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GlucocorticoidsSynthesis | Receptor | Effects
GlucocorticoidsSynthesis | Receptor | Effects
Arun ViswanathanIInd Sem, M.Sc.BMB
Adrenal Glands• The paired one of which lies superior to each kidney in the
retroperitoneal space• flattened pyramidal shape.• In an adult, each adrenal gland is 3–5 cm in height, 2–3 cm in
width, and a little less than 1 cm• thick, with a mass of 3.5–5 g, only half its size at birth.• differentiate into two structurally and functionally distinct
regions: a large, peripherally located adrenal cortex (80–90%of the gland) & a small, centrally located adrenal medulla
• Complete loss of adrenocortical hormones leads to deathdue to dehydration and electrolyte imbalances in a few days.
• The adrenal medulla produces three catecholaminehormones—norepinephrine, epinephrine, and a smallamount of dopamine.
• The paired one of which lies superior to each kidney in theretroperitoneal space
• flattened pyramidal shape.• In an adult, each adrenal gland is 3–5 cm in height, 2–3 cm in
width, and a little less than 1 cm• thick, with a mass of 3.5–5 g, only half its size at birth.• differentiate into two structurally and functionally distinct
regions: a large, peripherally located adrenal cortex (80–90%of the gland) & a small, centrally located adrenal medulla
• Complete loss of adrenocortical hormones leads to deathdue to dehydration and electrolyte imbalances in a few days.
• The adrenal medulla produces three catecholaminehormones—norepinephrine, epinephrine, and a smallamount of dopamine.
Adrenal Glands
Tortora.J.Gerard, Derrickson.B, ‘Principles of Anatomy and Physiology’(13th Edition), John Wiley & sons, Inc.,
Adrenal Cortex
• subdivided into 3 zones, each of which secretes different hormones• The outer zone - zona glomerulosa• Its cells, which are closely packed and arranged in spherical clusters
and arched columns, secrete hormones called mineralocorticoids• The middle zone - zona fasciculata is the widest of the three zones
and consists of cells arranged in long, straight columns.• secrete mainly glucocorticoids primarily cortisol• The cells of the inner zone - zona reticularis are arranged in
branching cords.• They synthesize small amounts of weak androgens steroid
hormones that have masculinizing effects.
• subdivided into 3 zones, each of which secretes different hormones• The outer zone - zona glomerulosa• Its cells, which are closely packed and arranged in spherical clusters
and arched columns, secrete hormones called mineralocorticoids• The middle zone - zona fasciculata is the widest of the three zones
and consists of cells arranged in long, straight columns.• secrete mainly glucocorticoids primarily cortisol• The cells of the inner zone - zona reticularis are arranged in
branching cords.• They synthesize small amounts of weak androgens steroid
hormones that have masculinizing effects.
Tortora.J.Gerard, Derrickson.B, ‘Principles of Anatomy and Physiology’(13th Edition), John Wiley & sons, Inc.,
Photomicrograph of the adrenal cortex (H&E stain). A: A low-power general view. I,the glomerulosa; II, the fasciculata; III, the reticularis. B: Electron micrograph of anormal adrenocortical steroid-producing cell (M, large mitochondria with tubularcristae; SER, smooth endoplasmic reticulum; L, lipid vacuole).
Aron.C.D, Findling J.W, & Blake T.J,Edited by Garner.G.D. ‘Greenspan’s Basic & Clinical Endocrinology,(8th Edition) ALANGE medicalBook, The McGraw-Hill Companies, Inc.
Adrenal Steroidogenesis• Cholesterol is the precursor for adrenal
steroidogenesis.• LDL Cholestrol is taken specific cell-surface LDL
receptors mediated Endocytosis• the resulting vesicles fuse with lysozymes, & free
cholesterol is produced after hydrolysis.• Cholesterol can be generated de novo within the
adrenal cortex from acetyl coenzyme A (CoA).• adrenal can utilize HDL cholesterol after uptake
through the putative HDL receptor, SR-B1
• Cholesterol is the precursor for adrenalsteroidogenesis.
• LDL Cholestrol is taken specific cell-surface LDLreceptors mediated Endocytosis
• the resulting vesicles fuse with lysozymes, & freecholesterol is produced after hydrolysis.
• Cholesterol can be generated de novo within theadrenal cortex from acetyl coenzyme A (CoA).
• adrenal can utilize HDL cholesterol after uptakethrough the putative HDL receptor, SR-B1
Adrenal Steroidogenesis
• the transport of intracellular cholesterol fromthe outer to inner mt membrane forconversion to pregnenolone by cyt P450 side-chain cleavage enzyme (P450scc) is mediatedby steroidogenic acute regulatory protein(StAR)
• the transport of intracellular cholesterol fromthe outer to inner mt membrane forconversion to pregnenolone by cyt P450 side-chain cleavage enzyme (P450scc) is mediatedby steroidogenic acute regulatory protein(StAR)
Melmed.S.,Polonsky.S.K,Larsen.P.R.,Kronenberg.H.M.‘Williams Textbook ofEndocrinology’(12th
Edition), ElsevirSaunders 2011
Aron.C.D, Findling J.W, & Blake T.J,Editedby Garner.G.D. ‘Greenspan’s Basic &Clinical Endocrinology,(8th Edition)ALANGE medical Book, The McGraw-HillCompanies, Inc.,
Glucocorticoid Secretion• ACTH is the principal hormone stimulating adrenal
glucocorticoid biosynthesis and secretion. 39 aa but issynthesized within the anterior pituitary as larger, 241-aaprecursor called pro-opiomelanocortin (POMC).
• ACTH bind to G protein coupled receptor melanocortin-2(MC2R) assisted by Melanocortin-2 receptor accessoryprotein (MRAP). Signaling is done through cAMP and Ca2+
• ACTH induce steroidogenesis through StAR mediated andincrease synthesis of all cyp enzymes
• POMC secretion is regulated by CRH and AVP.• CRP secreted into hypophyseal portal system binds type 1
CRH receptors and stimulate POMC transcription• AVP effect CRH through a V1B receptor to activate Kinase C
• ACTH is the principal hormone stimulating adrenalglucocorticoid biosynthesis and secretion. 39 aa but issynthesized within the anterior pituitary as larger, 241-aaprecursor called pro-opiomelanocortin (POMC).
• ACTH bind to G protein coupled receptor melanocortin-2(MC2R) assisted by Melanocortin-2 receptor accessoryprotein (MRAP). Signaling is done through cAMP and Ca2+
• ACTH induce steroidogenesis through StAR mediated andincrease synthesis of all cyp enzymes
• POMC secretion is regulated by CRH and AVP.• CRP secreted into hypophyseal portal system binds type 1
CRH receptors and stimulate POMC transcription• AVP effect CRH through a V1B receptor to activate Kinase C
Glucocortcoid Receptor
• the action of glucocorticoids is mediated by anintracellular protein, the glucocorticoid receptor(GR)
• The human (h) GR belongs to thesteroid/thyroid/retinoic acid nuclear receptorsuperfamily of transcription factor proteins andfunctions as a ligand dependent
• transcription factor that regulates the expressionof glucocorticoid-responsive elements (GRE)
• positively or negatively.
• the action of glucocorticoids is mediated by anintracellular protein, the glucocorticoid receptor(GR)
• The human (h) GR belongs to thesteroid/thyroid/retinoic acid nuclear receptorsuperfamily of transcription factor proteins andfunctions as a ligand dependent
• transcription factor that regulates the expressionof glucocorticoid-responsive elements (GRE)
• positively or negatively.
Human Glucocorticoid Receptor• The hGR gene consists of 9 exons and is located
on chromosome 5.• Alternative splicing of the hGR gene in exon 9
generates two highly homologous receptorisoforms, identical through amino acid 727– α : having an additional 50 amino acids, 97 kD, Classic
ligand dependent receptor.
– β: additional, nonhomologous 15 amino acids, and 94kD. exerts a dominant negative effect upon thetranscriptional activity of hGRα and doesn’t bindsglucocorticoid anatagonist.
• The hGR gene consists of 9 exons and is locatedon chromosome 5.
• Alternative splicing of the hGR gene in exon 9generates two highly homologous receptorisoforms, identical through amino acid 727– α : having an additional 50 amino acids, 97 kD, Classic
ligand dependent receptor.
– β: additional, nonhomologous 15 amino acids, and 94kD. exerts a dominant negative effect upon thetranscriptional activity of hGRα and doesn’t bindsglucocorticoid anatagonist.
Schematic representation of the structure of the human glucocorticoid receptor (hGR)gene. Alternative splicing of the primary transcript gives rise to the two mRNA andprotein isoforms, hGRα and hGRβ
NTD
• The N-terminal domain (NTD) of the hGRα contains amajor transactivation domain - activation function(AF)-1, which is located between amino acids 77 and262 of the hGRα and is ligand-independent.
• AF-1 plays an important role in the interaction of thereceptor with– coactivators,– Chromatin modulators– basal transcription factors, including RNA polymerase II,
TATA-binding protein (TBP) and a host of TBP-associatedproteins (TAFIIs)
• The N-terminal domain (NTD) of the hGRα contains amajor transactivation domain - activation function(AF)-1, which is located between amino acids 77 and262 of the hGRα and is ligand-independent.
• AF-1 plays an important role in the interaction of thereceptor with– coactivators,– Chromatin modulators– basal transcription factors, including RNA polymerase II,
TATA-binding protein (TBP) and a host of TBP-associatedproteins (TAFIIs)
DBD• The DNA-binding domain (DBD) of the hGRα - aa 420–
480• two zinc finger motifs through which the hGRα binds
to GREs in the promoter region• DBD is the most highly conserved• The two zinc finger motifs are able to tetrahedrally
coordinate a Zn atom and are held by four Cys residues• P Box : within the first zinc finger, responsible for
specific recognition of the cognate GREs• D box : within 2nd zinc finger, forms the weak
dimerization interface of the DBD.• contains sequences important for receptor
dimerization and nuclear translocation
• The DNA-binding domain (DBD) of the hGRα - aa 420–480
• two zinc finger motifs through which the hGRα bindsto GREs in the promoter region
• DBD is the most highly conserved• The two zinc finger motifs are able to tetrahedrally
coordinate a Zn atom and are held by four Cys residues• P Box : within the first zinc finger, responsible for
specific recognition of the cognate GREs• D box : within 2nd zinc finger, forms the weak
dimerization interface of the DBD.• contains sequences important for receptor
dimerization and nuclear translocation
Enlargement of part of the DBD showing the amino acid sequence (singleletter codes) of the two zinc fingers and the dimerization loop (in bold). TheA to T mutation at position 458 that could produce a dimerization defectivereceptor is shown
Hinge region D
• The hinge region or region D is a flexibleregion between the DNA- and ligand-bindingdomains.
• an integral part of the DBD and is involved inits dimerization.
• The hinge region confers structural flexibilityin the receptor dimmers allowing a singlereceptor dimmer to interact with multipleGREs
• The hinge region or region D is a flexibleregion between the DNA- and ligand-bindingdomains.
• an integral part of the DBD and is involved inits dimerization.
• The hinge region confers structural flexibilityin the receptor dimmers allowing a singlereceptor dimmer to interact with multipleGREs
Functional domains of the hGRα. The functional domains and subdomains are indicatedbeneath the linearized protein structures. AF, activation function; DBD, DNAbindingdomain; LBD, ligand-binding domain; NLS, nuclear localization signal.
LBD
• The ligand-binding domain (LBD) of the hGRαcorresponds to aa 481–777
• binds to glucocorticoids & plays a critical rolein the ligand-induced activation of hGRα.
• a second transactivation domain, termed AF-2, which is ligand-dependent, important forreceptor dimerization, nuclear translocation,binding to HSP &interaction with coactivators
• The ligand-binding domain (LBD) of the hGRαcorresponds to aa 481–777
• binds to glucocorticoids & plays a critical rolein the ligand-induced activation of hGRα.
• a second transactivation domain, termed AF-2, which is ligand-dependent, important forreceptor dimerization, nuclear translocation,binding to HSP &interaction with coactivators
Crystal structure of the ligandbinding domain (LBD) of the humanglucocorticoid receptor-α (hGRα). Stereotactic conformation of the agonist(left) and antagonist (right) form of the LBD of hGRα. The yellow arrowsindicate the position of Helix 12, which is critical for the formation of AF-2surface that allows interaction with activators
Nucleocytoplasmic Shuttling of hGRα
• hGRα resides mostly in the cytoplasm of cells aspart of a heterooligomeric complex with HSP 90,70, 50, Immunophilins as well as other proteins.
• HSP90 regulates– ligand binding– cytoplasmic retention of hGRα by exposing the ligand-
binding site– masking the two nuclear localization sequences (NLS),
NL1 and NL2, which are located adjacent to the DBDand in the LBD of the receptor.
• hGRα resides mostly in the cytoplasm of cells aspart of a heterooligomeric complex with HSP 90,70, 50, Immunophilins as well as other proteins.
• HSP90 regulates– ligand binding– cytoplasmic retention of hGRα by exposing the ligand-
binding site– masking the two nuclear localization sequences (NLS),
NL1 and NL2, which are located adjacent to the DBDand in the LBD of the receptor.
Nucleocytoplasmic Shuttling of hGRα
• Upon ligand-induced activation, the receptor undergoesa conformational change that results in dissociationfrom this multiprotein complex and translocation intothe nucleus
• within the nucleus and within the cytoplasm the hGRmay be recycled and/or degraded in the proteasome
• hGRα remains within the nucleus for a considerablelength of time and is then exported to the cytoplasm
• The nuclear export of hGR occurs slowly and is opposedactively by a nuclear retention signal (NRS) in the hingeregion of the receptor, which overlaps closely with theNL1
• Upon ligand-induced activation, the receptor undergoesa conformational change that results in dissociationfrom this multiprotein complex and translocation intothe nucleus
• within the nucleus and within the cytoplasm the hGRmay be recycled and/or degraded in the proteasome
• hGRα remains within the nucleus for a considerablelength of time and is then exported to the cytoplasm
• The nuclear export of hGR occurs slowly and is opposedactively by a nuclear retention signal (NRS) in the hingeregion of the receptor, which overlaps closely with theNL1
Nucleocytoplasmic shuttling of the glucocorticoid receptor. Upon binding to theligand, the activated hGRα dissociates from HSPs and translocates into the nucleus,where it homodimerizes and binds to GREs in the promoter region of target genes
Mechanism of transcriptionalActivation
• hGRα uses its transcriptional activation domains,AF-1 and AF-2
• Several coactivators form a bridge between theDNA-bound hGRα and the transcription initiationcomplex, and facilitate the transmission of theglucocorticoid signal to the RNA pol II
• These include:– CREB binding Proteins– P300/CBP associated factors (p/CAF) which is
accumulated by p160 coactivators
• hGRα uses its transcriptional activation domains,AF-1 and AF-2
• Several coactivators form a bridge between theDNA-bound hGRα and the transcription initiationcomplex, and facilitate the transmission of theglucocorticoid signal to the RNA pol II
• These include:– CREB binding Proteins– P300/CBP associated factors (p/CAF) which is
accumulated by p160 coactivators
Mechanism of transcriptionalActivation
• p/CAF and p160 intrinsic histoneacetyltransferase (HAT) activity - promoteschromatin decondensation, and allows thetranscription
• Other transactivation domains include– switching/sucrose non-fermenting (SWI/ SNF)
complex– components of the vitamin D receptor-interacting
protein/thyroid hormone receptor-associated protein(DRIP/TRAP) complex
• p/CAF and p160 intrinsic histoneacetyltransferase (HAT) activity - promoteschromatin decondensation, and allows thetranscription
• Other transactivation domains include– switching/sucrose non-fermenting (SWI/ SNF)
complex– components of the vitamin D receptor-interacting
protein/thyroid hormone receptor-associated protein(DRIP/TRAP) complex
Schematic representation of the interaction of AF-1 and AF-2 of hGRα with coactivators. AF:activation function; DRIP/TRAP: vitamin D receptor-interacting protein/thyroid hormonereceptorassociated protein; GR: glucocorticoid receptor; GREs: glucocorticoid response elements;HSP: heat shock protein; SWI/SNF: switching/sucrose non-fermenting; TF: transcription factor;TFRE: transcription factor-response element
Biological EffectsEmbryonic Development
• Schutz and colleagues conducted genetic studies with GRknockout mice.
• GR/ neonates die soon after birth due to respiratory failurearising from impaired lung development, indicating theimportant role of GR signaling in lung maturation
• profound alterations in the regulation of the liver, adrenalgland, brain, and HPA axis were observed in GR/ mice.
• thymocytes become resistant to apoptosis in the absenceof GR
• the presence of a functional GR during gestation is essentialfor postnatal survival as well as during development.
• Schutz and colleagues conducted genetic studies with GRknockout mice.
• GR/ neonates die soon after birth due to respiratory failurearising from impaired lung development, indicating theimportant role of GR signaling in lung maturation
• profound alterations in the regulation of the liver, adrenalgland, brain, and HPA axis were observed in GR/ mice.
• thymocytes become resistant to apoptosis in the absenceof GR
• the presence of a functional GR during gestation is essentialfor postnatal survival as well as during development.
Biological EffectsNervous System
• Elevation of glucocorticoids has been implicated inpsychiatric disorders such as schizophrenia, drugaddiction, post-traumatic stress disorder (PTSD), &mood disorders
• GR in the forebrain has been shown to regulate the HPAaxis and behavior under stressed conditions, whereas inthe amygdala it has been shown to play an importantrole in memory acquisition and fear conditioning.
• Several studies indicate that GR functions in the braincorrelate positively with anxiety behavior– Tronche et al.- brain-specific deletion of the GR resulted in
mice with decreased anxiety and lower levels of despair likebehavior
• Elevation of glucocorticoids has been implicated inpsychiatric disorders such as schizophrenia, drugaddiction, post-traumatic stress disorder (PTSD), &mood disorders
• GR in the forebrain has been shown to regulate the HPAaxis and behavior under stressed conditions, whereas inthe amygdala it has been shown to play an importantrole in memory acquisition and fear conditioning.
• Several studies indicate that GR functions in the braincorrelate positively with anxiety behavior– Tronche et al.- brain-specific deletion of the GR resulted in
mice with decreased anxiety and lower levels of despair likebehavior
Biological EffectsVisual System
• glucocorticoids in treating ocularinflammation (e.g., conjunctivitis, keratitis,uveitis), macular edema, and maculardegeneration
• used to inhibit neovascularization in the eyethat could lead to vision loss
• glucocorticoids confer protection onphotoreceptors in the retina by preventingtheir apoptosis
• glucocorticoids in treating ocularinflammation (e.g., conjunctivitis, keratitis,uveitis), macular edema, and maculardegeneration
• used to inhibit neovascularization in the eyethat could lead to vision loss
• glucocorticoids confer protection onphotoreceptors in the retina by preventingtheir apoptosis
• Increase blood glucose concentration• Stimulate glycogen deposition by increasing glycogen
synthase and inhibiting glycogen phosphorylase• Activates hepatic glucose 6- phosphate and PEPCK• Peripheral tissue: inhibit glucose uptake and utilization• Adipose tissue: Lipolysis is activated, HDL cholestrol
falls• Imparts insulin resistance to cells and increase glucose
through its permissive actions on other hormones
Biological EffectsCarbohydrate, Protein and Lipid Metabolism
• Increase blood glucose concentration• Stimulate glycogen deposition by increasing glycogen
synthase and inhibiting glycogen phosphorylase• Activates hepatic glucose 6- phosphate and PEPCK• Peripheral tissue: inhibit glucose uptake and utilization• Adipose tissue: Lipolysis is activated, HDL cholestrol
falls• Imparts insulin resistance to cells and increase glucose
through its permissive actions on other hormones
• used for treating cutaneous inflammatoryconditions : psoriasis and eczema
• adverse effects such as skin atrophy anddelayed wound healing
• Results from mice lacking GR in the skin(GREKO) demonstrated that the physiologicalrole of the GR in the skin is to regulateepithelial integrity and immune function
Biological EffectsIntegumentary System
• used for treating cutaneous inflammatoryconditions : psoriasis and eczema
• adverse effects such as skin atrophy anddelayed wound healing
• Results from mice lacking GR in the skin(GREKO) demonstrated that the physiologicalrole of the GR in the skin is to regulateepithelial integrity and immune function
• ‘ gold standard ‘ for immune suppression in organ transplantationpatients
• exert their classic anti-inflammatory role by acting on nearly all celltypes of the immune system
• glucocorticoids suppress dendritic cell maturation and convert theminto tolerogenic dendritic cells that possess weak T cell-stimulatingactivity
• Dendritic cell migration and apoptosis are also controlled byglucocorticoids
• By contrast:– GR has also been shown to enhance phagocytosis of neutrophils by
macrophages– regulate positively NLRP3, a component of the inflammasome complex
in macrophages, to augment the proinflammatory response– cooperate with the proinflammatory molecule TNFa to induce Toll-like
receptor 2 gene expression, thereby stimulating innate immunity
Biological EffectsImmune System
• ‘ gold standard ‘ for immune suppression in organ transplantationpatients
• exert their classic anti-inflammatory role by acting on nearly all celltypes of the immune system
• glucocorticoids suppress dendritic cell maturation and convert theminto tolerogenic dendritic cells that possess weak T cell-stimulatingactivity
• Dendritic cell migration and apoptosis are also controlled byglucocorticoids
• By contrast:– GR has also been shown to enhance phagocytosis of neutrophils by
macrophages– regulate positively NLRP3, a component of the inflammasome complex
in macrophages, to augment the proinflammatory response– cooperate with the proinflammatory molecule TNFa to induce Toll-like
receptor 2 gene expression, thereby stimulating innate immunity
• Glucocorticoids suppress migration of theseneutrophils by repressing the expression of celladhesion molecules
• mice lacking GRs in T cells by gene-targeteddeletion displayed resistance toglucocorticoid-induced apoptosis.
Biological EffectsImmune System
• Glucocorticoids suppress migration of theseneutrophils by repressing the expression of celladhesion molecules
• mice lacking GRs in T cells by gene-targeteddeletion displayed resistance toglucocorticoid-induced apoptosis.
Classic anti-inflamatory response of Glucocorticoids
Melmed.S., Polonsky.S.K, Larsen.P.R., Kronenberg.H.M. ‘Williams Textbook of Endocrinology’(12th Edition), Elsevir Saunders 2011
• inhaled corticosteroids, are the mostcommonly prescribed drugs for the treatmentof chronic inflammatory conditions
• In asthma: Glucocorticoids by inhibiting NF-kBand AP-1 activity, suppress the production andsecretion of cytokines, chemokines, and celladhesion molecules by the airway epithelium
Biological EffectsRespiratory System
• inhaled corticosteroids, are the mostcommonly prescribed drugs for the treatmentof chronic inflammatory conditions
• In asthma: Glucocorticoids by inhibiting NF-kBand AP-1 activity, suppress the production andsecretion of cytokines, chemokines, and celladhesion molecules by the airway epithelium
• Glucocorticoids suppress thyroid axis on thesecretion of TSH
• Inhibit 5’ deiodinase activity that mediates theconversiton of thyroxine to activetriidothyronine.
• Inhibit GnRH, LH and FSH
Biological EffectsEndocrine System
• Glucocorticoids suppress thyroid axis on thesecretion of TSH
• Inhibit 5’ deiodinase activity that mediates theconversiton of thyroxine to activetriidothyronine.
• Inhibit GnRH, LH and FSH
• Inhibits osteoblast function which accounts forosteopenia and osteoporosis in glucocorticoid excess.
• Inhibit Ca2+ absorption & increase renal Ca2+excreation
• the gonads and adrenals share a commonadrenogonadal primordium
• Long explosure leads to infertility at the same timecontroled explosure leads to fertility induction andovulation rate enhancement.
• There is an association between miscarriages andpolymorphism in NR3C1 suggesting the importance ofan intact functioning GR achieving a successfulpregnancy
Biological Effects• Inhibits osteoblast function which accounts for
osteopenia and osteoporosis in glucocorticoid excess.• Inhibit Ca2+ absorption & increase renal Ca2+
excreation• the gonads and adrenals share a common
adrenogonadal primordium• Long explosure leads to infertility at the same time
controled explosure leads to fertility induction andovulation rate enhancement.
• There is an association between miscarriages andpolymorphism in NR3C1 suggesting the importance ofan intact functioning GR achieving a successfulpregnancy
Biological Effects: Summary
Kadmiel.M, Cidlowski.A.J, ‘Glucocorticoid Receptor Signaling in Health and Disease’ (Review). Cell press, Trends in PharmacologicalSciences September 2013, Vol. 34, No. 9
References• Kadmiel.M, Cidlowski.A.J, ‘Glucocorticoid Receptor Signaling in Health and Disease’ (Review).
Cell press, Trends in Pharmacological Sciences September 2013, Vol. 34, No. 9• Nicolaides.C.N, Galata.Z, Kino.T, X, Chrousos.P.G, & Charmandari.E, ‘The Human Glucocorticoid
Receptor: Molecular Basis of Biologic Function’, PMC 2010 January 30, Volume 75(1):1,doi:10.1016/j.steroids.2009.09.002 ( National Institute of Health, Public Access, AuthorManuscript)
• Melmed.S., Polonsky.S.K, Larsen.P.R., Kronenberg.H.M. ‘Williams Textbook ofEndocrinology’(12th Edition), Elsevir Saunders 2011, p479-494
• Aron.C.D, Findling J.W, & Blake T.J,Edited by Garner.G.D. ‘Greenspan’s Basic & ClinicalEndocrinology,(8th Edition) ALANGE medical Book, The McGraw-Hill Companies, Inc., p346-378
• Gyton.C.A, Hall.E.J.‘Textbook of Medical Physiology’ (11th Edition), Elsevier Saunders 2006,p944-955
• Tortora.J.Gerard, Derrickson.B, ‘Principles of Anatomy and Physiology’(13th Edition), John Wiley& sons, Inc., p703-704
• Gottlicher M, Heck S, Herrlich P. ‘Transcriptional crosstalk, the second mode of steroidhormone receptor action’. J Mol Med 1998;76:480–489. [PubMed: 9660166]
• Schule R, Rangarajan P, Kliewer S, Ransone LJ, Bolado J, Yang N, Verma IM, Evans RM.‘Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor’. Cell1990;62:1217–1226. [PubMed: 2169353]
• Jonat C, Rahmsdorf HJ, Park KK, Cato AC, Gebel S, Ponta H, Herrlich P. ‘Antitumor promotionand anti inflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoidhormone’. Cell 1990;62:1189–1204. [PubMed: 2169351]
• Kadmiel.M, Cidlowski.A.J, ‘Glucocorticoid Receptor Signaling in Health and Disease’ (Review).Cell press, Trends in Pharmacological Sciences September 2013, Vol. 34, No. 9
• Nicolaides.C.N, Galata.Z, Kino.T, X, Chrousos.P.G, & Charmandari.E, ‘The Human GlucocorticoidReceptor: Molecular Basis of Biologic Function’, PMC 2010 January 30, Volume 75(1):1,doi:10.1016/j.steroids.2009.09.002 ( National Institute of Health, Public Access, AuthorManuscript)
• Melmed.S., Polonsky.S.K, Larsen.P.R., Kronenberg.H.M. ‘Williams Textbook ofEndocrinology’(12th Edition), Elsevir Saunders 2011, p479-494
• Aron.C.D, Findling J.W, & Blake T.J,Edited by Garner.G.D. ‘Greenspan’s Basic & ClinicalEndocrinology,(8th Edition) ALANGE medical Book, The McGraw-Hill Companies, Inc., p346-378
• Gyton.C.A, Hall.E.J.‘Textbook of Medical Physiology’ (11th Edition), Elsevier Saunders 2006,p944-955
• Tortora.J.Gerard, Derrickson.B, ‘Principles of Anatomy and Physiology’(13th Edition), John Wiley& sons, Inc., p703-704
• Gottlicher M, Heck S, Herrlich P. ‘Transcriptional crosstalk, the second mode of steroidhormone receptor action’. J Mol Med 1998;76:480–489. [PubMed: 9660166]
• Schule R, Rangarajan P, Kliewer S, Ransone LJ, Bolado J, Yang N, Verma IM, Evans RM.‘Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor’. Cell1990;62:1217–1226. [PubMed: 2169353]
• Jonat C, Rahmsdorf HJ, Park KK, Cato AC, Gebel S, Ponta H, Herrlich P. ‘Antitumor promotionand anti inflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoidhormone’. Cell 1990;62:1189–1204. [PubMed: 2169351]
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