao R Zhang L Dong and K Ying ldquoOverexpression ofgelsolin-like actin-capping protein is associated with progres-sion of lung adenocarcinomardquo Tohoku Journal of ExperimentalMedicine vol 225 no 2 pp 95ndash101 2011

[118] K Nishimura H-J Ting Y Harada et al ldquoModulation ofandrogen receptor transactivation by gelsolin a newly identi-fied androgen receptor coregulatorrdquo Cancer Research vol 63no 16 pp 4888ndash4894 2003

[119] J S Ahn I S Jang D I Kim et al ldquoAging-associated increaseof gelsolin for apoptosis resistancerdquoBiochemical and BiophysicalResearch Communications vol 312 no 4 pp 1335ndash1341 2003

[120] I Nalvarte T Schwend and J-A Gustafsson ldquoProteomicsanalysis of the estrogen receptor 120572 receptosomerdquoMolecular andCellular Proteomics vol 9 no 7 pp 1411ndash1422 2010

[121] L-H Miau C-J Chang B-J Shen W-H Tsai and S-C LeeldquoIdentification of heterogeneous nuclear ribonucleoprotein K(hnRNPK) as a repressor ofCEBP120573-mediated gene activationrdquoJournal of Biological Chemistry vol 273 no 17 pp 10784ndash107911998

[122] A Ostareck-Lederer D H Ostareck C Cans et al ldquoc-Src-mediated phosphorylation of hnRNP K drives translationalactivation of specifically silenced mRNAsrdquo Molecular and Cel-lular Biology vol 22 no 13 pp 4535ndash4543 2002

[123] P S Bagga G K Arhin and J Wilusz ldquoDSEF-1 is a member ofthe hnRNP H family of RNA-binding proteins and stimulatespre-mRNAcleavage and polyadenylation in vitrordquoNucleic AcidsResearch vol 26 no 23 pp 5343ndash5350 1998

[124] V Markovtsov J M Nikolic J A Goldman C W Turck M-Y Chou and D L Black ldquoCooperative assembly of an hnRNPcomplex induced by a tissue-specific homolog of polypyrimi-dine tract binding proteinrdquoMolecular and Cellular Biology vol20 no 20 pp 7463ndash7479 2000

[125] S Y Jung A Malovannaya J Wei B W OrsquoMalley and J QinldquoProteomic analysis of steady-state nuclear hormone receptorcoactivator complexesrdquoMolecular Endocrinology vol 19 no 10pp 2451ndash2465 2005

[126] W Hong R J Resnick C Rakowski D Shalloway S J Taylorand G A Blobel ldquoPhysical and functional interaction betweenthe transcriptional cofactor CBP and the KH domain proteinSam68rdquoMolecular Cancer Research vol 1 no 1 pp 48ndash55 2002

[127] R ShaoXWang BWeijdegard et al ldquoCoordinate regulation ofheterogeneous nuclear ribonucleoprotein dynamics by steroidhormones in the human fallopian tube and endometrium invivo and in vitrordquo American Journal of Physiology vol 302 no10 pp E1269ndashE1282 2012

[128] C SWoolley and B SMcEwen ldquoEstradiolmediates fluctuationin hippocampal synapse density during the estrous cycle in theadult ratrdquo Journal of Neuroscience vol 12 no 7 pp 2549ndash25541992

[129] C S Woolley H J Wenzel and P A Schwartzkroin ldquoEstradiolincreases the frequency of multiple synapse boutons in thehippocampal CA1 region of the adult female ratrdquo The Journalof Comparative Neurology vol 373 no 1 pp 108ndash117 1996

[130] C S Woolley ldquoEstrogen-mediated structural and functionalsynaptic plasticity in the female rat hippocampusrdquo Hormonesand Behavior vol 34 no 2 pp 140ndash148 1998

[131] D P Srivastava K M Woolfrey K A Jones et al ldquoRapidenhancement of two-step wiring plasticity by estrogen andNMDA receptor activityrdquo Proceedings of the National Academyof Sciences of the United States of America vol 105 no 38 pp14650ndash14655 2008

[132] M Ogiue-Ikeda N Tanabe H Mukai et al ldquoRapid modu-lation of synaptic plasticity by estrogens as well as endocrinedisrupters in hippocampal neuronsrdquo Brain Research Reviewsvol 57 no 2 pp 363ndash375 2008

[133] N J Sandstrom and C L Williams ldquoSpatial memory retentionis enhanced by acute and continuous estradiol replacementrdquoHormones and Behavior vol 45 no 2 pp 128ndash135 2004

[134] E Hogervorst J Williams M Budge W Riedel and JJolles ldquoThe nature of the effect of female gonadal hormonereplacement therapy on cognitive function in post-menopausalwomen a meta-analysisrdquo Neuroscience vol 101 no 3 pp 485ndash512 2000

[135] M E Bailey A C J Wang J Hao et al ldquoInteractive effects ofage and estrogen on cortical neurons implications for cognitiveagingrdquo Neuroscience vol 191 pp 148ndash158 2011

[136] A A Walf M E Rhodes and C A Frye ldquoOvarian steroidsenhance object recognition in naturally cycling and ovariec-tomized hormone-primed ratsrdquo Neurobiology of Learning andMemory vol 86 no 1 pp 35ndash46 2006

[137] V N Luine L F Jacome and N J Maclusky ldquoRapid enhance-ment of visual and place memory by estrogens in ratsrdquoEndocrinology vol 144 no 7 pp 2836ndash2844 2003

[138] L Fan Z Zhao P T Orr C H Chambers M C Lewis and KM Frick ldquoEstradiol-induced object memory consolidation inmiddle-aged femalemice requires dorsal hippocampal extracel-lular signal-regulated kinase and phosphatidylinositol 3-kinaseactivationrdquo Journal of Neuroscience vol 30 no 12 pp 4390ndash4400 2010

[139] D B Dubal and PMWise ldquoNeuroprotective effects of estradiolin middle-aged female ratsrdquo Endocrinology vol 142 no 1 pp43ndash48 2001

[140] S-H Yang J Shi A L Day and J W Simpkins ldquoEstradiolexerts neuroprotective effects when administered after ischemicinsultrdquo Stroke vol 31 no 3 pp 745ndash750 2000

[141] J W Simpkins G Rajakumar Y-Q Zhang et al ldquoEstrogensmay reduce mortality and ischemic damage caused by middlecerebral artery occlusion in the female ratrdquo Journal of Neuro-surgery vol 87 no 5 pp 724ndash730 1997

[142] J Shi K S Panickar S-H Yang O Rabbani A L Day and JWSimpkins ldquoEstrogen attenuates over-expression of 120573-amyloid

ISRN Endocrinology 15

precursor protein messager RNA in an animal model of focalischemiardquo Brain Research vol 810 no 1-2 pp 87ndash92 1998

[143] Q-H Zhang Y-H Huang Y-Z Hu et al ldquoDisruption ofestrogen receptor beta in mice brain results in pathologicalalterations resemblingAlzheimer diseaserdquoActa PharmacologicaSinica vol 25 no 4 pp 452ndash457 2004

[144] E F Rissman A L Heck J E Leonard M A Shupnik and J-A Gustafsson ldquoDisruption of estrogen receptor 120573 gene impairsspatial learning in female micerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no6 pp 3996ndash4001 2002

[145] M Day A Sung S Logue M Bowlby and R Arias ldquoBetaestrogen receptor knockout (BERKO) mice present attenuatedhippocampal CA1 long-term potentiation and related memorydeficits in contextual fear conditioningrdquo Behavioural BrainResearch vol 164 no 1 pp 128ndash131 2005

[146] R Vierk G Glassmeier L Zhou et al ldquoAromatase inhibitionabolishes LTP generation in female but not in male micerdquo TheJournal of Neuroscience vol 32 no 24 pp 8116ndash8126 2012

[147] R-M Vouimba M R Foy J G Foy and R FThompson ldquo17120573-estradiol suppresses expression of long-term depression in agedratsrdquo Brain Research Bulletin vol 53 no 6 pp 783ndash787 2000

[148] C E Andreescu B A Milojkovic E D Haasdijk et alldquoEstradiol improves cerebellar memory formation by activatingestrogen receptor 120573rdquo Journal of Neuroscience vol 27 no 40 pp10832ndash10839 2007

[149] Y-Y Huang P V Nguyen T Abel and E R Kandel ldquoLong-lasting forms of synaptic potentiation in the mammalian hip-pocampusrdquo Learning Memory vol 3 no 2-3 pp 74ndash85 1996

[150] H Mukai T Tsurugizawa G Murakami et al ldquoRapid mod-ulation of long-term depression and spinogenesis via synapticestrogen receptors in hippocampal principal neuronsrdquo Journalof Neurochemistry vol 100 no 4 pp 950ndash967 2007

[151] L Liu T P Wong M F Pozza et al ldquoRole of NMDA receptorsubtypes in governing the direction of hippocampal synapticplasticityrdquo Science vol 304 no 5673 pp 1021ndash1024 2004

[152] M Cyr O Ghribi C Thibault M Morissette M Landry andT di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[153] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[154] C C Smith and L L McMahon ldquoEstradiol-induced increasein the magnitude of long-term potentiation is prevented byblocking NR2B-containing receptorsrdquo Journal of Neurosciencevol 26 no 33 pp 8517ndash8522 2006

[155] Y Zhou J J Watters and D M Dorsa ldquoEstrogen rapidlyinduces the phosphorylation of the cAMP response elementbinding protein in rat brainrdquo Endocrinology vol 137 no 5 pp2163ndash2166 1996

[156] XGonda T TelekG Juhasz J Lazary AVargha andG BagdyldquoPatterns of mood changes throughout the reproductive cyclein healthy women without premenstrual dysphoric disordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 32 no 8 pp 1782ndash1788 2008

[157] E W Freeman ldquoPremenstrual syndrome and premenstrualdysphoric disorder definitions and diagnosisrdquo Psychoneuroen-docrinology vol 28 supplement 3 pp 25ndash37 2003

[158] T D Lund T Rovis W C J Chung and R J Handa ldquoNovelactions of estrogen receptor-120573 on anxiety-related behaviorsrdquoEndocrinology vol 146 no 2 pp 797ndash807 2005

[159] N Breslau L Schultz and E Peterson ldquoSex differences indepression a role for preexisting anxietyrdquo Psychiatry Researchvol 58 no 1 pp 1ndash12 1995

[160] P E Bebbington G Dunn R Jenkins et al ldquoThe influenceof age and sex on the prevalence of depressive conditionsreport from the National Survey of Psychiatric MorbidityrdquoPsychological Medicine vol 28 no 1 pp 9ndash19 1998

[161] G Aguilera J P Harwood and J X Wilson ldquoMechanisms ofaction of corticotropin-releasing factor and other regulators ofcorticotropin release in rat pituitary cellsrdquo Journal of BiologicalChemistry vol 258 no 13 pp 8039ndash8045 1983

[162] A Papadimitriou and K N Priftis ldquoRegulation of thehypothalamic-pituitary-adrenal axisrdquo NeuroImmunoModula-tion vol 16 no 5 pp 265ndash271 2009

[163] S Suzuki and R J Handa ldquoRegulation of estrogen receptor-120573expression in the female rat hypothalamus differential effectsof dexamethasone and estradiolrdquo Endocrinology vol 145 no 8pp 3658ndash3670 2004

[164] W J S Miller S Suzuki L K Miller R Handa and R M UhtldquoEstrogen receptor (ER)120573 isoforms rather than ER120572 regulatecorticotropin-releasing hormone promoter activity through analternate pathwayrdquo Journal of Neuroscience vol 24 no 47 pp10628ndash10635 2004

[165] C IsgorM CecchiM Kabbaj H Akil and S JWatson ldquoEstro-gen receptor 120573 in the paraventricular nucleus of hypothalamusregulates the neuroendocrine response to stress and is regulatedby corticosteronerdquo Neuroscience vol 121 no 4 pp 837ndash8452003

[166] M L Forsling I Kallo D E Hartley et al ldquoOestrogen receptor-120573 and neurohypophysial hormones functional interaction andneuroanatomical localisationrdquo Pharmacology Biochemistry andBehavior vol 76 no 3-4 pp 535ndash542 2003

[167] A S Lalmansingh and R M Uht ldquoEstradiol regulatescorticotropin-releasing hormone gene (crh) expression in arapid and phasic manner that parallels estrogen receptor-120572 and-120573 recruitment to a 3101584051015840-cyclic adenosine 51015840- monophosphateregulatory region of the proximal crh promoterrdquo Endocrinologyvol 149 no 1 pp 346ndash357 2008

[168] B N Roy R L Reid and D A van Vugt ldquoThe effects ofestrogen and progesterone on corticotropin-releasing hormoneand arginine vasopressin messenger ribonucleic acid levelsin the paraventricular nucleus and supraoptic nucleus of therhesus monkeyrdquo Endocrinology vol 140 no 5 pp 2191ndash21981999

[169] X Ni R C Nicholson B R King E-C Chan M A Read andR Smith ldquoEstrogen represses whereas the estrogen-antagonistICI 182780 stimulates placental CRH gene expressionrdquo Journalof Clinical Endocrinology and Metabolism vol 87 no 8 pp3774ndash3778 2002

[170] N C Vamvakopoulos and G P Chrousos ldquoEvidence of directestrogenic regulation of human corticotropin-releasing hor-mone gene expression Potential implications for the sexualdimophism of the stress response and immuneinflammatoryreactionrdquo Journal of Clinical Investigation vol 92 no 4 pp1896ndash1902 1993

[171] Y Hu D L Wu C X Luo et al ldquoHippocampal nitric oxidecontributes to sex difference in affective behaviorsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 35 pp 14224ndash14229 2012

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

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Diabetes ResearchJournal of

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Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Endocrinology 13

mouse gonadotropin-releasing hormone promoter activityrdquoEndocrinology vol 147 no 4 pp 1924ndash1931 2006

[84] T R Pak W C J Chung L R Hinds and R J HandaldquoEstrogen receptor-120573 mediates dihydrotestosterone-inducedstimulation of the arginine vasopressin promoter in neuronalcellsrdquo Endocrinology vol 148 no 7 pp 3371ndash3382 2007

[85] Y K Leung PMak S Hassan and SMHo ldquoEstrogen receptor(ER)-120573 isoforms a key to understanding ER-120573 signalingrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 103 no 35 pp 13162ndash13167 2006

[86] J M Wang X Hou S Adeosun et al ldquoA dominant negativeER120573 splice variant determines the effectiveness of early or lateestrogen therapy after ovariectomy in ratsrdquo PLoS One vol 7 no3 Article ID e33493 2012

[87] W C J Chung T R Pak S Suzuki W A Pouliot M EAndersen and R J Handa ldquoDetection and localization of anestrogen receptor beta splice variant protein (ER1205732) in theadult female rat forebrain and midbrain regionsrdquo Journal ofComparative Neurology vol 505 no 3 pp 249ndash267 2007

[88] R H Price Jr C A Butler P Webb R Uht P Kushner andR J Handa ldquoA splice variant of estrogen receptor 120573 missingexon 3 displays altered subnuclear localization and capacity fortranscriptional activationrdquo Endocrinology vol 142 no 5 pp2039ndash2049 2001

[89] Y Wang and R J Miksicek ldquoIdentification of a dominantnegative form of the human estrogen receptorrdquo MolecularEndocrinology vol 5 no 11 pp 1707ndash1715 1991

[90] E Kuppers and C Beyer ldquoExpression of estrogen receptor-120572and 120573 mRNA in the developing and adult mouse striatumrdquoNeuroscience Letters vol 276 no 2 pp 95ndash98 1999

[91] C Gundlah S G Kohama S J Mirkes V T Garyfallou H FUrbanski and C L Bethea ldquoDistribution of estrogen receptorbeta (ER120573) mRNA in hypothalamus midbrain and temporallobe of spayed macaque continued expression with hormonereplacementrdquo Brain Research Molecular Brain Research vol 76no 2 pp 191ndash204 2000

[92] Y Morishima P J M Murphy D-P Li E R Sanchez and WB Pratt ldquoStepwise assembly of a glucocorticoid receptorsdothsp90heterocomplex resolves two sequential ATP-dependent eventsinvolving first hsp70 and then hsp90 in opening of the steroidbinding pocketrdquo Journal of Biological Chemistry vol 275 no 24pp 18054ndash18060 2000

[93] K D Dittmar and W B Pratt ldquoFolding of the glucocorticoidreceptor by the reconstituted hsp90-based chaperone machin-eryThe initial hsp90sdotp60sdothsp70-dependent step is sufficient forcreating the steroid binding conformationrdquo Journal of BiologicalChemistry vol 272 no 20 pp 13047ndash13054 1997

[94] K I Kang X Meng J Devin-Leclerc et al ldquoThe molecularchaperone Hsp90 can negatively regulate the activity of aglucocorticosteroid-dependent promoterrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 4 pp 1439ndash1444 1999

[95] K Unno H Asakura Y Shibuya M Kaiho S Okada and NOku Naoto ldquoIncrease in basal level of Hsp70 consisting chieflyof constitutively expressed hsp70 (Hsc70) in aged rat brainrdquoJournals of Gerontology Series A vol 55 no 7 pp B329ndashB3352000

[96] U E Olazabal D W Pfaff and C V Mobbs ldquoSex differences inthe regulation of heat shock protein 70 kDa and 90 kDa in therat ventromedial hypothalamus by estrogenrdquo Brain Researchvol 596 no 1-2 pp 311ndash314 1992

[97] M A Pahlavani M D Harris S A Moore and A RichardsonldquoExpression of heat shock protein 70 in rat spleen lymphocytesis affected by age but not by food restrictionrdquo Journal ofNutrition vol 126 no 9 pp 2069ndash2075 1996

[98] A R Heydari B Wu R Takahashi R Strong and A Richard-son ldquoExpression of heat shock protein 70 is altered by age anddiet at the level of transcriptionrdquoMolecular andCellular Biologyvol 13 no 5 pp 2909ndash2918 1993

[99] M Sabbah K-I I Kang L Tora and G Redeuilh ldquoOestro-gen receptor facilitates the formation of preinitiation com-plex assembly involvement of the general transcription factorTFIIBrdquo Biochemical Journal vol 336 part 3 pp 639ndash646 1998

[100] S-Y Wu M C Thomas S Y Hou V Likhite and C-MChiang ldquoIsolation of mouse TFIID and functional character-ization of TBP and TFIID in mediating estrogen receptor andchromatin transcriptionrdquo Journal of Biological Chemistry vol274 no 33 pp 23480ndash23490 1999

[101] S Ghosh and M K Thakur ldquoTissue-specific expression ofreceptor-interacting protein in aging mouserdquo Age vol 30 no4 pp 237ndash243 2008

[102] J Frasor JM Danes B Komm K C N Chang C Richard Lyt-tle and B S Katzenellenbogen ldquoProfiling of estrogen up- anddown-regulated gene expression in human breast cancer cellsinsights into gene networks and pathways underlying estrogeniccontrol of proliferation and cell phenotyperdquo Endocrinology vol144 no 10 pp 4562ndash4574 2003

[103] J Frasor J M Danes C C Funk and B S Katzenellen-bogen ldquoEstrogen down-regulation of the corepressor N-CoRmechanism and implications for estrogen derepression of N-CoR-regulated genesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 102 no 37 pp13153ndash13157 2005

[104] N J McKenna and B W OrsquoMalley ldquoCombinatorial control ofgene expression by nuclear receptors and coregulatorsrdquoCell vol108 no 4 pp 465ndash474 2002

[105] T-P Yao G Ku N Zhou R Scully and D M Livingston ldquoThenuclear hormone receptor coactivator SRC-1 is a specific targetof p300rdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 93 no 20 pp 10626ndash10631 1996

[106] B Hanstein R Eckner J DiRenzo et al ldquop300 is a componentof an estrogen receptor coactivator complexrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 93 no 21 pp 11540ndash11545 1996

[107] S Halachmi E Marden G Martin H MacKay C Abbon-danza and M Brown ldquoEstrogen receptor-associated proteinspossible mediators of hormone-induced transcriptionsrdquo Sci-ence vol 264 no 5164 pp 1455ndash1458 1994

[108] A J Horlein AM Naar T Heinzel et al ldquoLigand-independentrepression by the thyroid hormone receptor mediated by anuclear receptor co-repressorrdquo Nature vol 377 no 6548 pp397ndash404 1995

[109] J D Chen and R M Evans ldquoA transcriptional co-repressor thatinteracts with nuclear hormone receptorsrdquo Nature vol 377 no6548 pp 454ndash457 1995

[110] A Malovannaya R B Lanz S Y Jung et al ldquoAnalysis of thehuman endogenous coregulator complexomerdquoCell vol 145 no5 pp 787ndash799 2011

[111] Z Nawaz D M Lonard C L Smith et al ldquoThe Angelmansyndrome-associated protein E6-AP is a coactivator for thenuclear hormone receptor superfamilyrdquoMolecular and CellularBiology vol 19 no 2 pp 1182ndash1189 1999

14 ISRN Endocrinology

[112] B Zheng M Han M Bernier and J-K Wen ldquoNuclear actinand actin-binding proteins in the regulation of transcriptionand gene expressionrdquo FEBS Journal vol 276 no 10 pp 2669ndash2685 2009

[113] W A Hofmann L Stojiljkovic B Fuchsova et al ldquoActin is partof pre-initiation complexes and is necessary for transcription byRNA polymerase IIrdquoNature Cell Biology vol 6 no 11 pp 1094ndash1101 2004

[114] K Tokunaga T Shibuya Y Ishihama et al ldquoNucleocytoplasmictransport of fluorescent mRNA in living mammalian cellsnuclear mRNA export is coupled to ongoing gene transcrip-tionrdquo Genes to Cells vol 11 no 3 pp 305ndash317 2006

[115] R Metivier G Penot M R Hubner et al ldquoEstrogen receptor-120572 directs ordered cyclical and combinatorial recruitment ofcofactors on a natural target promoterrdquo Cell vol 115 no 6 pp751ndash763 2003

[116] C Ambrosino R Tarallo A Bamundo et al ldquoIdentification of ahormone-regulated dynamic nuclear actin network associatedwith estrogen receptor 120572 in human breast cancer cell nucleirdquoMolecular and Cellular Proteomics vol 9 no 6 pp 1352ndash13672010

[117] F Shao R Zhang L Dong and K Ying ldquoOverexpression ofgelsolin-like actin-capping protein is associated with progres-sion of lung adenocarcinomardquo Tohoku Journal of ExperimentalMedicine vol 225 no 2 pp 95ndash101 2011

[118] K Nishimura H-J Ting Y Harada et al ldquoModulation ofandrogen receptor transactivation by gelsolin a newly identi-fied androgen receptor coregulatorrdquo Cancer Research vol 63no 16 pp 4888ndash4894 2003

[119] J S Ahn I S Jang D I Kim et al ldquoAging-associated increaseof gelsolin for apoptosis resistancerdquoBiochemical and BiophysicalResearch Communications vol 312 no 4 pp 1335ndash1341 2003

[120] I Nalvarte T Schwend and J-A Gustafsson ldquoProteomicsanalysis of the estrogen receptor 120572 receptosomerdquoMolecular andCellular Proteomics vol 9 no 7 pp 1411ndash1422 2010

[121] L-H Miau C-J Chang B-J Shen W-H Tsai and S-C LeeldquoIdentification of heterogeneous nuclear ribonucleoprotein K(hnRNPK) as a repressor ofCEBP120573-mediated gene activationrdquoJournal of Biological Chemistry vol 273 no 17 pp 10784ndash107911998

[122] A Ostareck-Lederer D H Ostareck C Cans et al ldquoc-Src-mediated phosphorylation of hnRNP K drives translationalactivation of specifically silenced mRNAsrdquo Molecular and Cel-lular Biology vol 22 no 13 pp 4535ndash4543 2002

[123] P S Bagga G K Arhin and J Wilusz ldquoDSEF-1 is a member ofthe hnRNP H family of RNA-binding proteins and stimulatespre-mRNAcleavage and polyadenylation in vitrordquoNucleic AcidsResearch vol 26 no 23 pp 5343ndash5350 1998

[124] V Markovtsov J M Nikolic J A Goldman C W Turck M-Y Chou and D L Black ldquoCooperative assembly of an hnRNPcomplex induced by a tissue-specific homolog of polypyrimi-dine tract binding proteinrdquoMolecular and Cellular Biology vol20 no 20 pp 7463ndash7479 2000

[125] S Y Jung A Malovannaya J Wei B W OrsquoMalley and J QinldquoProteomic analysis of steady-state nuclear hormone receptorcoactivator complexesrdquoMolecular Endocrinology vol 19 no 10pp 2451ndash2465 2005

[126] W Hong R J Resnick C Rakowski D Shalloway S J Taylorand G A Blobel ldquoPhysical and functional interaction betweenthe transcriptional cofactor CBP and the KH domain proteinSam68rdquoMolecular Cancer Research vol 1 no 1 pp 48ndash55 2002

[127] R ShaoXWang BWeijdegard et al ldquoCoordinate regulation ofheterogeneous nuclear ribonucleoprotein dynamics by steroidhormones in the human fallopian tube and endometrium invivo and in vitrordquo American Journal of Physiology vol 302 no10 pp E1269ndashE1282 2012

[128] C SWoolley and B SMcEwen ldquoEstradiolmediates fluctuationin hippocampal synapse density during the estrous cycle in theadult ratrdquo Journal of Neuroscience vol 12 no 7 pp 2549ndash25541992

[129] C S Woolley H J Wenzel and P A Schwartzkroin ldquoEstradiolincreases the frequency of multiple synapse boutons in thehippocampal CA1 region of the adult female ratrdquo The Journalof Comparative Neurology vol 373 no 1 pp 108ndash117 1996

[130] C S Woolley ldquoEstrogen-mediated structural and functionalsynaptic plasticity in the female rat hippocampusrdquo Hormonesand Behavior vol 34 no 2 pp 140ndash148 1998

[131] D P Srivastava K M Woolfrey K A Jones et al ldquoRapidenhancement of two-step wiring plasticity by estrogen andNMDA receptor activityrdquo Proceedings of the National Academyof Sciences of the United States of America vol 105 no 38 pp14650ndash14655 2008

[132] M Ogiue-Ikeda N Tanabe H Mukai et al ldquoRapid modu-lation of synaptic plasticity by estrogens as well as endocrinedisrupters in hippocampal neuronsrdquo Brain Research Reviewsvol 57 no 2 pp 363ndash375 2008

[133] N J Sandstrom and C L Williams ldquoSpatial memory retentionis enhanced by acute and continuous estradiol replacementrdquoHormones and Behavior vol 45 no 2 pp 128ndash135 2004

[134] E Hogervorst J Williams M Budge W Riedel and JJolles ldquoThe nature of the effect of female gonadal hormonereplacement therapy on cognitive function in post-menopausalwomen a meta-analysisrdquo Neuroscience vol 101 no 3 pp 485ndash512 2000

[135] M E Bailey A C J Wang J Hao et al ldquoInteractive effects ofage and estrogen on cortical neurons implications for cognitiveagingrdquo Neuroscience vol 191 pp 148ndash158 2011

[136] A A Walf M E Rhodes and C A Frye ldquoOvarian steroidsenhance object recognition in naturally cycling and ovariec-tomized hormone-primed ratsrdquo Neurobiology of Learning andMemory vol 86 no 1 pp 35ndash46 2006

[137] V N Luine L F Jacome and N J Maclusky ldquoRapid enhance-ment of visual and place memory by estrogens in ratsrdquoEndocrinology vol 144 no 7 pp 2836ndash2844 2003

[138] L Fan Z Zhao P T Orr C H Chambers M C Lewis and KM Frick ldquoEstradiol-induced object memory consolidation inmiddle-aged femalemice requires dorsal hippocampal extracel-lular signal-regulated kinase and phosphatidylinositol 3-kinaseactivationrdquo Journal of Neuroscience vol 30 no 12 pp 4390ndash4400 2010

[139] D B Dubal and PMWise ldquoNeuroprotective effects of estradiolin middle-aged female ratsrdquo Endocrinology vol 142 no 1 pp43ndash48 2001

[140] S-H Yang J Shi A L Day and J W Simpkins ldquoEstradiolexerts neuroprotective effects when administered after ischemicinsultrdquo Stroke vol 31 no 3 pp 745ndash750 2000

[141] J W Simpkins G Rajakumar Y-Q Zhang et al ldquoEstrogensmay reduce mortality and ischemic damage caused by middlecerebral artery occlusion in the female ratrdquo Journal of Neuro-surgery vol 87 no 5 pp 724ndash730 1997

[142] J Shi K S Panickar S-H Yang O Rabbani A L Day and JWSimpkins ldquoEstrogen attenuates over-expression of 120573-amyloid

ISRN Endocrinology 15

precursor protein messager RNA in an animal model of focalischemiardquo Brain Research vol 810 no 1-2 pp 87ndash92 1998

[143] Q-H Zhang Y-H Huang Y-Z Hu et al ldquoDisruption ofestrogen receptor beta in mice brain results in pathologicalalterations resemblingAlzheimer diseaserdquoActa PharmacologicaSinica vol 25 no 4 pp 452ndash457 2004

[144] E F Rissman A L Heck J E Leonard M A Shupnik and J-A Gustafsson ldquoDisruption of estrogen receptor 120573 gene impairsspatial learning in female micerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no6 pp 3996ndash4001 2002

[145] M Day A Sung S Logue M Bowlby and R Arias ldquoBetaestrogen receptor knockout (BERKO) mice present attenuatedhippocampal CA1 long-term potentiation and related memorydeficits in contextual fear conditioningrdquo Behavioural BrainResearch vol 164 no 1 pp 128ndash131 2005

[146] R Vierk G Glassmeier L Zhou et al ldquoAromatase inhibitionabolishes LTP generation in female but not in male micerdquo TheJournal of Neuroscience vol 32 no 24 pp 8116ndash8126 2012

[147] R-M Vouimba M R Foy J G Foy and R FThompson ldquo17120573-estradiol suppresses expression of long-term depression in agedratsrdquo Brain Research Bulletin vol 53 no 6 pp 783ndash787 2000

[148] C E Andreescu B A Milojkovic E D Haasdijk et alldquoEstradiol improves cerebellar memory formation by activatingestrogen receptor 120573rdquo Journal of Neuroscience vol 27 no 40 pp10832ndash10839 2007

[149] Y-Y Huang P V Nguyen T Abel and E R Kandel ldquoLong-lasting forms of synaptic potentiation in the mammalian hip-pocampusrdquo Learning Memory vol 3 no 2-3 pp 74ndash85 1996

[150] H Mukai T Tsurugizawa G Murakami et al ldquoRapid mod-ulation of long-term depression and spinogenesis via synapticestrogen receptors in hippocampal principal neuronsrdquo Journalof Neurochemistry vol 100 no 4 pp 950ndash967 2007

[151] L Liu T P Wong M F Pozza et al ldquoRole of NMDA receptorsubtypes in governing the direction of hippocampal synapticplasticityrdquo Science vol 304 no 5673 pp 1021ndash1024 2004

[152] M Cyr O Ghribi C Thibault M Morissette M Landry andT di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[153] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[154] C C Smith and L L McMahon ldquoEstradiol-induced increasein the magnitude of long-term potentiation is prevented byblocking NR2B-containing receptorsrdquo Journal of Neurosciencevol 26 no 33 pp 8517ndash8522 2006

[155] Y Zhou J J Watters and D M Dorsa ldquoEstrogen rapidlyinduces the phosphorylation of the cAMP response elementbinding protein in rat brainrdquo Endocrinology vol 137 no 5 pp2163ndash2166 1996

[156] XGonda T TelekG Juhasz J Lazary AVargha andG BagdyldquoPatterns of mood changes throughout the reproductive cyclein healthy women without premenstrual dysphoric disordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 32 no 8 pp 1782ndash1788 2008

[157] E W Freeman ldquoPremenstrual syndrome and premenstrualdysphoric disorder definitions and diagnosisrdquo Psychoneuroen-docrinology vol 28 supplement 3 pp 25ndash37 2003

[158] T D Lund T Rovis W C J Chung and R J Handa ldquoNovelactions of estrogen receptor-120573 on anxiety-related behaviorsrdquoEndocrinology vol 146 no 2 pp 797ndash807 2005

[159] N Breslau L Schultz and E Peterson ldquoSex differences indepression a role for preexisting anxietyrdquo Psychiatry Researchvol 58 no 1 pp 1ndash12 1995

[160] P E Bebbington G Dunn R Jenkins et al ldquoThe influenceof age and sex on the prevalence of depressive conditionsreport from the National Survey of Psychiatric MorbidityrdquoPsychological Medicine vol 28 no 1 pp 9ndash19 1998

[161] G Aguilera J P Harwood and J X Wilson ldquoMechanisms ofaction of corticotropin-releasing factor and other regulators ofcorticotropin release in rat pituitary cellsrdquo Journal of BiologicalChemistry vol 258 no 13 pp 8039ndash8045 1983

[162] A Papadimitriou and K N Priftis ldquoRegulation of thehypothalamic-pituitary-adrenal axisrdquo NeuroImmunoModula-tion vol 16 no 5 pp 265ndash271 2009

[163] S Suzuki and R J Handa ldquoRegulation of estrogen receptor-120573expression in the female rat hypothalamus differential effectsof dexamethasone and estradiolrdquo Endocrinology vol 145 no 8pp 3658ndash3670 2004

[164] W J S Miller S Suzuki L K Miller R Handa and R M UhtldquoEstrogen receptor (ER)120573 isoforms rather than ER120572 regulatecorticotropin-releasing hormone promoter activity through analternate pathwayrdquo Journal of Neuroscience vol 24 no 47 pp10628ndash10635 2004

[165] C IsgorM CecchiM Kabbaj H Akil and S JWatson ldquoEstro-gen receptor 120573 in the paraventricular nucleus of hypothalamusregulates the neuroendocrine response to stress and is regulatedby corticosteronerdquo Neuroscience vol 121 no 4 pp 837ndash8452003

[166] M L Forsling I Kallo D E Hartley et al ldquoOestrogen receptor-120573 and neurohypophysial hormones functional interaction andneuroanatomical localisationrdquo Pharmacology Biochemistry andBehavior vol 76 no 3-4 pp 535ndash542 2003

[167] A S Lalmansingh and R M Uht ldquoEstradiol regulatescorticotropin-releasing hormone gene (crh) expression in arapid and phasic manner that parallels estrogen receptor-120572 and-120573 recruitment to a 3101584051015840-cyclic adenosine 51015840- monophosphateregulatory region of the proximal crh promoterrdquo Endocrinologyvol 149 no 1 pp 346ndash357 2008

[168] B N Roy R L Reid and D A van Vugt ldquoThe effects ofestrogen and progesterone on corticotropin-releasing hormoneand arginine vasopressin messenger ribonucleic acid levelsin the paraventricular nucleus and supraoptic nucleus of therhesus monkeyrdquo Endocrinology vol 140 no 5 pp 2191ndash21981999

[169] X Ni R C Nicholson B R King E-C Chan M A Read andR Smith ldquoEstrogen represses whereas the estrogen-antagonistICI 182780 stimulates placental CRH gene expressionrdquo Journalof Clinical Endocrinology and Metabolism vol 87 no 8 pp3774ndash3778 2002

[170] N C Vamvakopoulos and G P Chrousos ldquoEvidence of directestrogenic regulation of human corticotropin-releasing hor-mone gene expression Potential implications for the sexualdimophism of the stress response and immuneinflammatoryreactionrdquo Journal of Clinical Investigation vol 92 no 4 pp1896ndash1902 1993

[171] Y Hu D L Wu C X Luo et al ldquoHippocampal nitric oxidecontributes to sex difference in affective behaviorsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 35 pp 14224ndash14229 2012

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

14 ISRN Endocrinology

[112] B Zheng M Han M Bernier and J-K Wen ldquoNuclear actinand actin-binding proteins in the regulation of transcriptionand gene expressionrdquo FEBS Journal vol 276 no 10 pp 2669ndash2685 2009

[113] W A Hofmann L Stojiljkovic B Fuchsova et al ldquoActin is partof pre-initiation complexes and is necessary for transcription byRNA polymerase IIrdquoNature Cell Biology vol 6 no 11 pp 1094ndash1101 2004

[114] K Tokunaga T Shibuya Y Ishihama et al ldquoNucleocytoplasmictransport of fluorescent mRNA in living mammalian cellsnuclear mRNA export is coupled to ongoing gene transcrip-tionrdquo Genes to Cells vol 11 no 3 pp 305ndash317 2006

[115] R Metivier G Penot M R Hubner et al ldquoEstrogen receptor-120572 directs ordered cyclical and combinatorial recruitment ofcofactors on a natural target promoterrdquo Cell vol 115 no 6 pp751ndash763 2003

[116] C Ambrosino R Tarallo A Bamundo et al ldquoIdentification of ahormone-regulated dynamic nuclear actin network associatedwith estrogen receptor 120572 in human breast cancer cell nucleirdquoMolecular and Cellular Proteomics vol 9 no 6 pp 1352ndash13672010

[117] F Shao R Zhang L Dong and K Ying ldquoOverexpression ofgelsolin-like actin-capping protein is associated with progres-sion of lung adenocarcinomardquo Tohoku Journal of ExperimentalMedicine vol 225 no 2 pp 95ndash101 2011

[118] K Nishimura H-J Ting Y Harada et al ldquoModulation ofandrogen receptor transactivation by gelsolin a newly identi-fied androgen receptor coregulatorrdquo Cancer Research vol 63no 16 pp 4888ndash4894 2003

[119] J S Ahn I S Jang D I Kim et al ldquoAging-associated increaseof gelsolin for apoptosis resistancerdquoBiochemical and BiophysicalResearch Communications vol 312 no 4 pp 1335ndash1341 2003

[120] I Nalvarte T Schwend and J-A Gustafsson ldquoProteomicsanalysis of the estrogen receptor 120572 receptosomerdquoMolecular andCellular Proteomics vol 9 no 7 pp 1411ndash1422 2010

[121] L-H Miau C-J Chang B-J Shen W-H Tsai and S-C LeeldquoIdentification of heterogeneous nuclear ribonucleoprotein K(hnRNPK) as a repressor ofCEBP120573-mediated gene activationrdquoJournal of Biological Chemistry vol 273 no 17 pp 10784ndash107911998

[122] A Ostareck-Lederer D H Ostareck C Cans et al ldquoc-Src-mediated phosphorylation of hnRNP K drives translationalactivation of specifically silenced mRNAsrdquo Molecular and Cel-lular Biology vol 22 no 13 pp 4535ndash4543 2002

[123] P S Bagga G K Arhin and J Wilusz ldquoDSEF-1 is a member ofthe hnRNP H family of RNA-binding proteins and stimulatespre-mRNAcleavage and polyadenylation in vitrordquoNucleic AcidsResearch vol 26 no 23 pp 5343ndash5350 1998

[124] V Markovtsov J M Nikolic J A Goldman C W Turck M-Y Chou and D L Black ldquoCooperative assembly of an hnRNPcomplex induced by a tissue-specific homolog of polypyrimi-dine tract binding proteinrdquoMolecular and Cellular Biology vol20 no 20 pp 7463ndash7479 2000

[125] S Y Jung A Malovannaya J Wei B W OrsquoMalley and J QinldquoProteomic analysis of steady-state nuclear hormone receptorcoactivator complexesrdquoMolecular Endocrinology vol 19 no 10pp 2451ndash2465 2005

[126] W Hong R J Resnick C Rakowski D Shalloway S J Taylorand G A Blobel ldquoPhysical and functional interaction betweenthe transcriptional cofactor CBP and the KH domain proteinSam68rdquoMolecular Cancer Research vol 1 no 1 pp 48ndash55 2002

[127] R ShaoXWang BWeijdegard et al ldquoCoordinate regulation ofheterogeneous nuclear ribonucleoprotein dynamics by steroidhormones in the human fallopian tube and endometrium invivo and in vitrordquo American Journal of Physiology vol 302 no10 pp E1269ndashE1282 2012

[128] C SWoolley and B SMcEwen ldquoEstradiolmediates fluctuationin hippocampal synapse density during the estrous cycle in theadult ratrdquo Journal of Neuroscience vol 12 no 7 pp 2549ndash25541992

[129] C S Woolley H J Wenzel and P A Schwartzkroin ldquoEstradiolincreases the frequency of multiple synapse boutons in thehippocampal CA1 region of the adult female ratrdquo The Journalof Comparative Neurology vol 373 no 1 pp 108ndash117 1996

[130] C S Woolley ldquoEstrogen-mediated structural and functionalsynaptic plasticity in the female rat hippocampusrdquo Hormonesand Behavior vol 34 no 2 pp 140ndash148 1998

[131] D P Srivastava K M Woolfrey K A Jones et al ldquoRapidenhancement of two-step wiring plasticity by estrogen andNMDA receptor activityrdquo Proceedings of the National Academyof Sciences of the United States of America vol 105 no 38 pp14650ndash14655 2008

[132] M Ogiue-Ikeda N Tanabe H Mukai et al ldquoRapid modu-lation of synaptic plasticity by estrogens as well as endocrinedisrupters in hippocampal neuronsrdquo Brain Research Reviewsvol 57 no 2 pp 363ndash375 2008

[133] N J Sandstrom and C L Williams ldquoSpatial memory retentionis enhanced by acute and continuous estradiol replacementrdquoHormones and Behavior vol 45 no 2 pp 128ndash135 2004

[134] E Hogervorst J Williams M Budge W Riedel and JJolles ldquoThe nature of the effect of female gonadal hormonereplacement therapy on cognitive function in post-menopausalwomen a meta-analysisrdquo Neuroscience vol 101 no 3 pp 485ndash512 2000

[135] M E Bailey A C J Wang J Hao et al ldquoInteractive effects ofage and estrogen on cortical neurons implications for cognitiveagingrdquo Neuroscience vol 191 pp 148ndash158 2011

[136] A A Walf M E Rhodes and C A Frye ldquoOvarian steroidsenhance object recognition in naturally cycling and ovariec-tomized hormone-primed ratsrdquo Neurobiology of Learning andMemory vol 86 no 1 pp 35ndash46 2006

[137] V N Luine L F Jacome and N J Maclusky ldquoRapid enhance-ment of visual and place memory by estrogens in ratsrdquoEndocrinology vol 144 no 7 pp 2836ndash2844 2003

[138] L Fan Z Zhao P T Orr C H Chambers M C Lewis and KM Frick ldquoEstradiol-induced object memory consolidation inmiddle-aged femalemice requires dorsal hippocampal extracel-lular signal-regulated kinase and phosphatidylinositol 3-kinaseactivationrdquo Journal of Neuroscience vol 30 no 12 pp 4390ndash4400 2010

[139] D B Dubal and PMWise ldquoNeuroprotective effects of estradiolin middle-aged female ratsrdquo Endocrinology vol 142 no 1 pp43ndash48 2001

[140] S-H Yang J Shi A L Day and J W Simpkins ldquoEstradiolexerts neuroprotective effects when administered after ischemicinsultrdquo Stroke vol 31 no 3 pp 745ndash750 2000

[141] J W Simpkins G Rajakumar Y-Q Zhang et al ldquoEstrogensmay reduce mortality and ischemic damage caused by middlecerebral artery occlusion in the female ratrdquo Journal of Neuro-surgery vol 87 no 5 pp 724ndash730 1997

[142] J Shi K S Panickar S-H Yang O Rabbani A L Day and JWSimpkins ldquoEstrogen attenuates over-expression of 120573-amyloid

ISRN Endocrinology 15

precursor protein messager RNA in an animal model of focalischemiardquo Brain Research vol 810 no 1-2 pp 87ndash92 1998

[143] Q-H Zhang Y-H Huang Y-Z Hu et al ldquoDisruption ofestrogen receptor beta in mice brain results in pathologicalalterations resemblingAlzheimer diseaserdquoActa PharmacologicaSinica vol 25 no 4 pp 452ndash457 2004

[144] E F Rissman A L Heck J E Leonard M A Shupnik and J-A Gustafsson ldquoDisruption of estrogen receptor 120573 gene impairsspatial learning in female micerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no6 pp 3996ndash4001 2002

[145] M Day A Sung S Logue M Bowlby and R Arias ldquoBetaestrogen receptor knockout (BERKO) mice present attenuatedhippocampal CA1 long-term potentiation and related memorydeficits in contextual fear conditioningrdquo Behavioural BrainResearch vol 164 no 1 pp 128ndash131 2005

[146] R Vierk G Glassmeier L Zhou et al ldquoAromatase inhibitionabolishes LTP generation in female but not in male micerdquo TheJournal of Neuroscience vol 32 no 24 pp 8116ndash8126 2012

[147] R-M Vouimba M R Foy J G Foy and R FThompson ldquo17120573-estradiol suppresses expression of long-term depression in agedratsrdquo Brain Research Bulletin vol 53 no 6 pp 783ndash787 2000

[148] C E Andreescu B A Milojkovic E D Haasdijk et alldquoEstradiol improves cerebellar memory formation by activatingestrogen receptor 120573rdquo Journal of Neuroscience vol 27 no 40 pp10832ndash10839 2007

[149] Y-Y Huang P V Nguyen T Abel and E R Kandel ldquoLong-lasting forms of synaptic potentiation in the mammalian hip-pocampusrdquo Learning Memory vol 3 no 2-3 pp 74ndash85 1996

[150] H Mukai T Tsurugizawa G Murakami et al ldquoRapid mod-ulation of long-term depression and spinogenesis via synapticestrogen receptors in hippocampal principal neuronsrdquo Journalof Neurochemistry vol 100 no 4 pp 950ndash967 2007

[151] L Liu T P Wong M F Pozza et al ldquoRole of NMDA receptorsubtypes in governing the direction of hippocampal synapticplasticityrdquo Science vol 304 no 5673 pp 1021ndash1024 2004

[152] M Cyr O Ghribi C Thibault M Morissette M Landry andT di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[153] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[154] C C Smith and L L McMahon ldquoEstradiol-induced increasein the magnitude of long-term potentiation is prevented byblocking NR2B-containing receptorsrdquo Journal of Neurosciencevol 26 no 33 pp 8517ndash8522 2006

[155] Y Zhou J J Watters and D M Dorsa ldquoEstrogen rapidlyinduces the phosphorylation of the cAMP response elementbinding protein in rat brainrdquo Endocrinology vol 137 no 5 pp2163ndash2166 1996

[156] XGonda T TelekG Juhasz J Lazary AVargha andG BagdyldquoPatterns of mood changes throughout the reproductive cyclein healthy women without premenstrual dysphoric disordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 32 no 8 pp 1782ndash1788 2008

[157] E W Freeman ldquoPremenstrual syndrome and premenstrualdysphoric disorder definitions and diagnosisrdquo Psychoneuroen-docrinology vol 28 supplement 3 pp 25ndash37 2003

[158] T D Lund T Rovis W C J Chung and R J Handa ldquoNovelactions of estrogen receptor-120573 on anxiety-related behaviorsrdquoEndocrinology vol 146 no 2 pp 797ndash807 2005

[159] N Breslau L Schultz and E Peterson ldquoSex differences indepression a role for preexisting anxietyrdquo Psychiatry Researchvol 58 no 1 pp 1ndash12 1995

[160] P E Bebbington G Dunn R Jenkins et al ldquoThe influenceof age and sex on the prevalence of depressive conditionsreport from the National Survey of Psychiatric MorbidityrdquoPsychological Medicine vol 28 no 1 pp 9ndash19 1998

[161] G Aguilera J P Harwood and J X Wilson ldquoMechanisms ofaction of corticotropin-releasing factor and other regulators ofcorticotropin release in rat pituitary cellsrdquo Journal of BiologicalChemistry vol 258 no 13 pp 8039ndash8045 1983

[162] A Papadimitriou and K N Priftis ldquoRegulation of thehypothalamic-pituitary-adrenal axisrdquo NeuroImmunoModula-tion vol 16 no 5 pp 265ndash271 2009

[163] S Suzuki and R J Handa ldquoRegulation of estrogen receptor-120573expression in the female rat hypothalamus differential effectsof dexamethasone and estradiolrdquo Endocrinology vol 145 no 8pp 3658ndash3670 2004

[164] W J S Miller S Suzuki L K Miller R Handa and R M UhtldquoEstrogen receptor (ER)120573 isoforms rather than ER120572 regulatecorticotropin-releasing hormone promoter activity through analternate pathwayrdquo Journal of Neuroscience vol 24 no 47 pp10628ndash10635 2004

[165] C IsgorM CecchiM Kabbaj H Akil and S JWatson ldquoEstro-gen receptor 120573 in the paraventricular nucleus of hypothalamusregulates the neuroendocrine response to stress and is regulatedby corticosteronerdquo Neuroscience vol 121 no 4 pp 837ndash8452003

[166] M L Forsling I Kallo D E Hartley et al ldquoOestrogen receptor-120573 and neurohypophysial hormones functional interaction andneuroanatomical localisationrdquo Pharmacology Biochemistry andBehavior vol 76 no 3-4 pp 535ndash542 2003

[167] A S Lalmansingh and R M Uht ldquoEstradiol regulatescorticotropin-releasing hormone gene (crh) expression in arapid and phasic manner that parallels estrogen receptor-120572 and-120573 recruitment to a 3101584051015840-cyclic adenosine 51015840- monophosphateregulatory region of the proximal crh promoterrdquo Endocrinologyvol 149 no 1 pp 346ndash357 2008

[168] B N Roy R L Reid and D A van Vugt ldquoThe effects ofestrogen and progesterone on corticotropin-releasing hormoneand arginine vasopressin messenger ribonucleic acid levelsin the paraventricular nucleus and supraoptic nucleus of therhesus monkeyrdquo Endocrinology vol 140 no 5 pp 2191ndash21981999

[169] X Ni R C Nicholson B R King E-C Chan M A Read andR Smith ldquoEstrogen represses whereas the estrogen-antagonistICI 182780 stimulates placental CRH gene expressionrdquo Journalof Clinical Endocrinology and Metabolism vol 87 no 8 pp3774ndash3778 2002

[170] N C Vamvakopoulos and G P Chrousos ldquoEvidence of directestrogenic regulation of human corticotropin-releasing hor-mone gene expression Potential implications for the sexualdimophism of the stress response and immuneinflammatoryreactionrdquo Journal of Clinical Investigation vol 92 no 4 pp1896ndash1902 1993

[171] Y Hu D L Wu C X Luo et al ldquoHippocampal nitric oxidecontributes to sex difference in affective behaviorsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 35 pp 14224ndash14229 2012

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Endocrinology 15

precursor protein messager RNA in an animal model of focalischemiardquo Brain Research vol 810 no 1-2 pp 87ndash92 1998

[143] Q-H Zhang Y-H Huang Y-Z Hu et al ldquoDisruption ofestrogen receptor beta in mice brain results in pathologicalalterations resemblingAlzheimer diseaserdquoActa PharmacologicaSinica vol 25 no 4 pp 452ndash457 2004

[144] E F Rissman A L Heck J E Leonard M A Shupnik and J-A Gustafsson ldquoDisruption of estrogen receptor 120573 gene impairsspatial learning in female micerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 99 no6 pp 3996ndash4001 2002

[145] M Day A Sung S Logue M Bowlby and R Arias ldquoBetaestrogen receptor knockout (BERKO) mice present attenuatedhippocampal CA1 long-term potentiation and related memorydeficits in contextual fear conditioningrdquo Behavioural BrainResearch vol 164 no 1 pp 128ndash131 2005

[146] R Vierk G Glassmeier L Zhou et al ldquoAromatase inhibitionabolishes LTP generation in female but not in male micerdquo TheJournal of Neuroscience vol 32 no 24 pp 8116ndash8126 2012

[147] R-M Vouimba M R Foy J G Foy and R FThompson ldquo17120573-estradiol suppresses expression of long-term depression in agedratsrdquo Brain Research Bulletin vol 53 no 6 pp 783ndash787 2000

[148] C E Andreescu B A Milojkovic E D Haasdijk et alldquoEstradiol improves cerebellar memory formation by activatingestrogen receptor 120573rdquo Journal of Neuroscience vol 27 no 40 pp10832ndash10839 2007

[149] Y-Y Huang P V Nguyen T Abel and E R Kandel ldquoLong-lasting forms of synaptic potentiation in the mammalian hip-pocampusrdquo Learning Memory vol 3 no 2-3 pp 74ndash85 1996

[150] H Mukai T Tsurugizawa G Murakami et al ldquoRapid mod-ulation of long-term depression and spinogenesis via synapticestrogen receptors in hippocampal principal neuronsrdquo Journalof Neurochemistry vol 100 no 4 pp 950ndash967 2007

[151] L Liu T P Wong M F Pozza et al ldquoRole of NMDA receptorsubtypes in governing the direction of hippocampal synapticplasticityrdquo Science vol 304 no 5673 pp 1021ndash1024 2004

[152] M Cyr O Ghribi C Thibault M Morissette M Landry andT di Paolo ldquoOvarian steroids and selective estrogen receptormodulators activity on rat brain NMDA and AMPA receptorsrdquoBrain Research Reviews vol 37 no 1ndash3 pp 153ndash161 2001

[153] MM Adams S E FinkW GM Janssen R A Shah and J HMorrison ldquoEstrogenmodulates synapticN-methyl-D-aspartatereceptor subunit distribution in the aged hippocampusrdquo Journalof Comparative Neurology vol 474 no 3 pp 419ndash426 2004

[154] C C Smith and L L McMahon ldquoEstradiol-induced increasein the magnitude of long-term potentiation is prevented byblocking NR2B-containing receptorsrdquo Journal of Neurosciencevol 26 no 33 pp 8517ndash8522 2006

[155] Y Zhou J J Watters and D M Dorsa ldquoEstrogen rapidlyinduces the phosphorylation of the cAMP response elementbinding protein in rat brainrdquo Endocrinology vol 137 no 5 pp2163ndash2166 1996

[156] XGonda T TelekG Juhasz J Lazary AVargha andG BagdyldquoPatterns of mood changes throughout the reproductive cyclein healthy women without premenstrual dysphoric disordersrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 32 no 8 pp 1782ndash1788 2008

[157] E W Freeman ldquoPremenstrual syndrome and premenstrualdysphoric disorder definitions and diagnosisrdquo Psychoneuroen-docrinology vol 28 supplement 3 pp 25ndash37 2003

[158] T D Lund T Rovis W C J Chung and R J Handa ldquoNovelactions of estrogen receptor-120573 on anxiety-related behaviorsrdquoEndocrinology vol 146 no 2 pp 797ndash807 2005

[159] N Breslau L Schultz and E Peterson ldquoSex differences indepression a role for preexisting anxietyrdquo Psychiatry Researchvol 58 no 1 pp 1ndash12 1995

[160] P E Bebbington G Dunn R Jenkins et al ldquoThe influenceof age and sex on the prevalence of depressive conditionsreport from the National Survey of Psychiatric MorbidityrdquoPsychological Medicine vol 28 no 1 pp 9ndash19 1998

[161] G Aguilera J P Harwood and J X Wilson ldquoMechanisms ofaction of corticotropin-releasing factor and other regulators ofcorticotropin release in rat pituitary cellsrdquo Journal of BiologicalChemistry vol 258 no 13 pp 8039ndash8045 1983

[162] A Papadimitriou and K N Priftis ldquoRegulation of thehypothalamic-pituitary-adrenal axisrdquo NeuroImmunoModula-tion vol 16 no 5 pp 265ndash271 2009

[163] S Suzuki and R J Handa ldquoRegulation of estrogen receptor-120573expression in the female rat hypothalamus differential effectsof dexamethasone and estradiolrdquo Endocrinology vol 145 no 8pp 3658ndash3670 2004

[164] W J S Miller S Suzuki L K Miller R Handa and R M UhtldquoEstrogen receptor (ER)120573 isoforms rather than ER120572 regulatecorticotropin-releasing hormone promoter activity through analternate pathwayrdquo Journal of Neuroscience vol 24 no 47 pp10628ndash10635 2004

[165] C IsgorM CecchiM Kabbaj H Akil and S JWatson ldquoEstro-gen receptor 120573 in the paraventricular nucleus of hypothalamusregulates the neuroendocrine response to stress and is regulatedby corticosteronerdquo Neuroscience vol 121 no 4 pp 837ndash8452003

[166] M L Forsling I Kallo D E Hartley et al ldquoOestrogen receptor-120573 and neurohypophysial hormones functional interaction andneuroanatomical localisationrdquo Pharmacology Biochemistry andBehavior vol 76 no 3-4 pp 535ndash542 2003

[167] A S Lalmansingh and R M Uht ldquoEstradiol regulatescorticotropin-releasing hormone gene (crh) expression in arapid and phasic manner that parallels estrogen receptor-120572 and-120573 recruitment to a 3101584051015840-cyclic adenosine 51015840- monophosphateregulatory region of the proximal crh promoterrdquo Endocrinologyvol 149 no 1 pp 346ndash357 2008

[168] B N Roy R L Reid and D A van Vugt ldquoThe effects ofestrogen and progesterone on corticotropin-releasing hormoneand arginine vasopressin messenger ribonucleic acid levelsin the paraventricular nucleus and supraoptic nucleus of therhesus monkeyrdquo Endocrinology vol 140 no 5 pp 2191ndash21981999

[169] X Ni R C Nicholson B R King E-C Chan M A Read andR Smith ldquoEstrogen represses whereas the estrogen-antagonistICI 182780 stimulates placental CRH gene expressionrdquo Journalof Clinical Endocrinology and Metabolism vol 87 no 8 pp3774ndash3778 2002

[170] N C Vamvakopoulos and G P Chrousos ldquoEvidence of directestrogenic regulation of human corticotropin-releasing hor-mone gene expression Potential implications for the sexualdimophism of the stress response and immuneinflammatoryreactionrdquo Journal of Clinical Investigation vol 92 no 4 pp1896ndash1902 1993

[171] Y Hu D L Wu C X Luo et al ldquoHippocampal nitric oxidecontributes to sex difference in affective behaviorsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 109 no 35 pp 14224ndash14229 2012

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

16 ISRN Endocrinology

[172] B E H Sumner and G Fink ldquoEstrogen increases the densityof 5-hydroxytryptamine(2A) receptors in cerebral cortex andnucleus accumbens in the female ratrdquo Journal of Steroid Bio-chemistry andMolecular Biology vol 54 no 1-2 pp 15ndash20 1995

[173] L J Smith J A Henderson C W Abell and C L BethealdquoEffects of ovarian steroids and raloxifene on proteins thatsynthesize transport and degrade serotonin in the raphe regionof macaquesrdquo Neuropsychopharmacology vol 29 no 11 pp2035ndash2045 2004

[174] D B Imwalle J-A Gustafsson and E F Rissman ldquoLack offunctional estrogen receptor 120573 influences anxiety behavior andserotonin content in female micerdquo Physiology and Behavior vol84 no 1 pp 157ndash163 2005

[175] K Tomihara T Soga M Nomura et al ldquoEffect of ER-120573 genedisruption on estrogenic regulation of anxiety in female micerdquoPhysiology and Behavior vol 96 no 2 pp 300ndash306 2009

[176] A A Walf C Koonce K Manley and C A Frye ldquoProestrouscompared to diestrous wildtype but not estrogen receptor betaknockout mice have better performance in the spontaneousalternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus andmirrormazerdquo BehaviouralBrain Research vol 196 no 2 pp 254ndash260 2009

[177] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile administration towild type but not estrogenreceptor beta knockout mice enhances performance in theobject recognition and object placement tasksrdquo Neurobiology ofLearning and Memory vol 89 no 4 pp 513ndash521 2008

[178] A A Walf C J Koonce and C A Frye ldquoEstradiol ordiarylpropionitrile decrease anxiety-like behavior of wildtypebut not estrogen receptor beta knockout micerdquo BehavioralNeuroscience vol 122 no 5 pp 974ndash981 2008

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom