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Volume 1 - Number 1 May - September 1997
Volume 15 - Number 11 November 2011
The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with
the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific
Research (CNRS) on its electronic publishing platform I-Revues.
Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in
open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more
traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology,
and educational items in the various related topics for students in Medicine and in Sciences.
Editorial correspondance
Jean-Loup Huret Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
tel +33 5 49 44 45 46 or +33 5 49 45 47 67
[email protected] or [email protected]
Staff Mohammad Ahmad, Mélanie Arsaban, Marie-Christine Jacquemot-Perbal, Maureen Labarussias, Vanessa Le
Berre, Anne Malo, Catherine Morel-Pair, Laurent Rassinoux, Alain Zasadzinski.
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave
Roussy Institute – Villejuif – France).
The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times
a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of
the French National Center for Scientific Research (INIST-CNRS) since 2008.
The Atlas is hosted by INIST-CNRS (http://www.inist.fr)
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Editor
Jean-Loup Huret
(Poitiers, France)
Editorial Board
Sreeparna Banerjee (Ankara, Turkey) Solid Tumours Section
Alessandro Beghini (Milan, Italy) Genes Section
Anne von Bergh (Rotterdam, The Netherlands) Genes / Leukaemia Sections
Judith Bovée (Leiden, The Netherlands) Solid Tumours Section
Vasantha Brito-Babapulle (London, UK) Leukaemia Section
Charles Buys (Groningen, The Netherlands) Deep Insights Section
Anne Marie Capodano (Marseille, France) Solid Tumours Section
Fei Chen (Morgantown, West Virginia) Genes / Deep Insights Sections
Antonio Cuneo (Ferrara, Italy) Leukaemia Section
Paola Dal Cin (Boston, Massachussetts) Genes / Solid Tumours Section
Louis Dallaire (Montreal, Canada) Education Section
Brigitte Debuire (Villejuif, France) Deep Insights Section
François Desangles (Paris, France) Leukaemia / Solid Tumours Sections
Enric Domingo-Villanueva (London, UK) Solid Tumours Section
Ayse Erson (Ankara, Turkey) Solid Tumours Section
Richard Gatti (Los Angeles, California) Cancer-Prone Diseases / Deep Insights Sections
Ad Geurts van Kessel (Nijmegen, The Netherlands) Cancer-Prone Diseases Section
Oskar Haas (Vienna, Austria) Genes / Leukaemia Sections
Anne Hagemeijer (Leuven, Belgium) Deep Insights Section
Nyla Heerema (Colombus, Ohio) Leukaemia Section
Jim Heighway (Liverpool, UK) Genes / Deep Insights Sections
Sakari Knuutila (Helsinki, Finland) Deep Insights Section
Lidia Larizza (Milano, Italy) Solid Tumours Section
Lisa Lee-Jones (Newcastle, UK) Solid Tumours Section
Edmond Ma (Hong Kong, China) Leukaemia Section
Roderick McLeod (Braunschweig, Germany) Deep Insights / Education Sections
Cristina Mecucci (Perugia, Italy) Genes / Leukaemia Sections
Yasmin Mehraein (Homburg, Germany) Cancer-Prone Diseases Section
Fredrik Mertens (Lund, Sweden) Solid Tumours Section
Konstantin Miller (Hannover, Germany) Education Section
Felix Mitelman (Lund, Sweden) Deep Insights Section
Hossain Mossafa (Cergy Pontoise, France) Leukaemia Section
Stefan Nagel (Braunschweig, Germany) Deep Insights / Education Sections
Florence Pedeutour (Nice, France) Genes / Solid Tumours Sections
Elizabeth Petty (Ann Harbor, Michigan) Deep Insights Section
Susana Raimondi (Memphis, Tennesse) Genes / Leukaemia Section
Mariano Rocchi (Bari, Italy) Genes Section
Alain Sarasin (Villejuif, France) Cancer-Prone Diseases Section
Albert Schinzel (Schwerzenbach, Switzerland) Education Section
Clelia Storlazzi (Bari, Italy) Genes Section
Sabine Strehl (Vienna, Austria) Genes / Leukaemia Sections
Nancy Uhrhammer (Clermont Ferrand, France) Genes / Cancer-Prone Diseases Sections
Dan Van Dyke (Rochester, Minnesota) Education Section
Roberta Vanni (Montserrato, Italy) Solid Tumours Section
Franck Viguié (Paris, France) Leukaemia Section
José Luis Vizmanos (Pamplona, Spain) Leukaemia Section
Thomas Wan (Hong Kong, China) Genes / Leukaemia Sections
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Volume 15, Number 11, November 2011
Table of contents
Gene Section
CTCF (CCCTC-binding factor (zinc finger protein)) 914 Jacques Piette
EPS8 (epidermal growth factor receptor pathway substrate 8) 921 Anna A Bulysheva, W Andrew Yeudall
FAM107A (family with sequence similarity 107, member A) 925 Kenji Kadomatsu, Ping Mu
GAST (gastrin) 928 Celia Chao, Mark R Hellmich
PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2) 935 Yuan-Hao Hsu
TGFBRAP1 (transforming growth factor, beta receptor associated protein 1) 938 Jens U Wurthner
AXIN1 (axin 1) 940 Nives Pecina-Slaus, Tamara Nikuseva Martic, Tomislav Kokotovic
CCR2 (chemokine (C-C motif) receptor 2) 945 Jérôme Moreaux
DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase)) 949 Dimitra Florou, Andreas Scorilas, Dido Vassilacopoulou, Emmanuel G Fragoulis
DDR1 (discoidin domain receptor tyrosine kinase 1) 958 Barbara Roig, Elisabet Vilella
ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)) 963 Luca Braccioli, Marilena V Iorio, Patrizia Casalini
KIAA0101 (KIAA0101) 972 Shannon Joseph, Lingbo Hu, Fiona Simpson
PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8) 975 Nikki Minnebo, Nele Van Dessel, Monique Beullens, Aleyde van Eynde, Mathieu Bollen
SMYD2 (SET and MYND domain containing 2) 979 Hitoshi Tsuda, Shuhei Komatsu
Leukaemia Section
t(1;9)(p34;q34) 981 Jean-Loup Huret
t(11;14)(q13;q32) in multiple myeloma Huret JL, Laï JL
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Deep Insight Section
Understanding the structure and function of ASH2L 983 Paul F South, Scott D Briggs
Case Report Section
A new case of t(4;12)(q12;p13) in a secondary acute myeloid leukemia with review of literature 989 Sarah M Heaton, Frederick Koppitch, Anwar N Mohamed
Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myelodysplastic syndrome. Case 0002M. 992 Kavita S Reddy
Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myeloproliferative neoplasm. Case 0001M. 994 Kavita S Reddy
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 914
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
CTCF (CCCTC-binding factor (zinc finger protein)) Jacques Piette
Institut de Genetique Moleculaire de Montpellier (CNRS-Université de Montpellier I-II UMR5535),
1919 Route de Mende, 34293, Montpellier-Cedex 5, France (JP)
Published in Atlas Database: April 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/CTCFID40187ch16q22.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI CTCFID40187ch16q22.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
HGNC (Hugo): CTCF
Location: 16q22.1
Local order: AGRP, FAM65A, CTCF, RLTPR,
ACD, PARD6A.
DNA/RNA
Note
See figure 1.
Description
76776 bp gene (Ensembl).
Transcription
Ubiquitously highly expressed gene (GeneCards),
12 exons, 11 introns with at least 5 differentially
spliced transcripts (Ensembl).
Pseudogene
No.
Figure 1. Schematic representation of CTCF location on chromosome 16, gene structure and transcripts. Chromosome 16 is represented with the characteristic banding pattern. The region surrounding the CTCF gene is enlarged. Genes are
represented by arrows pointing in the direction of transcription. Transcripts are represented with exons as vertical bars and introns as lines. Distances are in kilo bases (NCBI Map Viewer).
CTCF (CCCTC-binding factor (zinc finger protein)) Piette J
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 915
Figure 2. Schematic representation of the CTCF protein. Protein sequences encoded by exons are boxed. 11 ring fingers are indicated by green boxes as also putative AT-hooks by blue boxes (Ensembl). Phosphorylated residues are in black
(PhosphoSitePlus), those sensitive to rapamycin are indicated by R (Chen et al., 2009) and those phosphorylated by CKII by CKII (El-Kady et al., 2005; Klenova et al., 2001), sumoylated residues are in red (Kitchen et al., 2010; MacPherson et al., 2009),
acetylated residue is indicated by Ac (Choudhary et al., 2009). The domain containing poly(ADPribosyl)ation sites (PAR) is boxed in red (Farrar et al., 2010). Residues mutated in tumors are indicated (see further), BT = breast tumor, PT = prostate
tumor and WT = Wilms tumor.
Protein
Description
CTCF was originally described as a c-myc activator
(Klenova et al., 1993). It is a 727 aa protein with a
MW of 82.8 kD, a charge of 8.5 and an iso electric
point of 6.95 (Ensembl). The central domain with
11 zinc fingers of the C2H2 type is highly
conserved.
Expression
CTCF is an abundant and ubiquitously expressed
protein, yet absent in primary spermatocytes
(Loukinov et al., 2002). It is downregulated during
differentiation of human myeloid leukemia cells
(Delgado et al., 1999; Torrano et al., 2005). Post-
traductional modifications include acetylation
(Choudhary et al., 2009), sumoylation (Kitchen et
al., 2010; MacPherson et al., 2009),
phosphorylation, in particular ser604-612 by CKII
(El-Kady et al., 2005; Klenova et al., 2001), and
poly(ADPribo)sylation (see figure 2). The latter
modification is lost or decreased in proliferating
cells and in BT (Docquier et al., 2009) (for sites and
role see Farrar et al., 2010 and Yu et al., 2004).
CTCF is a downstream target protein of growth
factor-induced pathways and is regulated by EGF
and insulin through activation of ERK and AKT
signaling cascades (Gao et al., 2007). It was
recently shown to be regulated by NF-kB (Lu et al.,
2010).
Localisation
CTCF is localized in the nucleoplasm of
proliferating cells with exclusion from the
nucleolus. It was detected at the centrosomes and
midbody during mitosis (Zhang et al., 2004). It is
associated with the nuclear matrix (Dunn et al.,
2003; Yusufzai et al., 2004a) and the Lamina
(Guelen et al., 2008; Ottaviani et al., 2009).
Nucleolar translocation after growth arrest is
accompanied by inhibition of nucleolar
transcription (Torrano et al., 2006). Cytoplasmic
expression was described in sporadic breast tumors
(Rakha et al., 2004).
Function
CTCF is an essential protein, since KO mice die
before ED 9.5 (Heath et al., 2008) (reviewed in
Filippova, 2008 and Phillips et al., 2009). It
interacts with up to 39609 genomic sites (in ES
cells) (Chen et al., 2008; Bao et al., 2007; Barski et
al., 2007; Kim et al., 2007). The 11 Zn fingers
would provide flexibility in DNA recognition
(Filippova et al., 1996), the central 4 bind to a
consensus DNA sequence (Filippova et al., 1998;
Renda et al., 2007). Multiple interacting proteins
were described including RNA polymerase II
(Chernukhin et al., 2007), cohesin (Parelho et al.,
2008; Rubio et al., 2008; Wendt et al., 2008), Suz12
(Li et al., 2008), CHD8 (Ishihara et al., 2006), YY1
(Donohoe et al., 2007), nucleophosmin (Yusufzai et
al., 2004b), Kaiso (Defossez et al., 2005) and
Sin3A (Lutz et al., 2000).
CTCF (CCCTC-binding factor (zinc finger protein)) Piette J
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 916
Mediating DNA looping (Splinter et al., 2006)
could be at the basis of most functions of CTCF.
Long range interactions are cell type specific (Hou
et al., 2010) and would depend on the chromosomal
environment of the CTCF-binding sites, in
particular its interaction with other factors (see
concept of modular insulators in Weth et al., 2010).
One thoroughly studied factor is the thyroid
receptor (Awad et al., 1999; Lutz et al., 2003). Its
chromosomal environment could also explain the
multiple (not necessarily exclusive) functions that
were described for CTCF, including chromatin
barrier (Cuddapah et al., 2008; Witcher et al.,
2009), promoter insulation from enhancer (Bell et
al., 1999) or silencer (Hou et al., 2008),
transcriptional activation (Gombert et al., 2009) (for
instance of the tumour suppressor genes
INK4A/ARF (Rodriguez et al., 2010) and p53
(Soto-Reyes et al., 2010)), repression (for instance
hTERT (Renaud et al., 2005)), nucleosome
positioning (Fu et al., 2008b), protection from DNA
methylation (Mukhopadhyay et al., 2004;
Schoenherr et al., 2003; Guastafierro et al., 2008),
preservation of triplet-repeat stability (Cho et al.,
2005; Filippova et al., 2001; Libby et al., 2008),
imprinting (Fedoriw et al., 2004; Fitzpatrick et al.,
2007), X chromosome inactivation (Chao et al.,
2002), chromosome "kissing" (Ling et al., 2006),
transvection (Liu et al., 2008), death signaling
(Docquier et al., 2005; Gomes et al., 2010; Li et al.,
2007), replication timing (Bergstrom et al., 2007),
mitotic bookmarking (Burke et al., 2005) or MHC
class II gene expression (Majumder et al., 2008).
Homology
49 orthologues were described including D.
melanogaster (Smith et al., 2009) and C. elegans
proteins (Moon et al., 2005), 3 paralogues: CTCFL
or BORIS, originating from a gene duplication in
reptiles (Hore et al., 2008; Loukinov et al., 2002),
and possibly ZFP64 (Mack et al., 1997) and the
Histone H4 transcription factor HINF-P (van
Wijnen et al., 1991).
Mutations
Note
SNP at AA 630 /K /E 90 /D /G 447 fR (NCBI).
Germinal
Non-coding mutations only.
Somatic
Mutations are rare and include point mutations of
Zn-fingers in breast (BT) (Aulmann et al., 2003),
prostate (PT) and Wilms tumor (WT) (Filippova et
al., 2002) and insertion in BT (Aulmann et al.,
2003) (see figure 2).
Implicated in
Various cancers
Note
LOH of CTCF was described in many cancers
together with potential tumor suppressor genes
(TSG), including E-Cad, since it is part of a larger
deletion (Cancer Chromosomes; Sanger institute).
In addition to WT (Yeh et al., 2002; Mummert et
al., 2005), BT (Rakha et al., 2004), PT (Filippova et
al., 1998), LOH was found in laryngeal squamous
cell carcinoma (Grbesa et al., 2008), however, there
is no evidence that CTCF is the TSG at 16q22.1
(Rakha et al., 2005), except possibly in lobular
carcinoma in situ of the breast (Green et al., 2009).
CTCF was also described to be overexpressed in
BT (Docquier et al., 2005). An indirect role of
CTCF in tumor progression is mainly suggested by
mutation or aberrant methylation of its bindings
sites (reviewed by Recillas-Targa et al., 2006).
Interestingly, a causal link between LOH of CTCF
and hypermethylation was proposed by Mummert
et al. in 2005, although no real correlation was
found by Yeh et al. in 2002. Methylation of CTCF
sites was first described in the IGF2 imprinting
control region in WT (Cui et al., 2001). Aberrant
methylation of this region was also found in PT (Fu
et al., 2008a; Paradowska et al., 2009), HNSCC (De
Castro Valente Esteves et al., 2006; Esteves et al.,
2005), colorectal cancer (Nakagawa et al., 2001),
osteosarcoma (Ulaner et al., 2003), ovarian
carcinoma (Dammann et al., 2010) and laryngeal
squamous cell carcinoma (Grbesa et al., 2008).
Hypomethylation was described in bladder cancer
(Takai et al., 2001). Microdeletions were described
in Beckwith-Wiedemann syndrome and WT
(Prawitt et al., 2005; Sparago et al., 2007). Other
methylated CTCF targets were found in the genes
AWT1 or WT1-AS in WT (Hancock et al., 2007),
Bcl6 in B cell lymphomas (Lai et al., 2010), p53,
pRb (De La Rosa-Velazquez et al., 2007), ARF
(Tam et al., 2003; Rodriguez et al., 2010), INK4B,
BRCA1 (Butcher et al., 2004; Butcher et al., 2007;
Xu et al., 2010) and Rasgrf1 (Yoon et al., 2005).
We describe below the rare cases of point mutations
affecting the CTCF protein.
Invasive ductal breast carcinoma, grade 2
Note
G2 grade tumor, no protein detected (Aulmann et
al., 2003).
Cytogenetics
14 bp insertion at AA D91, see figure 2.
Invasive ductal breast carcinoma, grade 3
Note
G3 grade tumor (Aulmann et al., 2003).
Cytogenetics
LOH and Q72H, figure 2.
CTCF (CCCTC-binding factor (zinc finger protein)) Piette J
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 917
Breast cancer
Note
Zinc finger mutation (Filippova et al., 2002).
Cytogenetics
LOH and K343E, figure 2.
Prostate cancer
Note
Zinc finger mutation (Filippova et al., 2002).
Cytogenetics
LOH and H344E, figure 2.
Wilms tumor
Note
Zinc finger mutation (Filippova et al., 2002).
Cytogenetics
LOH and R339W or R448Q, figure 2.
References van Wijnen AJ, Ramsey-Ewing AL, Bortell R, Owen TA, Lian JB, Stein JL, Stein GS. Transcriptional element H4-site II of cell cycle regulated human H4 histone genes is a multipartite protein/DNA interaction site for factors HiNF-D, HiNF-M, and HiNF-P: involvement of phosphorylation. J Cell Biochem. 1991 Jun;46(2):174-89
Klenova EM, Nicolas RH, Paterson HF, Carne AF, Heath CM, Goodwin GH, Neiman PE, Lobanenkov VV. CTCF, a conserved nuclear factor required for optimal transcriptional activity of the chicken c-myc gene, is an 11-Zn-finger protein differentially expressed in multiple forms. Mol Cell Biol. 1993 Dec;13(12):7612-24
Filippova GN, Fagerlie S, Klenova EM, Myers C, Dehner Y, Goodwin G, Neiman PE, Collins SJ, Lobanenkov VV. An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes. Mol Cell Biol. 1996 Jun;16(6):2802-13
Mack HG, Beck F, Bowtell DD. A search for a mammalian homologue of the Drosophila photoreceptor development gene glass yields Zfp64, a zinc finger encoding gene which maps to the distal end of mouse chromosome 2. Gene. 1997 Jan 31;185(1):11-7
Filippova GN, Lindblom A, Meincke LJ, Klenova EM, Neiman PE, Collins SJ, Doggett NA, Lobanenkov VV. A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16q22.1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers. Genes Chromosomes Cancer. 1998 May;22(1):26-36
Awad TA, Bigler J, Ulmer JE, Hu YJ, Moore JM, Lutz M, Neiman PE, Collins SJ, Renkawitz R, Lobanenkov VV, Filippova GN. Negative transcriptional regulation mediated by thyroid hormone response element 144 requires binding of the multivalent factor CTCF to a novel target DNA sequence. J Biol Chem. 1999 Sep 17;274(38):27092-8
Bell AC, West AG, Felsenfeld G. The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell. 1999 Aug 6;98(3):387-96
Delgado MD, Chernukhin IV, Bigas A, Klenova EM, León J. Differential expression and phosphorylation of CTCF, a c-myc transcriptional regulator, during differentiation of human myeloid cells. FEBS Lett. 1999 Feb 5;444(1):5-10
Lutz M, Burke LJ, Barreto G, Goeman F, Greb H, Arnold R, Schultheiss H, Brehm A, Kouzarides T, Lobanenkov V, Renkawitz R. Transcriptional repression by the insulator protein CTCF involves histone deacetylases. Nucleic Acids Res. 2000 Apr 15;28(8):1707-13
Cui H, Niemitz EL, Ravenel JD, Onyango P, Brandenburg SA, Lobanenkov VV, Feinberg AP. Loss of imprinting of insulin-like growth factor-II in Wilms' tumor commonly involves altered methylation but not mutations of CTCF or its binding site. Cancer Res. 2001 Jul 1;61(13):4947-50
Filippova GN, Thienes CP, Penn BH, Cho DH, Hu YJ, Moore JM, Klesert TR, Lobanenkov VV, Tapscott SJ. CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nat Genet. 2001 Aug;28(4):335-43
Klenova EM, Chernukhin IV, El-Kady A, Lee RE, Pugacheva EM, Loukinov DI, Goodwin GH, Delgado D, Filippova GN, León J, Morse HC 3rd, Neiman PE, Lobanenkov VV. Functional phosphorylation sites in the C-terminal region of the multivalent multifunctional transcriptional factor CTCF. Mol Cell Biol. 2001 Mar;21(6):2221-34
Nakagawa H, Chadwick RB, Peltomaki P, Plass C, Nakamura Y, de La Chapelle A. Loss of imprinting of the insulin-like growth factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer. Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):591-6
Takai D, Gonzales FA, Tsai YC, Thayer MJ, Jones PA. Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer. Hum Mol Genet. 2001 Nov 1;10(23):2619-26
Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT. CTCF, a candidate trans-acting factor for X-inactivation choice. Science. 2002 Jan 11;295(5553):345-7
Filippova GN, Qi CF, Ulmer JE, Moore JM, Ward MD, Hu YJ, Loukinov DI, Pugacheva EM, Klenova EM, Grundy PE, Feinberg AP, Cleton-Jansen AM, Moerland EW, Cornelisse CJ, Suzuki H, Komiya A, Lindblom A, Dorion-Bonnet F, Neiman PE, Morse HC 3rd, Collins SJ, Lobanenkov VV. Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter tts DNA-binding specificity. Cancer Res. 2002 Jan 1;62(1):48-52
Loukinov DI, Pugacheva E, Vatolin S, Pack SD, Moon H, Chernukhin I, Mannan P, Larsson E, Kanduri C, Vostrov AA, Cui H, Niemitz EL, Rasko JE, Docquier FM, Kistler M, Breen JJ, Zhuang Z, Quitschke WW, Renkawitz R, Klenova EM, Feinberg AP, Ohlsson R, Morse HC 3rd, Lobanenkov VV. BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma. Proc Natl Acad Sci U S A. 2002 May 14;99(10):6806-11
Yeh A, Wei M, Golub SB, Yamashiro DJ, Murty VV, Tycko B. Chromosome arm 16q in Wilms tumors: unbalanced chromosomal translocations, loss of heterozygosity, and assessment of the CTCF gene. Genes Chromosomes Cancer. 2002 Oct;35(2):156-63
Aulmann S, Bläker H, Penzel R, Rieker RJ, Otto HF, Sinn HP. CTCF gene mutations in invasive ductal breast cancer. Breast Cancer Res Treat. 2003 Aug;80(3):347-52
Dunn KL, Zhao H, Davie JR. The insulator binding protein CTCF associates with the nuclear matrix. Exp Cell Res. 2003 Aug 1;288(1):218-23
Lutz M, Burke LJ, LeFevre P, Myers FA, Thorne AW, Crane-Robinson C, Bonifer C, Filippova GN, Lobanenkov
CTCF (CCCTC-binding factor (zinc finger protein)) Piette J
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 918
V, Renkawitz R. Thyroid hormone-regulated enhancer blocking: cooperation of CTCF and thyroid hormone receptor. EMBO J. 2003 Apr 1;22(7):1579-87
Schoenherr CJ, Levorse JM, Tilghman SM. CTCF maintains differential methylation at the Igf2/H19 locus. Nat Genet. 2003 Jan;33(1):66-9
Tam AS, Devereux TR, Patel AC, Foley JF, Maronpot RR, Massey TE. Perturbations of the Ink4a/Arf gene locus in aflatoxin B1-induced mouse lung tumors. Carcinogenesis. 2003 Jan;24(1):121-32
Ulaner GA, Vu TH, Li T, Hu JF, Yao XM, Yang Y, Gorlick R, Meyers P, Healey J, Ladanyi M, Hoffman AR. Loss of imprinting of IGF2 and H19 in osteosarcoma is accompanied by reciprocal methylation changes of a CTCF-binding site. Hum Mol Genet. 2003 Mar 1;12(5):535-49
Butcher DT, Mancini-DiNardo DN, Archer TK, Rodenhiser DI. DNA binding sites for putative methylation boundaries in the unmethylated region of the BRCA1 promoter. Int J Cancer. 2004 Sep 20;111(5):669-78
Fedoriw AM, Stein P, Svoboda P, Schultz RM, Bartolomei MS. Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting. Science. 2004 Jan 9;303(5655):238-40
Mukhopadhyay R, Yu W, Whitehead J, Xu J, Lezcano M, Pack S, Kanduri C, Kanduri M, Ginjala V, Vostrov A, Quitschke W, Chernukhin I, Klenova E, Lobanenkov V, Ohlsson R. The binding sites for the chromatin insulator protein CTCF map to DNA methylation-free domains genome-wide. Genome Res. 2004 Aug;14(8):1594-602
Rakha EA, Pinder SE, Paish CE, Ellis IO. Expression of the transcription factor CTCF in invasive breast cancer: a candidate gene located at 16q22.1. Br J Cancer. 2004 Oct 18;91(8):1591-6
Yu W, Ginjala V, Pant V, Chernukhin I, Whitehead J, Docquier F, Farrar D, Tavoosidana G, Mukhopadhyay R, Kanduri C, Oshimura M, Feinberg AP, Lobanenkov V, Klenova E, Ohlsson R. Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation. Nat Genet. 2004 Oct;36(10):1105-10
Yusufzai TM, Felsenfeld G. The 5'-HS4 chicken beta-globin insulator is a CTCF-dependent nuclear matrix-associated element. Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8620-4
Yusufzai TM, Tagami H, Nakatani Y, Felsenfeld G. CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species. Mol Cell. 2004 Jan 30;13(2):291-8
Zhang R, Burke LJ, Rasko JE, Lobanenkov V, Renkawitz R. Dynamic association of the mammalian insulator protein CTCF with centrosomes and the midbody. Exp Cell Res. 2004 Mar 10;294(1):86-93
Zhou XL, Werelius B, Lindblom A. A screen for germline mutations in the gene encoding CCCTC-binding factor (CTCF) in familial non-BRCA1/BRCA2 breast cancer. Breast Cancer Res. 2004;6(3):R187-90
Burke LJ, Zhang R, Bartkuhn M, Tiwari VK, Tavoosidana G, Kurukuti S, Weth C, Leers J, Galjart N, Ohlsson R, Renkawitz R. CTCF binding and higher order chromatin structure of the H19 locus are maintained in mitotic chromatin. EMBO J. 2005 Sep 21;24(18):3291-300
Cho DH, Thienes CP, Mahoney SE, Analau E, Filippova GN, Tapscott SJ. Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF. Mol Cell. 2005 Nov 11;20(3):483-9
Defossez PA, Kelly KF, Filion GJ, Pérez-Torrado R, Magdinier F, Menoni H, Nordgaard CL, Daniel JM, Gilson E. The human enhancer blocker CTC-binding factor interacts with the transcription factor Kaiso. J Biol Chem. 2005 Dec 30;280(52):43017-23
Docquier F, Farrar D, D'Arcy V, Chernukhin I, Robinson AF, Loukinov D, Vatolin S, Pack S, Mackay A, Harris RA, Dorricott H, O'Hare MJ, Lobanenkov V, Klenova E. Heightened expression of CTCF in breast cancer cells is associated with resistance to apoptosis. Cancer Res. 2005 Jun 15;65(12):5112-22
El-Kady A, Klenova E. Regulation of the transcription factor, CTCF, by phosphorylation with protein kinase CK2. FEBS Lett. 2005 Feb 28;579(6):1424-34
Esteves LI, Javaroni AC, Nishimoto IN, Magrin J, Squire JA, Kowalski LP, Rainho CA, Rogatto SR. DNA methylation in the CTCF-binding site I and the expression pattern of the H19 gene: does positive expression predict poor prognosis in early stage head and neck carcinomas? Mol Carcinog. 2005 Oct;44(2):102-10
Moon H, Filippova G, Loukinov D, Pugacheva E, Chen Q, Smith ST, Munhall A, Grewe B, Bartkuhn M, Arnold R, Burke LJ, Renkawitz-Pohl R, Ohlsson R, Zhou J, Renkawitz R, Lobanenkov V. CTCF is conserved from Drosophila to humans and confers enhancer blocking of the Fab-8 insulator. EMBO Rep. 2005 Feb;6(2):165-70
Mummert SK, Lobanenkov VA, Feinberg AP. Association of chromosome arm 16q loss with loss of imprinting of insulin-like growth factor-II in Wilms tumor. Genes Chromosomes Cancer. 2005 Jun;43(2):155-61
Prawitt D, Enklaar T, Gärtner-Rupprecht B, Spangenberg C, Oswald M, Lausch E, Schmidtke P, Reutzel D, Fees S, Lucito R, Korzon M, Brozek I, Limon J, Housman DE, Pelletier J, Zabel B. Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor. Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4085-90
Rakha EA, Armour JA, Pinder SE, Paish CE, Ellis IO. High-resolution analysis of 16q22.1 in breast carcinoma using DNA amplifiable probes (multiplex amplifiable probe hybridization technique) and immunohistochemistry. Int J Cancer. 2005 May 1;114(5):720-9
Renaud S, Loukinov D, Bosman FT, Lobanenkov V, Benhattar J. CTCF binds the proximal exonic region of hTERT and inhibits its transcription. Nucleic Acids Res. 2005;33(21):6850-60
Torrano V, Chernukhin I, Docquier F, D'Arcy V, León J, Klenova E, Delgado MD. CTCF regulates growth and erythroid differentiation of human myeloid leukemia cells. J Biol Chem. 2005 Jul 29;280(30):28152-61
Yoon B, Herman H, Hu B, Park YJ, Lindroth A, Bell A, West AG, Chang Y, Stablewski A, Piel JC, Loukinov DI, Lobanenkov VV, Soloway PD. Rasgrf1 imprinting is regulated by a CTCF-dependent methylation-sensitive enhancer blocker. Mol Cell Biol. 2005 Dec;25(24):11184-90
De Castro Valente Esteves LI, De Karla Cervigne N, Do Carmo Javaroni A, Magrin J, Kowalski LP, Rainho CA, Rogatto SR. H19-DMR allele-specific methylation analysis reveals epigenetic heterogeneity of CTCF binding site 6 but not of site 5 in head-and-neck carcinomas: a pilot case-control analysis. Int J Mol Med. 2006 Feb;17(2):397-404
Ishihara K, Oshimura M, Nakao M. CTCF-dependent chromatin insulator is linked to epigenetic remodeling. Mol Cell. 2006 Sep 1;23(5):733-42
CTCF (CCCTC-binding factor (zinc finger protein)) Piette J
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 919
Ling JQ, Li T, Hu JF, Vu TH, Chen HL, Qiu XW, Cherry AM, Hoffman AR. CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1. Science. 2006 Apr 14;312(5771):269-72
Recillas-Targa F, De La Rosa-Velázquez IA, Soto-Reyes E, Benítez-Bribiesca L. Epigenetic boundaries of tumour suppressor gene promoters: the CTCF connection and its role in carcinogenesis. J Cell Mol Med. 2006 Jul-Sep;10(3):554-68
Splinter E, Heath H, Kooren J, Palstra RJ, Klous P, Grosveld F, Galjart N, de Laat W. CTCF mediates long-range chromatin looping and local histone modification in the beta-globin locus. Genes Dev. 2006 Sep 1;20(17):2349-54
Torrano V, Navascués J, Docquier F, Zhang R, Burke LJ, Chernukhin I, Farrar D, León J, Berciano MT, Renkawitz R, Klenova E, Lafarga M, Delgado MD. Targeting of CTCF to the nucleolus inhibits nucleolar transcription through a poly(ADP-ribosyl)ation-dependent mechanism. J Cell Sci. 2006 May 1;119(Pt 9):1746-59
Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K. High-resolution profiling of histone methylations in the human genome. Cell. 2007 May 18;129(4):823-37
Bergström R, Whitehead J, Kurukuti S, Ohlsson R. CTCF regulates asynchronous replication of the imprinted H19/Igf2 domain. Cell Cycle. 2007 Feb 15;6(4):450-4
Butcher DT, Rodenhiser DI. Epigenetic inactivation of BRCA1 is associated with aberrant expression of CTCF and DNA methyltransferase (DNMT3B) in some sporadic breast tumours. Eur J Cancer. 2007 Jan;43(1):210-9
Chernukhin I, Shamsuddin S, Kang SY, Bergström R, Kwon YW, Yu W, Whitehead J, Mukhopadhyay R, Docquier F, Farrar D, Morrison I, Vigneron M, Wu SY, Chiang CM, Loukinov D, Lobanenkov V, Ohlsson R, Klenova E. CTCF interacts with and recruits the largest subunit of RNA polymerase II to CTCF target sites genome-wide. Mol Cell Biol. 2007 Mar;27(5):1631-48
De La Rosa-Velázquez IA, Rincón-Arano H, Benítez-Bribiesca L, Recillas-Targa F. Epigenetic regulation of the human retinoblastoma tumor suppressor gene promoter by CTCF. Cancer Res. 2007 Mar 15;67(6):2577-85
Donohoe ME, Zhang LF, Xu N, Shi Y, Lee JT. Identification of a Ctcf cofactor, Yy1, for the X chromosome binary switch. Mol Cell. 2007 Jan 12;25(1):43-56
Fitzpatrick GV, Pugacheva EM, Shin JY, Abdullaev Z, Yang Y, Khatod K, Lobanenkov VV, Higgins MJ. Allele-specific binding of CTCF to the multipartite imprinting control region KvDMR1. Mol Cell Biol. 2007 Apr;27(7):2636-47
Gao J, Li T, Lu L. Functional role of CCCTC binding factor in insulin-stimulated cell proliferation. Cell Prolif. 2007 Dec;40(6):795-808
Hancock AL, Brown KW, Moorwood K, Moon H, Holmgren C, Mardikar SH, Dallosso AR, Klenova E, Loukinov D, Ohlsson R, Lobanenkov VV, Malik K. A CTCF-binding silencer regulates the imprinted genes AWT1 and WT1-AS and exhibits sequential epigenetic defects during Wilms' tumourigenesis. Hum Mol Genet. 2007 Feb 1;16(3):343-54
Kim TH, Abdullaev ZK, Smith AD, Ching KA, Loukinov DI, Green RD, Zhang MQ, Lobanenkov VV, Ren B. Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell. 2007 Mar 23;128(6):1231-45
Li T, Lu L. Functional role of CCCTC binding factor (CTCF) in stress-induced apoptosis. Exp Cell Res. 2007 Aug 15;313(14):3057-65
Renda M, Baglivo I, Burgess-Beusse B, Esposito S, Fattorusso R, Felsenfeld G, Pedone PV. Critical DNA binding interactions of the insulator protein CTCF: a small number of zinc fingers mediate strong binding, and a single finger-DNA interaction controls binding at imprinted loci. J Biol Chem. 2007 Nov 16;282(46):33336-45
Sparago A, Russo S, Cerrato F, Ferraiuolo S, Castorina P, Selicorni A, Schwienbacher C, Negrini M, Ferrero GB, Silengo MC, Anichini C, Larizza L, Riccio A. Mechanisms causing imprinting defects in familial Beckwith-Wiedemann syndrome with Wilms' tumour. Hum Mol Genet. 2007 Feb 1;16(3):254-64
Bao L, Zhou M, Cui Y. CTCFBSDB: a CTCF-binding site database for characterization of vertebrate genomic insulators. Nucleic Acids Res. 2008 Jan;36(Database issue):D83-7
Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, Wong E, Orlov YL, Zhang W, Jiang J, Loh YH, Yeo HC, Yeo ZX, Narang V, Govindarajan KR, Leong B, Shahab A, Ruan Y, Bourque G, Sung WK, Clarke ND, Wei CL, Ng HH. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell. 2008 Jun 13;133(6):1106-17
Filippova GN. Genetics and epigenetics of the multifunctional protein CTCF. Curr Top Dev Biol. 2008;80:337-60
Fu VX, Dobosy JR, Desotelle JA, Almassi N, Ewald JA, Srinivasan R, Berres M, Svaren J, Weindruch R, Jarrard DF. Aging and cancer-related loss of insulin-like growth factor 2 imprinting in the mouse and human prostate. Cancer Res. 2008 Aug 15;68(16):6797-802
Fu Y, Sinha M, Peterson CL, Weng Z. The insulator binding protein CTCF positions 20 nucleosomes around its binding sites across the human genome. PLoS Genet. 2008 Jul 25;4(7):e1000138
Grbesa I, Marinkovic M, Ivkic M, Kruslin B, Novak-Kujundzic R, Pegan B, Bogdanovic O, Bedekovic V, Gall-Troselj K. Loss of imprinting of IGF2 and H19, loss of heterozygosity of IGF2R and CTCF, and Helicobacter pylori infection in laryngeal squamous cell carcinoma. J Mol Med (Berl). 2008 Sep;86(9):1057-66
Guastafierro T, Cecchinelli B, Zampieri M, Reale A, Riggio G, Sthandier O, Zupi G, Calabrese L, Caiafa P. CCCTC-binding factor activates PARP-1 affecting DNA methylation machinery. J Biol Chem. 2008 Aug 8;283(32):21873-80
Heath H, Ribeiro de Almeida C, Sleutels F, Dingjan G, van de Nobelen S, Jonkers I, Ling KW, Gribnau J, Renkawitz R, Grosveld F, Hendriks RW, Galjart N. CTCF regulates cell cycle progression of alphabeta T cells in the thymus. EMBO J. 2008 Nov 5;27(21):2839-50
Hore TA, Deakin JE, Marshall Graves JA. The evolution of epigenetic regulators CTCF and BORIS/CTCFL in amniotes. PLoS Genet. 2008 Aug 29;4(8):e1000169
Hou C, Zhao H, Tanimoto K, Dean A. CTCF-dependent enhancer-blocking by alternative chromatin loop formation. Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20398-403
Li T, Hu JF, Qiu X, Ling J, Chen H, Wang S, Hou A, Vu TH, Hoffman AR. CTCF regulates allelic expression of Igf2 by orchestrating a promoter-polycomb repressive complex 2 intrachromosomal loop. Mol Cell Biol. 2008 Oct;28(20):6473-82
Libby RT, Hagerman KA, Pineda VV, Lau R, Cho DH, Baccam SL, Axford MM, Cleary JD, Moore JM, Sopher BL, Tapscott SJ, Filippova GN, Pearson CE, La Spada AR. CTCF cis-regulates trinucleotide repeat instability in an
CTCF (CCCTC-binding factor (zinc finger protein)) Piette J
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 920
epigenetic manner: a novel basis for mutational hot spot determination. PLoS Genet. 2008 Nov;4(11):e1000257
Liu H, Huang J, Wang J, Jiang S, Bailey AS, Goldman DC, Welcker M, Bedell V, Slovak ML, Clurman B, Thayer M, Fleming WH, Epner E. Transvection mediated by the translocated cyclin D1 locus in mantle cell lymphoma. J Exp Med. 2008 Aug 4;205(8):1843-58
Majumder P, Gomez JA, Chadwick BP, Boss JM. The insulator factor CTCF controls MHC class II gene expression and is required for the formation of long-distance chromatin interactions. J Exp Med. 2008 Apr 14;205(4):785-98
Parelho V, Hadjur S, Spivakov M, Leleu M, Sauer S, Gregson HC, Jarmuz A, Canzonetta C, Webster Z, Nesterova T, Cobb BS, Yokomori K, Dillon N, Aragon L, Fisher AG, Merkenschlager M. Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell. 2008 Feb 8;132(3):422-33
Rubio ED, Reiss DJ, Welcsh PL, Disteche CM, Filippova GN, Baliga NS, Aebersold R, Ranish JA, Krumm A. CTCF physically links cohesin to chromatin. Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8309-14
Wendt KS, Yoshida K, Itoh T, Bando M, Koch B, Schirghuber E, Tsutsumi S, Nagae G, Ishihara K, Mishiro T, Yahata K, Imamoto F, Aburatani H, Nakao M, Imamoto N, Maeshima K, Shirahige K, Peters JM. Cohesin mediates transcriptional insulation by CCCTC-binding factor. Nature. 2008 Feb 14;451(7180):796-801
Chen RQ, Yang QK, Lu BW, Yi W, Cantin G, Chen YL, Fearns C, Yates JR 3rd, Lee JD. CDC25B mediates rapamycin-induced oncogenic responses in cancer cells. Cancer Res. 2009 Mar 15;69(6):2663-8
Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009 Aug 14;325(5942):834-40
Cuddapah S, Jothi R, Schones DE, Roh TY, Cui K, Zhao K. Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. Genome Res. 2009 Jan;19(1):24-32
Docquier F, Kita GX, Farrar D, Jat P, O'Hare M, Chernukhin I, Gretton S, Mandal A, Alldridge L, Klenova E. Decreased poly(ADP-ribosyl)ation of CTCF, a transcription factor, is associated with breast cancer phenotype and cell proliferation. Clin Cancer Res. 2009 Sep 15;15(18):5762-71
Gombert WM, Krumm A. Targeted deletion of multiple CTCF-binding elements in the human C-MYC gene reveals a requirement for CTCF in C-MYC expression. PLoS One. 2009 Jul 1;4(7):e6109
Green AR, Krivinskas S, Young P, Rakha EA, Paish EC, Powe DG, Ellis IO. Loss of expression of chromosome 16q genes DPEP1 and CTCF in lobular carcinoma in situ of the breast. Breast Cancer Res Treat. 2009 Jan;113(1):59-66
MacPherson MJ, Beatty LG, Zhou W, Du M, Sadowski PD. The CTCF insulator protein is posttranslationally modified by SUMO. Mol Cell Biol. 2009 Feb;29(3):714-25
Ottaviani A, Schluth-Bolard C, Rival-Gervier S, Boussouar A, Rondier D, Foerster AM, Morere J, Bauwens S, Gazzo S, Callet-Bauchu E, Gilson E, Magdinier F. Identification of a perinuclear positioning element in human subtelomeres that requires A-type lamins and CTCF. EMBO J. 2009 Aug 19;28(16):2428-36
Paradowska A, Fenic I, Konrad L, Sturm K, Wagenlehner F, Weidner W, Steger K. Aberrant epigenetic modifications
in the CTCF binding domain of the IGF2/H19 gene in prostate cancer compared with benign prostate hyperplasia. Int J Oncol. 2009 Jul;35(1):87-96
Phillips JE, Corces VG. CTCF: master weaver of the genome. Cell. 2009 Jun 26;137(7):1194-211
Smith ST, Wickramasinghe P, Olson A, Loukinov D, Lin L, Deng J, Xiong Y, Rux J, Sachidanandam R, Sun H, Lobanenkov V, Zhou J. Genome wide ChIP-chip analyses reveal important roles for CTCF in Drosophila genome organization. Dev Biol. 2009 Apr 15;328(2):518-28
Witcher M, Emerson BM. Epigenetic silencing of the p16(INK4a) tumor suppressor is associated with loss of CTCF binding and a chromatin boundary. Mol Cell. 2009 May 15;34(3):271-84
Dammann RH, Kirsch S, Schagdarsurengin U, Dansranjavin T, Gradhand E, Schmitt WD, Hauptmann S. Frequent aberrant methylation of the imprinted IGF2/H19 locus and LINE1 hypomethylation in ovarian carcinoma. Int J Oncol. 2010 Jan;36(1):171-9
Farrar D, Rai S, Chernukhin I, Jagodic M, Ito Y, Yammine S, Ohlsson R, Murrell A, Klenova E. Mutational analysis of the poly(ADP-ribosyl)ation sites of the transcription factor CTCF provides an insight into the mechanism of its regulation by poly(ADP-ribosyl)ation. Mol Cell Biol. 2010 Mar;30(5):1199-216
Gomes NP, Espinosa JM. Gene-specific repression of the p53 target gene PUMA via intragenic CTCF-Cohesin binding. Genes Dev. 2010 May 15;24(10):1022-34
Hou C, Dale R, Dean A. Cell type specificity of chromatin organization mediated by CTCF and cohesin. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3651-6
Kitchen NS, Schoenherr CJ. Sumoylation modulates a domain in CTCF that activates transcription and decondenses chromatin. J Cell Biochem. 2010 Oct 15;111(3):665-75
Lai AY, Fatemi M, Dhasarathy A, Malone C, Sobol SE, Geigerman C, Jaye DL, Mav D, Shah R, Li L, Wade PA. DNA methylation prevents CTCF-mediated silencing of the oncogene BCL6 in B cell lymphomas. J Exp Med. 2010 Aug 30;207(9):1939-50
Lu L, Wang L, Li T, Wang J. NF-kappaB subtypes regulate CCCTC binding factor affecting corneal epithelial cell fate. J Biol Chem. 2010 Mar 26;285(13):9373-82
Rodriguez C, Borgel J, Court F, Cathala G, Forné T, Piette J. CTCF is a DNA methylation-sensitive positive regulator of the INK/ARF locus. Biochem Biophys Res Commun. 2010 Feb 5;392(2):129-34
Soto-Reyes E, Recillas-Targa F. Epigenetic regulation of the human p53 gene promoter by the CTCF transcription factor in transformed cell lines. Oncogene. 2010 Apr 15;29(15):2217-27
Weth O, Weth C, Bartkuhn M, Leers J, Uhle F, Renkawitz R. Modular insulators: genome wide search for composite CTCF/thyroid hormone receptor binding sites. PLoS One. 2010 Apr 9;5(4):e10119
Xu J, Huo D, Chen Y, Nwachukwu C, Collins C, Rowell J, Slamon DJ, Olopade OI. CpG island methylation affects accessibility of the proximal BRCA1 promoter to transcription factors. Breast Cancer Res Treat. 2010 Apr;120(3):593-601
This article should be referenced as such:
Piette J. CTCF (CCCTC-binding factor (zinc finger protein)). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):914-920.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 921
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
EPS8 (epidermal growth factor receptor pathway substrate 8) Anna A Bulysheva, W Andrew Yeudall
VCU Philips Institute of Oral and Craniofacial Molecular Biology, Virginia Commonwealth
University, Richmond, VA 23298, USA (AAB, WAY)
Published in Atlas Database: April 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/EPS8ID40476ch12p12.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI EPS8ID40476ch12p12.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
HGNC (Hugo): EPS8
Location: 12p12.3
DNA/RNA
Description
The EPS8 gene can be found on chromosome 12 at
12p12.3, starting at position 15664342 bp and
ending at 15833601 bp from pter on the reverse
strand. It contains 21 exons.
Transcription
The transcript consists of 4.1 kb and translates to a
822 residue protein.
Protein
Description
822 amino acids; contains pleckstrin homology
(PH) domain at amino acids 69-129 and 381-414;
contains Src homology (SH3) domain at amino
acids 531-590; intertwined dimer.
Expression
Ubiquitous in adult; temporal expression in
developing mouse embryo, in frontonasal neural
crest cells, branchial arches, liver primordium,
central nervous system and submandibular glands.
Localisation
Plasma membrane; cytoplasm; perinuclear; possibly
nuclear.
Function
Scaffolding protein; participates in signal
transduction downstream of receptor tyrosine
kinases (incl. EGFR, CSF1R, PDGFR); receptor
endocytosis; cell motility; actin reorganization.
Homology
45 orthologues identified (Ensembl).
3 paralogues: EPS8L1; EPS8L2; EPS8L3.
Schematic representation of Homo sapiens EPS8.
EPS8 (epidermal growth factor receptor pathway substrate 8) Bulysheva AA, Yeudall WA
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 922
Implicated in
Cancer
Note
Eps8 is reported to be expressed at elevated levels
in a range of human malignancies, including breast
cancer, pancreatic cancer, colon cancer and head
and neck squamous cell carcinoma.
Oncogenesis
Overexpression of EPS8 has been reported to be
sufficient to transform non-tumorigenic human
cells to a tumorigenic phenotype. In a model system
using murine fibroblasts, EPS8 overexpression led
to enhanced mitogenic signaling and growth factor-
dependent cellular transformation. Constitutive
tyrosine phosphorylation of EPS8 has been
documented in human tumor cell lines, although the
significance of this for tumorigenesis remains to be
established.
Breast cancer
Oncogenesis
EPS8 overexpression has been shown via integrated
cDNA array comparative genomic hybridization
and serial analyses of gene expression in a number
of human breast cancer cell lines such as ductal
carcinoma in situ cell lines, invasive ductal
carcinomas and lymph node metastases, as novel
candidate breast cancer oncogenes.
Pancreatic cancer
Oncogenesis
EPS8 was found to be overexpressed in multiple
pancreatic tumors, with elevated levels primarily
found in pancreatic ductal cells, cell lines derived
from malignancies and ascites compared to lower
levels in primary tumors and normal pancreatic
tissues. EPS8 was reported to localize to the tips of
F-actin filaments, filopodia, and the leading edge of
the cells, and was therefore correlated with the
migratory potential of tumor cells.
Colon cancer
Oncogenesis
EPS8 was found to be overexpressed in the
majority of colorectal tumors compared to their
normal counterparts. It was also found to modulate
FAK expression and together, EPS8 and FAK were
found to play an important role in cell locomotion.
Head and neck squamous cell carcinoma
Oncogenesis
Greater expression of EPS8 was found in malignant
head and neck squamous cell carcinoma cell lines
(HN12) compared to the primary tumor derived
cells (HN4) from the same patient. Ectopic
overexpression of EPS8 in HN4 cells led to
increased cell proliferation and migration in vitro
and tumorgenicity in vivo.
Signaling processes involving EPS8. Dashed lines, direct protein interactions; blue circles, effector proteins.
EPS8 (epidermal growth factor receptor pathway substrate 8) Bulysheva AA, Yeudall WA
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 923
Knockdown of EPS8 in HN12 cells led to reduced
migration in vitro and reduced tumorgenicity in
vivo. EPS8 was found to mediate alphavbeta6 and
alpha5beta1 integrin dependent activation of Rac1
and resulting cell migration. Suppression of either
EPS8 or Rac1 resulted in reduced cell motility of
the same tumor cells, however constitutive
expression of Rac1 rescued reduced cell migration
in EPS8 knockdown cells. Therefore EPS8 and
Rac1 likely modulate integrin-dependent tumor cell
motility. FOXM1, a cell cycle related transcription
factor, was found to be upregulated in tumor cells
with elevated EPS8. Further studies showed cell
proliferation and migration due to EPS8 occurs in
part by FOXM1 deregulation and induction of
CXC-chemokine expression, which is mediated by
PI3K and AKT-dependent mechanisms.
References Fazioli F, Minichiello L, Matoska V, Castagnino P, Miki T, Wong WT, Di Fiore PP. Eps8, a substrate for the epidermal growth factor receptor kinase, enhances EGF-dependent mitogenic signals. EMBO J. 1993 Oct;12(10):3799-808
Alvarez CV, Shon KJ, Miloso M, Beguinot L. Structural requirements of the epidermal growth factor receptor for tyrosine phosphorylation of eps8 and eps15, substrates lacking Src SH2 homology domains. J Biol Chem. 1995 Jul 7;270(27):16271-6
Avantaggiato V, Torino A, Wong WT, Di Fiore PP, Simeone A. Expression of the receptor tyrosine kinase substrate genes eps8 and eps15 during mouse development. Oncogene. 1995 Sep 21;11(6):1191-8
Castagnino P, Biesova Z, Wong WT, Fazioli F, Gill GN, Di Fiore PP. Direct binding of eps8 to the juxtamembrane domain of EGFR is phosphotyrosine- and SH2-independent. Oncogene. 1995 Feb 16;10(4):723-9
Matoskova B, Wong WT, Salcini AE, Pelicci PG, Di Fiore PP. Constitutive phosphorylation of eps8 in tumor cell lines: relevance to malignant transformation. Mol Cell Biol. 1995 Jul;15(7):3805-12
Matòsková B, Wong WT, Nomura N, Robbins KC, Di Fiore PP. RN-tre specifically binds to the SH3 domain of eps8 with high affinity and confers growth advantage to NIH3T3 upon carboxy-terminal truncation. Oncogene. 1996 Jun 20;12(12):2679-88
Matòsková B, Wong WT, Seki N, Nagase T, Nomura N, Robbins KC, Di Fiore PP. RN-tre identifies a family of tre-related proteins displaying a novel potential protein binding domain. Oncogene. 1996 Jun 20;12(12):2563-71
Biesova Z, Piccoli C, Wong WT. Isolation and characterization of e3B1, an eps8 binding protein that regulates cell growth. Oncogene. 1997 Jan 16;14(2):233-41
Gallo R, Provenzano C, Carbone R, Di Fiore PP, Castellani L, Falcone G, Alemà S. Regulation of the tyrosine kinase substrate Eps8 expression by growth factors, v-Src and terminal differentiation. Oncogene. 1997 Oct 16;15(16):1929-36
Kishan KV, Scita G, Wong WT, Di Fiore PP, Newcomer ME. The SH3 domain of Eps8 exists as a novel intertwined dimer. Nat Struct Biol. 1997 Sep;4(9):739-43
Inobe M, Katsube K, Miyagoe Y, Nabeshima Y, Takeda S. Identification of EPS8 as a Dvl1-associated molecule.
Biochem Biophys Res Commun. 1999 Dec 9;266(1):216-21
Maa MC, Lai JR, Lin RW, Leu TH. Enhancement of tyrosyl phosphorylation and protein expression of eps8 by v-Src. Biochim Biophys Acta. 1999 Jul 8;1450(3):341-51
Scita G, Nordstrom J, Carbone R, Tenca P, Giardina G, Gutkind S, Bjarnegård M, Betsholtz C, Di Fiore PP. EPS8 and E3B1 transduce signals from Ras to Rac. Nature. 1999 Sep 16;401(6750):290-3
Lanzetti L, Rybin V, Malabarba MG, Christoforidis S, Scita G, Zerial M, Di Fiore PP. The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5. Nature. 2000 Nov 16;408(6810):374-7
Burke P, Schooler K, Wiley HS. Regulation of epidermal growth factor receptor signaling by endocytosis and intracellular trafficking. Mol Biol Cell. 2001 Jun;12(6):1897-910
Kishan KV, Newcomer ME, Rhodes TH, Guilliot SD. Effect of pH and salt bridges on structural assembly: molecular structures of the monomer and intertwined dimer of the Eps8 SH3 domain. Protein Sci. 2001 May;10(5):1046-55
Maa MC, Hsieh CY, Leu TH. Overexpression of p97Eps8 leads to cellular transformation: implication of pleckstrin homology domain in p97Eps8-mediated ERK activation. Oncogene. 2001 Jan 4;20(1):106-12
Scita G, Tenca P, Areces LB, Tocchetti A, Frittoli E, Giardina G, Ponzanelli I, Sini P, Innocenti M, Di Fiore PP. An effector region in Eps8 is responsible for the activation of the Rac-specific GEF activity of Sos-1 and for the proper localization of the Rac-based actin-polymerizing machine. J Cell Biol. 2001 Sep 3;154(5):1031-44
Innocenti M, Tenca P, Frittoli E, Faretta M, Tocchetti A, Di Fiore PP, Scita G. Mechanisms through which Sos-1 coordinates the activation of Ras and Rac. J Cell Biol. 2002 Jan 7;156(1):125-36
Calderwood DA, Fujioka Y, de Pereda JM, García-Alvarez B, Nakamoto T, Margolis B, McGlade CJ, Liddington RC, Ginsberg MH. Integrin beta cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2272-7
Innocenti M, Frittoli E, Ponzanelli I, Falck JR, Brachmann SM, Di Fiore PP, Scita G. Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1. J Cell Biol. 2003 Jan 6;160(1):17-23
Croce A, Cassata G, Disanza A, Gagliani MC, Tacchetti C, Malabarba MG, Carlier MF, Scita G, Baumeister R, Di Fiore PP. A novel actin barbed-end-capping activity in EPS-8 regulates apical morphogenesis in intestinal cells of Caenorhabditis elegans. Nat Cell Biol. 2004 Dec;6(12):1173-9
Disanza A, Carlier MF, Stradal TE, Didry D, Frittoli E, Confalonieri S, Croce A, Wehland J, Di Fiore PP, Scita G. Eps8 controls actin-based motility by capping the barbed ends of actin filaments. Nat Cell Biol. 2004 Dec;6(12):1180-8
Funato Y, Terabayashi T, Suenaga N, Seiki M, Takenawa T, Miki H. IRSp53/Eps8 complex is important for positive regulation of Rac and cancer cell motility/invasiveness. Cancer Res. 2004 Aug 1;64(15):5237-44
Leu TH, Yeh HH, Huang CC, Chuang YC, Su SL, Maa MC. Participation of p97Eps8 in Src-mediated transformation. J Biol Chem. 2004 Mar 12;279(11):9875-81
Offenhäuser N, Borgonovo A, Disanza A, Romano P, Ponzanelli I, Iannolo G, Di Fiore PP, Scita G. The eps8
EPS8 (epidermal growth factor receptor pathway substrate 8) Bulysheva AA, Yeudall WA
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 924
family of proteins links growth factor stimulation to actin reorganization generating functional redundancy in the Ras/Rac pathway. Mol Biol Cell. 2004 Jan;15(1):91-8
Wunsch A, Strothmann K, Simoni M, Gromoll J, Nieschlag E, Luetjens CM. Epidermal growth factor receptor pathway substrate 8 (Eps8) expression in maturing testis. Asian J Androl. 2004 Sep;6(3):195-203
Roffers-Agarwal J, Xanthos JB, Miller JR. Regulation of actin cytoskeleton architecture by Eps8 and Abi1. BMC Cell Biol. 2005 Oct 14;6:36
Disanza A, Mantoani S, Hertzog M, Gerboth S, Frittoli E, Steffen A, Berhoerster K, Kreienkamp HJ, Milanesi F, Di Fiore PP, Ciliberto A, Stradal TE, Scita G. Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8-IRSp53 complex. Nat Cell Biol. 2006 Dec;8(12):1337-47
Khanday FA, Santhanam L, Kasuno K, Yamamori T, Naqvi A, Dericco J, Bugayenko A, Mattagajasingh I, Disanza A, Scita G, Irani K. Sos-mediated activation of rac1 by p66shc. J Cell Biol. 2006 Mar 13;172(6):817-22
Yao J, Weremowicz S, Feng B, Gentleman RC, Marks JR, Gelman R, Brennan C, Polyak K. Combined cDNA array comparative genomic hybridization and serial analysis of gene expression analysis of breast tumor progression. Cancer Res. 2006 Apr 15;66(8):4065-78
Maa MC, Lee JC, Chen YJ, Chen YJ, Lee YC, Wang ST, Huang CC, Chow NH, Leu TH. Eps8 facilitates cellular growth and motility of colon cancer cells by increasing the expression and activity of focal adhesion kinase. J Biol Chem. 2007 Jul 6;282(27):19399-409
Welsch T, Endlich K, Giese T, Büchler MW, Schmidt J. Eps8 is increased in pancreatic cancer and required for dynamic actin-based cell protrusions and intercellular cytoskeletal organization. Cancer Lett. 2007 Oct 8;255(2):205-18
Chen YJ, Shen MR, Chen YJ, Maa MC, Leu TH. Eps8 decreases chemosensitivity and affects survival of cervical cancer patients. Mol Cancer Ther. 2008 Jun;7(6):1376-85
Wang H, Patel V, Miyazaki H, Gutkind JS, Yeudall WA. Role for EPS8 in squamous carcinogenesis. Carcinogenesis. 2009 Jan;30(1):165-74
Xu M, Shorts-Cary L, Knox AJ, Kleinsmidt-DeMasters B, Lillehei K, Wierman ME. Epidermal growth factor receptor pathway substrate 8 is overexpressed in human pituitary tumors: role in proliferation and survival. Endocrinology. 2009 May;150(5):2064-71
Yap LF, Jenei V, Robinson CM, Moutasim K, Benn TM, Threadgold SP, Lopes V, Wei W, Thomas GJ, Paterson IC. Upregulation of Eps8 in oral squamous cell carcinoma promotes cell migration and invasion through integrin-dependent Rac1 activation. Oncogene. 2009 Jul 9;28(27):2524-34
Zhang W, Wang L, Liu Y, Xu J, Zhu G, Cang H, Li X, Bartlam M, Hensley K, Li G, Rao Z, Zhang XC. Structure of human lanthionine synthetase C-like protein 1 and its interaction with Eps8 and glutathione. Genes Dev. 2009 Jun 15;23(12):1387-92
Liu PS, Jong TH, Maa MC, Leu TH. The interplay between Eps8 and IRSp53 contributes to Src-mediated transformation. Oncogene. 2010 Jul 8;29(27):3977-89
Wang H, Teh MT, Ji Y, Patel V, Firouzabadian S, Patel AA, Gutkind JS, Yeudall WA. EPS8 upregulates FOXM1 expression, enhancing cell growth and motility. Carcinogenesis. 2010 Jun;31(6):1132-41
Welsch T, Younsi A, Disanza A, Rodriguez JA, Cuervo AM, Scita G, Schmidt J. Eps8 is recruited to lysosomes and subjected to chaperone-mediated autophagy in cancer cells. Exp Cell Res. 2010 Jul 15;316(12):1914-24
Yang TP, Chiou HL, Maa MC, Wang CJ. Mithramycin inhibits human epithelial carcinoma cell proliferation and migration involving downregulation of Eps8 expression. Chem Biol Interact. 2010 Jan 5;183(1):181-6
This article should be referenced as such:
Bulysheva AA, Yeudall WA. EPS8 (epidermal growth factor receptor pathway substrate 8). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):921-924.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 925
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
FAM107A (family with sequence similarity 107, member A) Kenji Kadomatsu, Ping Mu
Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho,
Showa-ku, Nagoya 466-8550, Japan (KK, PM)
Published in Atlas Database: April 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/FAM107AID42728ch3p14.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI FAM107AID42728ch3p14.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: DRR1; FLJ30158; FLJ45473;
TU3A
HGNC (Hugo): FAM107A
Location: 3p14.3
Note: The FAM107A protein is encoded by
FAM107A gene.
DNA/RNA
Description
FAM107A DNA contains 17742 bps (genomic
size), on negative strand.
Transcription
FAM107A has two transcript variants. FAM107A
transcript variant 1 mRNA contains 3465 bps and 5
exons. FAM107A transcript variant 2 mRNA
contains 3367 bps and 4 exons. These two
transcript variants encode for the same protein.
Protein
Description
144 amino acids, 17,5 kDa.
FAM107A protein includes a nuclear localization
signal (NLS) and a coiled domain (Yamato et al.,
1999; Wang et al., 2000).
Expression
FAM107A protein is expressed in a wide variety of
normal tissues. High expression is found in the
brain and heart (Wang et al., 2000; Zhao et al.,
2007).
Localisation
Nucleus and cytoplasm (Wang et al., 2000; Zhao et
al., 2007; Le et al., 2010).
Function
FAM107A is a candidate tumor suppressor gene.
FAM107A protein is downregulated in several
tumor cell lines and primary tumors.
Overexpression of FAM107A can suppress tumor
cell growth (Yamato et al., 1999; Wang et al., 2000;
Kholodnyuk et al., 2006; van den Boom et al.,
2006; Liu et al., 2009; Asano et al., 2010; Le et al.,
2010).
FAM107A protein is also involved in neuronal cell
survival. Downregulation of FAM107A protein in
primary cultured cortical neurons decrease cell
number (Asano et al., 2010).
FAM107A protein probably plays important roles
in embryo development (Zhao et al., 2007).
FAM107A protein is a cytoskeletal crosslinker that
regulates FA dynamics and cell movement.
FAM107A protein is an important molecular in cell
invasion (Le et al., 2010).
Homology
No proteins with significant homology with
FAM107A protein were found (Wang et al., 2000).
FAM107A (family with sequence similarity 107, member A) Kadomatsu K, Mu P
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 926
Mutations
Note
Up to now, no point mutations were identified.
Implicated in
Renal cell carcimoma
Disease
Loss of FAM107A gene was found on 3p21.1 in
renal cell carcinoma. Reduced expression was
found in renal cell carcinoma cell lines and primary
renal cell carcinomas. Overexpression of
FAM107A in renal cell carcinoma cell line resulted
in growth suppression of these cells (Yamato et al.,
1999; Wang et al., 2000). Also, FAM107A
hypermethylation was detected in renal cell
carcimomas and significantly associated with
advanced tumor stage (Awakura et al., 2008).
Astrocytomas
Disease
FAM107A was expressed at significantly lower
levels in secondary glioblastomas as compared to
diffuse astrocytomas (Van den Boom et al., 2006).
Lung cancer
Disease
Loss of expression of FAM107A was found in non-
small cell lung cancer and primary lung cancers.
Overexpression of FAM107A in non-small cell
lung cancer cell line reduced cell proliferation
activity and induced apoptosis (Liu et al., 2009).
Neuroblastoma
Disease
FAM107A protein was detected in the normal
ganglions and the ganglions exhibiting neuroblast
hyperplasia from 2 weeks hemizygote MYCN
transgenic mice. However, the expression of
FAM107A completely disappeared in the tumors
from 8 weeks hemizygote MYCN transgenic mice
(Asano et al., 2010).
Brain tumor
Disease
FAM107A is not expressed in normal glial cells, it
is highly expressed in the invasive component of
gliomas. It was found that FAM107A associates
with and organizes the actin and microtubular
cytoskeletons. FAM107A regulates focal adhesion
disassembly and cell invasion (Le et al., 2010).
Embryo development
Note
The expression level of FAM107A gene increases
gradually with embryo development in the early
stages (Zhao et al., 2007).
Schizophrenia and bipolar disorder
Note
High expression level of FAM107A was found in
the dorsolateral prefrontal cortex from
schizophrenia and bipolar disorder patient (Shao et
al., 2007).
Neuronal cell survival
Note
FAM107A protein was mainly localized in the
neurites of the primary culture of cerebral cortical
neurons. Downregulation of FAM107A expression
with siRNA decreased neuron cell number. These
data suggest that FAM107A plays a critical role in
neuronal cell survival (Asano et al., 2010).
References Yamato T, Orikasa K, Fukushige S, Orikasa S, Horii A. Isolation and characterization of the novel gene, TU3A, in a commonly deleted region on 3p14.3-->p14.2 in renal cell carcinoma. Cytogenet Cell Genet. 1999;87(3-4):291-5
Wang L, Darling J, Zhang JS, Liu W, Qian J, Bostwick D, et al. Loss of expression of the DRR 1 gene at chromosomal segment 3p21.1 in renal cell carcinoma. Genes Chromosomes Cancer. 2000 Jan;27(1):1-10
Kholodnyuk ID, Kozireva S, Kost-Alimova M, Kashuba V, Klein G, Imreh S. Down regulation of 3p genes, LTF, SLC38A3 and DRR1, upon growth of human chromosome 3-mouse fibrosarcoma hybrids in severe combined immunodeficiency mice. Int J Cancer. 2006 Jul 1;119(1):99-107
van den Boom J, Wolter M, Blaschke B, Knobbe CB, Reifenberger G. Identification of novel genes associated with astrocytoma progression using suppression subtractive hybridization and real-time reverse transcription-polymerase chain reaction. Int J Cancer. 2006 Nov 15;119(10):2330-8
Zhao XY, Liang SF, Yao SH, Ma FX, Hu ZG, Yan F, Yuan Z, Ruan XZ, Yang HS, Zhou Q, Wei YQ. Identification and preliminary function study of Xenopus laevis DRR1 gene. Biochem Biophys Res Commun. 2007 Sep 14;361(1):74-8
Awakura Y, Nakamura E, Ito N, Kamoto T, Ogawa O. Methylation-associated silencing of TU3A in human cancers. Int J Oncol. 2008 Oct;33(4):893-9
Shao L, Vawter MP. Shared gene expression alterations in schizophrenia and bipolar disorder. Biol Psychiatry. 2008 Jul 15;64(2):89-97
Zhao XY, Li HX, Liang SF, Yuan Z, Yan F, Ruan XZ, You J, Xiong SQ, Tang MH, Wei YQ. Soluble expression of human DRR1 (down-regulated in renal cell carcinoma 1) in Escherichia coli and preparation of its polyclonal antibodies. Biotechnol Appl Biochem. 2008 Jan;49(Pt 1):17-23
Liu Q, Zhao XY, Bai RZ, Liang SF, Nie CL, Yuan Z, Wang CT, Wu Y, Chen LJ, Wei YQ. Induction of tumor inhibition and apoptosis by a candidate tumor suppressor gene DRR1 on 3p21.1. Oncol Rep. 2009 Nov;22(5):1069-75
Asano Y, Kishida S, Mu P, Sakamoto K, Murohara T, Kadomatsu K. DRR1 is expressed in the developing nervous system and downregulated during neuroblastoma carcinogenesis. Biochem Biophys Res Commun. 2010 Apr 9;394(3):829-35
Frijters R, Fleuren W, Toonen EJ, Tuckermann JP, et al Prednisolone-induced differential gene expression in mouse liver carrying wild type or a dimerization-defective glucocorticoid receptor. BMC Genomics. 2010 Jun 5;11:359
FAM107A (family with sequence similarity 107, member A) Kadomatsu K, Mu P
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 927
Le PU, Angers-Loustau A, de Oliveira RM, Ajlan A, Brassard CL, Dudley A, Brent H, Siu V, Trinh G, Mölenkamp G, Wang J, Seyed Sadr M, Bedell B, Del Maestro RF, Petrecca K. DRR drives brain cancer invasion by regulating cytoskeletal-focal adhesion dynamics. Oncogene. 2010 Aug 19;29(33):4636-47
This article should be referenced as such:
Kadomatsu K, Mu P. FAM107A (family with sequence similarity 107, member A). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):925-927.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 928
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
GAST (gastrin) Celia Chao, Mark R Hellmich
Department of Surgery, Sealy Center for Cancer Cell Biology, University of Texas Medical Branch,
Galveston, TX 77555, USA (CC, MRH)
Published in Atlas Database: April 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/GASTID44214ch17q21.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI GASTID44214ch17q21.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: GAS
HGNC (Hugo): GAST
Location: 17q21.2
DNA/RNA
Note
The 4.3 kb gene for human gastrin contains two
introns and 3 exons that encode preprogastrin, the
gastrin precursor. It is located on chromosome
17(q21), and consists of three exons that contain the
code sequence for a prepropeptide of 101 amino
acid residues with a calculated molecular mass of
11.4 kDa (see diagram below). The primary
structure of human preprogastrin protein consists of
an N-terminal 21-amino acid signal sequence
followed by a spacer peptide, a bioactive domain,
and finally a hexapeptide C-terminal flanking
peptide (CTFP). Upon initiation of translation, the
signal sequence facilitates the translocation of the
elongating polypeptide into the endoplasmic
reticulum (ER), where it is subsequently removed
by a membrane-bound signal peptidase that cleaves
the growing polypeptide chain between alanine
residue 21 and serine 22 to generate the 80 amino
acid peptide, progastrin. Progastrin is further
processed (see protein section below) into the two
principal C-terminal alpha-amidated forms of
circulating gastrin generated from the proteolytic
cleavage of progastrin are gastrin-17 (G17) and
gastrin-34 (G34).
Protein
Note
It should be noted that the numbering system of
critical amino acid residues involved in peptide
cleavage and post-translational modifications of
gastrin varies within the scientific literature. This is
due to the fact that the numbering system of some
authors is based on the sequence of preprogastrin,
which includes the 21 amino acids of the signal
peptide sequence, whereas the numbering system of
others is based on the sequence of progastrin. Our
description of prohormone processing will be based
on the 80 amino acid peptide sequence of
progastrin.
After signal peptide cleavage, progastrin undergoes
additional post-translational modifications as it
transits from the ER through the Golgi to the trans-
Golgi network before it is sorted into immature
secretory vesicles of the regulated exocytosis
(secretory) pathway. The modifications include O-
sulfation at tyrosine residue 66 of the propeptide by
tyrosylprotein sulfotransferases and/or
phosphorylation at serine 75 by a calcium-
dependent casein-like kinase. Although O-sulfation
is thought to occur primarily in the trans-Golgi
network, a recent study provides evidence
suggesting that it may continue through later
compartments of the regulated secretory pathway.
Chromosome 17 - NC_000017.10.
GAST (gastrin) Chao C, Hellmich MR
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 929
Schematic representation of the preprogastrin gene, its mRNA, and the peptide precursor preprogastrin. The gene is transcribed as a 303 nucleotide RNA transcript and the mRNA is processed into a 101 amino acid (aa) preprohormone. The
preprogastrin peptide consists of a 21-aa signal sequence, which is co-translationally cleaved, a N-terminal spacer, the active peptide and the C-terminal flanking peptide (CTFP). Progastrin is formed after removal of the signal peptide.
The extent of gastrin O-sulfation varies with
species and cellular localization of peptide
synthesis within the GI tract as well as the
developmental stage of the tissues. For example, in
adult humans, approximately half of the gastrin
peptide synthesized in G cells of the antrum and
duodenum, and released into the circulation are
sulfated, whereas all of the gastrin peptide produced
by the fetal pancreas appears to be sulfated.
Functionally, sulfation of gastrin enhances
endoproteolytic processing of progastrin, and may
promote protein-protein interactions and peptide
sorting between secretory pathways. However,
unlike sulfation of the related peptide,
cholecystokinin (CCK), sulfation of gastrin does
not significantly affect its affinity for its
physiologic receptor.
Phosphorylation of serine 75 of progastrin may
promote proteolytic processing at the upstream
arginine residues at positions 73 and 74 (arginine
73-arginine 74) releasing the C-terminal flanking
peptide, and may affect the conversion of glycine-
extended gastrin intermediates to mature C-terminal
alpha-amidated peptides. However, since
phosphorylation is not essential for progastrin
processing, its biological significance remains an
enigma.
Following sulfation and/or phosphorylation,
progastrin exits the trans-Golgi network and enters
immature granules of the regulated secretory
pathway. The major proteolytic processing of
progastrin to its biologically active peptides occurs
in the maturing dense core secretory granules of the
regulated pathway. Progastrin is cleaved by two
types of proteases: endo- and exopeptidases.
Endopeptidases, also known as prohormone
convertases (PC), typically cleave polypeptides
downstream of two adjacent basic amino acid
residues at the general motif (lysine/arginine)-(X)n-
(lysine/arginine), where n=0, 2, 4, or 6 and X is any
amino acid, but usually not a Cysteine. PC1/3 and
PC2 are involved in progastrin processing.
The two principal biologically active forms of
circulating gastrin are gastrin-17 (G17) and gastrin-
34 (G34). In rodent and human G cells of antrum
and proximal duodenum, approximately 95% of the
progastrin is processed to partially sulfated G17
(85%) and G34 (10%). Although G17 is the
predominant product, G34 is the major circulating
form of gastrin due to its slower rate of clearance.
In both humans, the half-life of circulating G34 is
approximately five times longer than that of G17.
The proteolytic processing of progastrin involves
convertase-specific cleavage at three dibasic
consensus sites. PC1/3 is active early in the
secretory pathway in granules with a neutral pH
(i.e., pH ≈ 7) and cleaves the prohormone after the
arginine 36-arginine 37 and arginine 73-arginine 74
sequences, releasing the C-terminal flanking
peptide, and generating G34. The post-cleavage
residual basic residues are then removed by
carboxypeptidase E, generating what are commonly
referred to as the glycine-extended gastrins (i.e.,
G34-Glycine). In contrast to PC1/3, PC2 is mainly
active in mature granules at an acidic pH (i.e., pH ≈
5). Cleavage of G34-glycine by PC2 after the
dibasic amino acid sequence lysine 53-lysine 54
produces G17-glycine. These glycine-extended
peptides are substrates for the peptidyl-glycine
alpha-amidating monooxygenase (PAM) that
utilizes the glycyl residue as an amide donor to
alpha-amidate the carboxyl group of the C-terminus
of the peptide. The ratio of amidated gastrins to
processing intermediates varies considerably across
tissues and cell types. Processing intermediates are
quite scarce in the gastric antrum, making up only
about 1-5% of gastrin gene products, while in the
duodenum the value has been reported to be as high
GAST (gastrin) Chao C, Hellmich MR
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 930
Processing of gastrin. The numbering system of critical amino acid residues involved in peptide cleavage and post-translational modifications of gastrin varies within the scientific literature. This is due to the fact that the numbering system of some authors is
based on the sequence of preprogastrin, which includes the 21 amino acids of the signal peptide sequence, whereas the numbering system of others is based on the sequence of progastrin. The numbers at the top of the diagram represents the
amino acid (aa) sequence for preprogastrin; the numbers at the bottom of the diagram represents the aa sequence for progastrin. The signal peptide is cleaved co-translationally in the rough ER by signal peptidase. In the Trans-Golgi-Network
(TGN), progastrin is modified by sulfation at Tyr 66 and phosphorylation of Ser 75 by a casein-like kinase. Prohormone convertases (PC) and carboxypeptidase E (CPE) sequentially convert the prohormone to the glycine-extended forms (G71-Gly,
G34-Gly, G17-Gly). Abbreviations: CTFP: C-terminal flanking peptide, TPST: tyrosyl-protein sulfotransferase, PAM: peptidyl-alpha-amidating-monooxygenase.
as 20%. Carboxyl-terminus alpha-amidation is a
prerequisite for high affinity binding of gastrin to
its cognate receptor, CCK2 receptor.
Mutations
Note
There are no known mutations in the gastrin gene
causing a pathologic entity. Overexpression of
gastrin, or aberrant expression of gastrin, have both
been associated with gastric, colorectal, esophageal
and pancreatic cancers.
Implicated in
Gastrinomas
Note
Gastrinomas are neuroendocrine tumors that can
arise from the stomach, duodenum or pancreas.
Patients with multiple endocrine neoplasia type 1
(MEN1) have a mutation in the menin gene and are
at very high risk for developing gastrinomas. In
patients with hypergastrinemia due to pernicious
anemia or MEN1, tissue and plasma levels of PAI-2
are elevated. Gastrin directly regulates PAI-2
expression in CCK2 receptor-positive cells, and in
neighboring receptor-negative cells, by way of
paracrine mediators released from the CCK2
receptor-expressing cells. Direct regulation involves
cell automous activation of CRE and AP-1
transcription factors via a PKC, Ras, Raf, RhoA,
and the NFkappaB signaling pathways in CCK2
receptor-expressing cells by gastrin. The CRE and
AP-1 transcription factors, in turn, regulate
expression of the genes for IL-8 and COX2. IL-8
acts through a GACAGA site via the activating
signal cointegrator 1 (ASC-1) complex, whereas
prostaglandins, resulting from the activation of
COX2, target the Myc-associated zinc finger
protein (MAZ site via the small GTPase RhoA to
stimulate PAI-2 expression in adjacent CCK2
receptor-negative cells.
Inflammation-associated carcinomas
Note
In a rat intestinal epithelial cell model, MAPKs
mediate CCK2 receptor regulation of cyclooxgenase
2 (COX-2). COX-2 is an inducible enzyme
catalyzing the rate-limiting step in prostaglandin
synthesis, converting arachidonic acid to
prostaglandin H2. A large body of genetic and
biochemical evidence support the important role of
GAST (gastrin) Chao C, Hellmich MR
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 931
COX-2 and the subsequent synthesis of
prostaglandins in the regulation of inflammation
and promotion of tumorigenesis. Gastrin has been
shown to increase COX-2 expression in colorectal,
gastric, and esophageal cancers.
Gastric cancer
Note
Gastric carcinogenesis is a multistep process that
arises from superficial gastritis, chronic atrophic
gastritis, progressing to intestinal metaplasia,
dysplasia, and finally carcinoma. H. pylori is the
most common known cause of chronic gastritis in
humans, secretes urease, which converts urea to
ammonia, and neutralizes the acid in the stomach.
H. pylori initiates a host inflammatory response that
is associated with the recruitment of mononuclear
and polymorphonuclear leukocytes, and bone
marrow-derived cells. Specific inflammatory
cytokines from immune cells are required for the
initiation and promotion of carcinogenesis. In
addition to local inflammation, H. pylori induces
the systemic elevation of serum gastrin
(hypergastrinemia). The combination of
achlorhydria and hypergastrinemia, induced by H.
pylori infection, results in gastric bacterial
overgrowth, lack of parietal cell differentiation,
development of gastric metaplasia, and eventual
progression to gastric carcinoma.
Colorectal cancer
Note
Gastrin and gastrin-like peptides are upregulated
locally in 78% of premalignant adenomatous
polyps, before the appearance of invasive
carcinoma, and gastrin expression has been linked
to key mutations in the initiation of colorectal
carcinogenesis. When the APCmin-/+
mouse was
crossed with a gastrin gene knockout mouse, the
hybrid developed fewer intestinal polyps. Gastrin
transcription is linked to the Wnt/beta-catenin
pathway by a binding site for the transcription
factor TCF4 in the gastrin promoter. Induction of
the wild-type APC decreased gastrin mRNA
expression, while transfection of constitutively
active beta-catenin increased gastrin promoter
activity.
References GREGORY RA, TRACY HJ. THE CONSTITUTION AND PROPERTIES OF TWO GASTRINS EXTRACTED FROM HOG ANTRAL MUCOSA. Gut. 1964 Apr;5:103-14
Korman MG, John DJ, Hansky J. Studies on serum gastrin levels in pernicious anaemia. Gut. 1970 Nov;11(11):981
Rehfeld JF, Stadil F. Gel filtration studies on immunoreactive gastrin in serum from Zollinger-Ellison patients. Gut. 1973 May;14(5):369-73
Stadil F, Rehfeld JF. Release of gastrin by epinephrine in man. Gastroenterology. 1973 Aug;65(2):210-5
Walsh JH, Debas HT, Grossman MI. Pure human big gastrin. Immunochemical properties, disappearance half time, and acid-stimulating action in dogs. J Clin Invest. 1974 Aug;54(2):477-85
Dockray GJ, Taylor IL. Heptadecapeptide gastrin: measurement in blood by specific radioimmunoassay. Gastroenterology. 1976 Dec;71(6):971-7
Larsson LI, Rehfeld JF, Sundler F, Håkanson R. Pancreatic gastrin in foetal and neonatal rats. Nature. 1976 Aug 12;262(5569):609-10
Walsh JH, Isenberg JI, Ansfield J, Maxwell V. Clearance and acid-stimulating action of human big and little gastrins in duodenal ulcer subjects. J Clin Invest. 1976 May;57(5):1125-31
Feldman M, Walsh JH, Wong HC, Richardson CT. Role of gastrin heptadecapeptide in the acid secretory response to amino acids in man. J Clin Invest. 1978 Feb;61(2):308-13
Thompson JC, Lowder WS, Peurifoy JT, Swierczek JS, Rayford PL. Effect of selective proximal vagotomy and truncal vagotomy on gastric acid and serum gastrin responses to a meal in duodenal ulcer patients. Ann Surg. 1978 Oct;188(4):431-8
Hirschowitz BI, Helman CA. Effects of fundic vagotomy and cholinergic replacement on pentagastrin dose responsive gastric acid and pepsin secretion in man. Gut. 1982 Aug;23(8):675-82
Taylor IL, Byrne WJ, Christie DL, Ament ME, Walsh JH. Effect of individual l-amino acids on gastric acid secretion and serum gastrin and pancreatic polypeptide release in humans. Gastroenterology. 1982 Jul;83(1 Pt 2):273-8
Boel E, Vuust J, Norris F, Norris K, Wind A, Rehfeld JF, Marcker KA. Molecular cloning of human gastrin cDNA: evidence for evolution of gastrin by gene duplication. Proc Natl Acad Sci U S A. 1983 May;80(10):2866-9
Andersen BN. Measurement and occurrence of sulfated gastrins. Scand J Clin Lab Invest Suppl. 1984;168:5-24
Brand SJ, Andersen BN, Rehfeld JF. Complete tyrosine-O-sulphation of gastrin in neonatal rat pancreas. Nature. 1984 May 31-Jun 6;309(5967):456-8
Brand SJ, Klarlund J, Schwartz TW, Rehfeld JF. Biosynthesis of tyrosine O-sulfated gastrins in rat antral mucosa. J Biol Chem. 1984 Nov 10;259(21):13246-52
Ito R, Sato K, Helmer T, Jay G, Agarwal K. Structural analysis of the gene encoding human gastrin: the large intron contains an Alu sequence. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4662-6
Saffouri B, DuVal JW, Makhlouf GM. Stimulation of gastrin secretion in vitro by intraluminal chemicals: regulation by intramural cholinergic and noncholinergic neurons. Gastroenterology. 1984 Sep;87(3):557-61
Wiborg O, Berglund L, Boel E, Norris F, Norris K, Rehfeld JF, Marcker KA, Vuust J. Structure of a human gastrin gene. Proc Natl Acad Sci U S A. 1984 Feb;81(4):1067-9
Hollinshead JW, Debas HT, Yamada T, Elashoff J, Osadchey B, Walsh JH. Hypergastrinemia develops within 24 hours of truncal vagotomy in dogs. Gastroenterology. 1985 Jan;88(1 Pt 1):35-40
Nishi S, Seino Y, Takemura J, Ishida H, Seno M, Chiba T, Yanaihara C, Yanaihara N, Imura H. Vagal regulation of GRP, gastric somatostatin, and gastrin secretion in vitro. Am J Physiol. 1985 Apr;248(4 Pt 1):E425-31
Schubert ML, Saffouri B, Walsh JH, Makhlouf GM. Inhibition of neurally mediated gastrin secretion by bombesin antiserum. Am J Physiol. 1985 Apr;248(4 Pt 1):G456-62
GAST (gastrin) Chao C, Hellmich MR
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 932
Larsson H, Carlsson E, Mattsson H, Lundell L, Sundler F, Sundell G, Wallmark B, Watanabe T, Håkanson R. Plasma gastrin and gastric enterochromaffinlike cell activation and proliferation. Studies with omeprazole and ranitidine in intact and antrectomized rats. Gastroenterology. 1986 Feb;90(2):391-9
Lund T, Geurts van Kessel AH, Haun S, Dixon JE. The genes for human gastrin and cholecystokinin are located on different chromosomes. Hum Genet. 1986 May;73(1):77-80
Dockray GJ, Varro A, Desmond H, Young J, Gregory H, Gregory RA. Post-translational processing of the porcine gastrin precursor by phosphorylation of the COOH-terminal fragment. J Biol Chem. 1987 Jun 25;262(18):8643-7
Holst JJ, Knuhtsen S, Orskov C, Skak-Nielsen T, Poulsen SS, Jensen SL, Nielsen OV. GRP nerves in pig antrum: role of GRP in vagal control of gastrin secretion. Am J Physiol. 1987 Nov;253(5 Pt 1):G643-9
Sandvik AK, Waldum HL, Kleveland PM, Schulze Søgnen B. Gastrin produces an immediate and dose-dependent histamine release preceding acid secretion in the totally isolated, vascularly perfused rat stomach. Scand J Gastroenterol. 1987 Sep;22(7):803-8
Schubert ML, Makhlouf GM. Neural regulation of gastrin and somatostatin secretion in rat gastric antral mucosa. Am J Physiol. 1987 Dec;253(6 Pt 1):G721-5
Varro A, Desmond H, Pauwels S, Gregory H, Young J, Dockray GJ. The human gastrin precursor. Characterization of phosphorylated forms and fragments. Biochem J. 1988 Dec 15;256(3):951-7
Jensen S, Borch K, Hilsted L, Rehfeld JF. Progastrin processing during antral G-cell hypersecretion in humans. Gastroenterology. 1989 Apr;96(4):1063-70
Karnik PS, Monahan SJ, Wolfe MM. Inhibition of gastrin gene expression by somatostatin. J Clin Invest. 1989 Feb;83(2):367-72
Kovacs TO, Walsh JH, Maxwell V, Wong HC, Azuma T, Katt E. Gastrin is a major mediator of the gastric phase of acid secretion in dogs: proof by monoclonal antibody neutralization. Gastroenterology. 1989 Dec;97(6):1406-13
Karnik PS, Wolfe MM. Somatostatin stimulates gastrin mRNA turnover in dog antral mucosa. J Biol Chem. 1990 Feb 15;265(5):2550-5
Varro A, Nemeth J, Bridson J, Lonovics J, Dockray GJ. Modulation of posttranslational processing of gastrin precursor in dogs. Am J Physiol. 1990 Jun;258(6 Pt 1):G904-9
Wu SV, Giraud A, Mogard M, Sumii K, Walsh JH. Effects of inhibition of gastric secretion on antral gastrin and somatostatin gene expression in rats. Am J Physiol. 1990 May;258(5 Pt 1):G788-93
Wu SV, Sumii K, Walsh JH. Studies of regulation of gastrin synthesis and post-translational processing by molecular biology approaches. Ann N Y Acad Sci. 1990;597:17-27
Dimaline R, Evans D, Varro A, Dockray GJ. Reversal by omeprazole of the depression of gastrin cell function by fasting in the rat. J Physiol. 1991 Feb;433:483-93
Merchant JL, Demediuk B, Brand SJ. A GC-rich element confers epidermal growth factor responsiveness to transcription from the gastrin promoter. Mol Cell Biol. 1991 May;11(5):2686-96
Sandvik AK, Waldum HL. CCK-B (gastrin) receptor regulates gastric histamine release and acid secretion. Am J Physiol. 1991 Jun;260(6 Pt 1):G925-8
Bachwich D, Merchant J, Brand SJ. Identification of a cis-regulatory element mediating somatostatin inhibition of epidermal growth factor-stimulated gastrin gene transcription. Mol Endocrinol. 1992 Aug;6(8):1175-84
Chuang CN, Tanner M, Chen MC, Davidson S, Soll AH. Gastrin induction of histamine release from primary cultures of canine oxyntic mucosal cells. Am J Physiol. 1992 Oct;263(4 Pt 1):G460-5
Schubert ML, Coy DH, Makhlouf GM. Peptone stimulates gastrin secretion from the stomach by activating bombesin/GRP and cholinergic neurons. Am J Physiol. 1992 Apr;262(4 Pt 1):G685-9
Dimaline R, Sandvik AK, Evans D, Forster ER, Dockray GJ. Food stimulation of histidine decarboxylase messenger RNA abundance in rat gastric fundus. J Physiol. 1993 Jun;465:449-58
Chen D, Monstein HJ, Nylander AG, Zhao CM, Sundler F, Håkanson R. Acute responses of rat stomach enterochromaffinlike cells to gastrin: secretory activation and adaptation. Gastroenterology. 1994 Jul;107(1):18-27
Prinz C, Scott DR, Hurwitz D, Helander HF, Sachs G. Gastrin effects on isolated rat enterochromaffin-like cells in primary culture. Am J Physiol. 1994 Oct;267(4 Pt 1):G663-75
Rehfeld JF, Johnsen AH. Identification of gastrin component I as gastrin-71. The largest possible bioactive progastrin product. Eur J Biochem. 1994 Aug 1;223(3):765-73
Rehfeld JF, van Solinge WW. The tumor biology of gastrin and cholecystokinin. Adv Cancer Res. 1994;63:295-347
Sandvik AK, Dimaline R, Mårvik R, Brenna E, Waldum HL. Gastrin regulates histidine decarboxylase activity and mRNA abundance in rat oxyntic mucosa. Am J Physiol. 1994 Aug;267(2 Pt 1):G254-8
Bundgaard JR, Vuust J, Rehfeld JF. Tyrosine O-sulfation promotes proteolytic processing of progastrin. EMBO J. 1995 Jul 3;14(13):3073-9
Dickinson CJ, Sawada M, Guo YJ, Finniss S, Yamada T. Specificity of prohormone convertase endoproteolysis of progastrin in AtT-20 cells. J Clin Invest. 1995 Sep;96(3):1425-31
Hersey SJ, Sachs G. Gastric acid secretion. Physiol Rev. 1995 Jan;75(1):155-89
Rehfeld JF, Hansen CP, Johnsen AH. Post-poly(Glu) cleavage and degradation modified by O-sulfated tyrosine: a novel post-translational processing mechanism. EMBO J. 1995 Jan 16;14(2):389-96
Bate GW, Varro A, Dimaline R, Dockray GJ. Control of preprogastrin messenger RNA translation by gastric acid in the rat. Gastroenterology. 1996 Nov;111(5):1224-9
Lehmann FS, Golodner EH, Wang J, Chen MC, Avedian D, Calam J, Walsh JH, Dubinett S, Soll AH. Mononuclear cells and cytokines stimulate gastrin release from canine antral cells in primary culture. Am J Physiol. 1996 May;270(5 Pt 1):G783-8
Merchant JL, Iyer GR, Taylor BR, Kitchen JR, Mortensen ER, Wang Z, Flintoft RJ, Michel JB, Bassel-Duby R. ZBP-89, a Krüppel-like zinc finger protein, inhibits epidermal growth factor induction of the gastrin promoter. Mol Cell Biol. 1996 Dec;16(12):6644-53
Ohning GV, Wong HC, Lloyd KC, Walsh JH. Gastrin mediates the gastric mucosal proliferative response to feeding. Am J Physiol. 1996 Sep;271(3 Pt 1):G470-6
GAST (gastrin) Chao C, Hellmich MR
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 933
Waldum HL, Sandvik AK, Brenna E, Kleveland PM. The gastrin-histamine sequence. Gastroenterology. 1996 Sep;111(3):838-9
Carrasco M, Hernanz A, De La Fuente M. Effect of cholecystokinin and gastrin on human peripheral blood lymphocyte functions, implication of cyclic AMP and interleukin 2. Regul Pept. 1997 Jun 18;70(2-3):135-42
De la Fuente M, Carrasco M, Hernanz A. Modulation of human neutrophil function in vitro by gastrin. J Endocrinol. 1997 Jun;153(3):475-83
Ford MG, Valle JD, Soroka CJ, Merchant JL. EGF receptor activation stimulates endogenous gastrin gene expression in canine G cells and human gastric cell cultures. J Clin Invest. 1997 Jun 1;99(11):2762-71
Koh TJ, Goldenring JR, Ito S, Mashimo H, Kopin AS, Varro A, Dockray GJ, Wang TC. Gastrin deficiency results in altered gastric differentiation and decreased colonic proliferation in mice. Gastroenterology. 1997 Sep;113(3):1015-25
Lacourse KA, Friis-Hansen L, Rehfeld JF, Samuelson LC. Disturbed progastrin processing in carboxypeptidase E-deficient fat mice. FEBS Lett. 1997 Oct 13;416(1):45-50
Matsuno M, Matsui T, Iwasaki A, Arakawa Y. Role of acetylcholine and gastrin-releasing peptide (GRP) in gastrin secretion. J Gastroenterol. 1997 Oct;32(5):579-86
Todisco A, Takeuchi Y, Urumov A, Yamada J, Stepan VM, Yamada T. Molecular mechanisms for the growth factor action of gastrin. Am J Physiol. 1997 Oct;273(4 Pt 1):G891-8
Bishop L, Dimaline R, Blackmore C, Deavall D, Dockray GJ, Varro A. Modulation of the cleavage of the gastrin precursor by prohormone phosphorylation. Gastroenterology. 1998 Nov;115(5):1154-62
Friis-Hansen L, Sundler F, Li Y, Gillespie PJ, Saunders TL, Greenson JK, Owyang C, Rehfeld JF, Samuelson LC. Impaired gastric acid secretion in gastrin-deficient mice. Am J Physiol. 1998 Mar;274(3 Pt 1):G561-8
McWilliams DF, Watson SA, Crosbee DM, Michaeli D, Seth R. Coexpression of gastrin and gastrin receptors (CCK-B and delta CCK-B) in gastrointestinal tumour cell lines. Gut. 1998 Jun;42(6):795-8
Nakata H, Wang SL, Chung DC, Westwick JK, Tillotson LG. Oncogenic ras induces gastrin gene expression in colon cancer. Gastroenterology. 1998 Nov;115(5):1144-53
Merchant JL, Du M, Todisco A. Sp1 phosphorylation by Erk 2 stimulates DNA binding. Biochem Biophys Res Commun. 1999 Jan 19;254(2):454-61
Miyazaki Y, Shinomura Y, Tsutsui S, Zushi S, Higashimoto Y, Kanayama S, Higashiyama S, Taniguchi N, Matsuzawa Y. Gastrin induces heparin-binding epidermal growth factor-like growth factor in rat gastric epithelial cells transfected with gastrin receptor. Gastroenterology. 1999 Jan;116(1):78-89
Tillotson LG. RIN ZF, a novel zinc finger gene, encodes proteins that bind to the CACC element of the gastrin promoter. J Biol Chem. 1999 Mar 19;274(12):8123-8
Chen D, Zhao CM, Dockray GJ, Varro A, Van Hoek A, Sinclair NF, Wang TC, Koh TJ. Glycine-extended gastrin synergizes with gastrin 17 to stimulate acid secretion in gastrin-deficient mice. Gastroenterology. 2000 Sep;119(3):756-65
Chupreta S, Du M, Todisco A, Merchant JL. EGF stimulates gastrin promoter through activation of Sp1 kinase activity. Am J Physiol Cell Physiol. 2000 Apr;278(4):C697-708
Koh TJ, Bulitta CJ, Fleming JV, Dockray GJ, Varro A, Wang TC. Gastrin is a target of the beta-catenin/TCF-4 growth-signaling pathway in a model of intestinal polyposis. J Clin Invest. 2000 Aug;106(4):533-9
Konturek PC, Hartwich A, Zuchowicz M, Labza H, Pierzchalski P, Karczewska E, Bielanski W, Hahn EG, Konturek SJ. Helicobacter pylori, gastrin and cyclooxygenases in gastric cancer. J Physiol Pharmacol. 2000 Dec;51(4 Pt 1):737-49
Smith AM, Watson SA. Gastrin and gastrin receptor activation: an early event in the adenoma-carcinoma sequence. Gut. 2000 Dec;47(6):820-4
Dockray GJ, Varro A, Dimaline R, Wang T. The gastrins: their production and biological activities. Annu Rev Physiol. 2001;63:119-39
Hartwich J, Konturek SJ, Pierzchalski P, Zuchowicz M, Konturek PC, Bielański W, Marlicz K, Starzyńska T, Ławniczak M. Molecular basis of colorectal cancer - role of gastrin and cyclooxygenase-2. Med Sci Monit. 2001 Nov-Dec;7(6):1171-81
Shulkes A, Baldwin G. Biology and pathology of non-amidated gastrins. Scand J Clin Lab Invest Suppl. 2001;234:123-8
Todisco A, Ramamoorthy S, Witham T, Pausawasdi N, Srinivasan S, Dickinson CJ, Askari FK, Krametter D. Molecular mechanisms for the antiapoptotic action of gastrin. Am J Physiol Gastrointest Liver Physiol. 2001 Feb;280(2):G298-307
Bierkamp C, Kowalski-Chauvel A, Dehez S, Fourmy D, Pradayrol L, Seva C. Gastrin mediated cholecystokinin-2 receptor activation induces loss of cell adhesion and scattering in epithelial MDCK cells. Oncogene. 2002 Oct 31;21(50):7656-70
Guo YS, Cheng JZ, Jin GF, Gutkind JS, Hellmich MR, Townsend CM Jr. Gastrin stimulates cyclooxygenase-2 expression in intestinal epithelial cells through multiple signaling pathways. Evidence for involvement of ERK5 kinase and transactivation of the epidermal growth factor receptor. J Biol Chem. 2002 Dec 13;277(50):48755-63
Jensen RT. Involvement of cholecystokinin/gastrin-related peptides and their receptors in clinical gastrointestinal disorders. Pharmacol Toxicol. 2002 Dec;91(6):333-50
Kirton CM, Wang T, Dockray GJ. Regulation of parietal cell migration by gastrin in the mouse. Am J Physiol Gastrointest Liver Physiol. 2002 Sep;283(3):G787-93
Nakajima T, Konda Y, Izumi Y, Kanai M, Hayashi N, Chiba T, Takeuchi T. Gastrin stimulates the growth of gastric pit cell precursors by inducing its own receptors. Am J Physiol Gastrointest Liver Physiol. 2002 Feb;282(2):G359-66
Rehfeld JF, Lindberg I, Friis-Hansen L. Progastrin processing differs in 7B2 and PC2 knockout animals: a role for 7B2 independent of action on PC2. FEBS Lett. 2002 Jan 2;510(1-2):89-93
Wroblewski LE, Pritchard DM, Carter S, Varro A. Gastrin-stimulated gastric epithelial cell invasion: the role and mechanism of increased matrix metalloproteinase 9 expression. Biochem J. 2002 Aug 1;365(Pt 3):873-9
Haigh CR, Attwood SE, Thompson DG, Jankowski JA, Kirton CM, Pritchard DM, Varro A, Dimaline R. Gastrin induces proliferation in Barrett's metaplasia through activation of the CCK2 receptor. Gastroenterology. 2003 Mar;124(3):615-25
Abdalla SI, Lao-Sirieix P, Novelli MR, Lovat LB, Sanderson IR, Fitzgerald RC. Gastrin-induced cyclooxygenase-2 expression in Barrett's carcinogenesis. Clin Cancer Res. 2004 Jul 15;10(14):4784-92
GAST (gastrin) Chao C, Hellmich MR
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 934
Aly A, Shulkes A, Baldwin GS. Gastrins, cholecystokinins and gastrointestinal cancer. Biochim Biophys Acta. 2004 Jul 6;1704(1):1-10
Bundgaard JR, Birkedal H, Rehfeld JF. Progastrin is directed to the regulated secretory pathway by synergistically acting basic and acidic motifs. J Biol Chem. 2004 Feb 13;279(7):5488-93
Ferrand A, Kowalski-Chauvel A, Bertrand C, Pradayrol L, Fourmy D, Dufresne M, Seva C. Involvement of JAK2 upstream of the PI 3-kinase in cell-cell adhesion regulation by gastrin. Exp Cell Res. 2004 Dec 10;301(2):128-38
Harris JC, Clarke PA, Awan A, Jankowski J, Watson SA. An antiapoptotic role for gastrin and the gastrin/CCK-2 receptor in Barrett's esophagus. Cancer Res. 2004 Mar 15;64(6):1915-9
Lei S, Dubeykovskiy A, Chakladar A, Wojtukiewicz L, Wang TC. The murine gastrin promoter is synergistically activated by transforming growth factor-beta/Smad and Wnt signaling pathways. J Biol Chem. 2004 Oct 8;279(41):42492-502
Olszewska-Pazdrak B, Townsend CM Jr, Hellmich MR. Agonist-independent activation of Src tyrosine kinase by a cholecystokinin-2 (CCK2) receptor splice variant. J Biol Chem. 2004 Sep 24;279(39):40400-4
Sinclair NF, Ai W, Raychowdhury R, Bi M, Wang TC, Koh TJ, McLaughlin JT. Gastrin regulates the heparin-binding epidermal-like growth factor promoter via a PKC/EGFR-dependent mechanism. Am J Physiol Gastrointest Liver Physiol. 2004 Jun;286(6):G992-9
Colucci R, Blandizzi C, Tanini M, Vassalle C, Breschi MC, Del Tacca M. Gastrin promotes human colon cancer cell growth via CCK-2 receptor-mediated cyclooxygenase-2 induction and prostaglandin E2 production. Br J Pharmacol. 2005 Feb;144(3):338-48
Dufner MM, Kirchhoff P, Remy C, Hafner P, Müller MK, Cheng SX, Tang LQ, Hebert SC, Geibel JP, Wagner CA. The calcium-sensing receptor acts as a modulator of gastric acid secretion in freshly isolated human gastric glands. Am J Physiol Gastrointest Liver Physiol. 2005 Dec;289(6):G1084-90
Müerköster S, Isberner A, Arlt A, Witt M, Reimann B, Blaszczuk E, Werbing V, Fölsch UR, Schmitz F, Schäfer H. Gastrin suppresses growth of CCK2 receptor expressing colon cancer cells by inducing apoptosis in vitro and in vivo. Gastroenterology. 2005 Sep;129(3):952-68
Alvarez A, Ibiza S, Hernández C, Alvarez-Barrientos A, Esplugues JV, Calatayud S. Gastrin induces leukocyte-endothelial cell interactions in vivo and contributes to the inflammation caused by Helicobacter pylori. FASEB J. 2006 Nov;20(13):2396-8
Jensen RT. Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas. Basic Clin Pharmacol Toxicol. 2006 Jan;98(1):4-19
Ottewell PD, Duckworth CA, Varro A, Dimaline R, Wang TC, Watson AJ, Dockray GJ, Pritchard DM. Gastrin
increases murine intestinal crypt regeneration following injury. Gastroenterology. 2006 Apr;130(4):1169-80
Bundgaard JR, Rehfeld JF. Distinct linkage between post-translational processing and differential secretion of progastrin derivatives in endocrine cells. J Biol Chem. 2008 Feb 15;283(7):4014-21
Rehfeld JF, Zhu X, Norrbom C, Bundgaard JR, Johnsen AH, Nielsen JE, Vikesaa J, Stein J, Dey A, Steiner DF, Friis-Hansen L. Prohormone convertases 1/3 and 2 together orchestrate the site-specific cleavages of progastrin to release gastrin-34 and gastrin-17. Biochem J. 2008 Oct 1;415(1):35-43
Almeida-Vega S, Catlow K, Kenny S, Dimaline R, Varro A. Gastrin activates paracrine networks leading to induction of PAI-2 via MAZ and ASC-1. Am J Physiol Gastrointest Liver Physiol. 2009 Feb;296(2):G414-23
Chakravorty M, Datta De D, Choudhury A, Roychoudhury S. IL1B promoter polymorphism regulates the expression of gastric acid stimulating hormone gastrin. Int J Biochem Cell Biol. 2009 Jul;41(7):1502-10
Ibiza S, Alvarez A, Romero W, Barrachina MD, Esplugues JV, Calatayud S. Gastrin induces the interaction between human mononuclear leukocytes and endothelial cells through the endothelial expression of P-selectin and VCAM-1. Am J Physiol Cell Physiol. 2009 Dec;297(6):C1588-95
Jin G, Ramanathan V, Quante M, Baik GH, Yang X, Wang SS, Tu S, Gordon SA, Pritchard DM, Varro A, Shulkes A, Wang TC. Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice. J Clin Invest. 2009 Sep;119(9):2691-701
Kidd M, Hauso Ø, Drozdov I, Gustafsson BI, Modlin IM. Delineation of the chemomechanosensory regulation of gastrin secretion using pure rodent G cells. Gastroenterology. 2009 Jul;137(1):231-41, 241.e1-10
Baldwin GS, Patel O, Shulkes A. Evolution of gastrointestinal hormones: the cholecystokinin/gastrin family. Curr Opin Endocrinol Diabetes Obes. 2010 Feb;17(1):77-88
Bundgaard JR, Rehfeld JF. Posttranslational processing of progastrin. Results Probl Cell Differ. 2010;50:207-20
Ericsson P, Håkanson R, Norlén P. Gastrin response to candidate messengers in intact conscious rats monitored by antrum microdialysis. Regul Pept. 2010 Aug 9;163(1-3):24-30
Feng J, Petersen CD, Coy DH, Jiang JK, Thomas CJ, Pollak MR, Wank SA. Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion. Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17791-6
This article should be referenced as such:
Chao C, Hellmich MR. GAST (gastrin). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):928-934.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 935
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2) Yuan-Hao Hsu
Department of Chemistry and Biochemistry and Pharmacology, School of Medicine, San Diego, La
Jolla, California 92093-0601, USA (YHH)
Published in Atlas Database: April 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/PAK2ID41634ch3q29.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI PAK2ID41634ch3q29.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: PAK65; PAKgamma
HGNC (Hugo): PAK2
Location: 3q29
DNA/RNA
Description
Pak2 gene at 193763319 to 193859670 bp from pter
contains 96352 bases and 34 exons. Pak2 gene at
the alternative location starts at 196466728 and
ends at 196559518 bp from pter. The PAK2 gene in
this location contains 20 exons.
Protein
Description
Pak2 has an N-terminal regulatory domain and a C-
terminal catalytic domain. In the regulatory domain,
Pak2 have several conserved regions, including an
autoinhibitory domain (AID), a p21-binding
domain (PBD), dimerization domain, proline-rich
regions, and an acidic region. The schematic
structure of Pak2 is shown in figure above. The
catalytic domain of Pak is a conserved bilobal
structure in most of the protein kinases.
Expression
Pak2 is 58.8 kDa (524 residues) and expressed
ubiquitously in mammalian cells.
Function
PAK activation is through disruption of
autoinhibition, followed by autophosphorylation. In
the inactive state, the AID interacts with the
catalytic domain to inhibit its kinase activity. GTP-
bound Cdc42 can disrupt autoinhibition, which, in
turn, leads to autophosphorylation and activation of
PAK. Pak2's basal autophosphorylation activity is
observed and Pak2 is autophosphorylated at 5 sites,
serines 19, 20, 55, 192 and 197. Additional three
phosphorylation sites (serines 141 and 165 and
threonine 402) are autophosphorylated in the
presence of Cdc42(GTP) and ATP.
Autophosphorylation of Thr402 in the activation
loop is required for the kinase activity of Pak2.
Pak2 can be activated in response to a lot of
stresses. Moderate stresses, like hyperosmolarity,
ionizing radiation, DNA-damaging agents and
serum-deprivation, induce Pak2 activation in cells
and lead to cell cycle arrest at G2/M. Activated
Pak2 inhibits translation by phosphorylation of
various substrates. Pak2 has specific protein
substrates, e.g. histone 4, myosin light chain
(MLC), prolactin, c-Abl, eukaryote translation
initiation factor 3 (eIF3), eIF4B, eIF4G, and Mnk1.
Pak2 recognizes the consensus sequence
(K/RRXS).
Pak2 is the only member of the PAK family that is
directly activated by caspase 3. When Pak2 is
cleaved and activated by caspase 3, Pak2 promotes
the morphological and biochemical changes of
apoptosis. The pro-apoptosis protease, caspase 3
cleaves Pak2 after Asp 212, and thus produces a
p27 fragment containing primarily the regulatory
domain, and a p34 fragment containing a small
piece of the regulatory domain and the entire
catalytic domain. Autophosphorylation results in a
constitutively active p34 kinase domain.
PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2) Hsu YH
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 936
The Linear schematic of Pak2. Functional domains, including proline rich regions (P), acidic region (A), p21-binding domain
(PBD), Cdc42 and Rac interaction and binding sequence (CRIB) and autoinhibitory domain (AID) are designated. Autophosphorylation sites (*) and caspase 3 cleavage site (v) are marked. The regulatory domain is blue; the protein kinase
domain is green; the overlapping region between PBD and AID is pink.
The nuclear import signal (245-251) is required for
nuclear localization. Disruption of the region (197-
246), containing nuclear export signal results in the
nuclear localization of the Pak2 p34 fragment.
Homology
Pak1, Pak2 and Pak3 are highly homologous. The
primary sequence of human Pak2 is 72 % identical
to Pak1 and 71 % identical to Pak3.
Mutations
Note
None is reported.
Implicated in
Tumors
Prognosis
Huang (2004) showed Pak2 is a negative regulator
of Myc and suggested Pak2 may be the product of a
tumor suppressor gene. Coniglio (2008) reported
Pak2 mediates tumor invasion in breast carcinoma
cells. Inhibition of RhoA in Pak2-depleted cells
decreases MLC phosphorylation and restores cell
invasion. Also, the NF2 tumor suppressor Merlin is
a substrate of Pak2. Wilkes (2009) showed that
Erbin regulates the function of Merlin through Pak2
binding to Merlin.
Immunodeficiency
Note
Human immunodeficiency virus type 1 HIV-1.
Prognosis
Human immunodeficiency virus type 1 Nef
associates with a active Pak2 independently of
binding to Nck or PIX. Nef recruits the GEF Vav1
to plasma membrane to associate with Pak2.
References Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature. 1994 Jan 6;367(6458):40-6
Lee N, MacDonald H, Reinhard C, Halenbeck R, Roulston A, Shi T, Williams LT. Activation of hPAK65 by caspase cleavage induces some of the morphological and biochemical changes of apoptosis. Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13642-7
Rudel T, Bokoch GM. Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2. Science. 1997 Jun 6;276(5318):1571-4
Tuazon PT, Spanos WC, Gump EL, Monnig CA, Traugh JA. Determinants for substrate phosphorylation by p21-activated protein kinase (gamma-PAK). Biochemistry. 1997 Dec 23;36(51):16059-64
Frost JA, Khokhlatchev A, Stippec S, White MA, Cobb MH. Differential effects of PAK1-activating mutations reveal activity-dependent and -independent effects on cytoskeletal regulation. J Biol Chem. 1998 Oct 23;273(43):28191-8
Walter BN, Huang Z, Jakobi R, Tuazon PT, Alnemri ES, Litwack G, Traugh JA. Cleavage and activation of p21-activated protein kinase gamma-PAK by CPP32 (caspase 3). Effects of autophosphorylation on activity. J Biol Chem. 1998 Oct 30;273(44):28733-9
Zhao ZS, Manser E, Chen XQ, Chong C, Leung T, Lim L. A conserved negative regulatory region in alphaPAK: inhibition of PAK kinases reveals their morphological roles downstream of Cdc42 and Rac1. Mol Cell Biol. 1998 Apr;18(4):2153-63
Gatti A, Huang Z, Tuazon PT, Traugh JA. Multisite autophosphorylation of p21-activated protein kinase gamma-PAK as a function of activation. J Biol Chem. 1999 Mar 19;274(12):8022-8
Tu H, Wigler M. Genetic evidence for Pak1 autoinhibition and its release by Cdc42. Mol Cell Biol. 1999 Jan;19(1):602-11
Roig J, Traugh JA. Cytostatic p21 G protein-activated protein kinase gamma-PAK. Vitam Horm. 2001;62:167-98
Kissil JL, Johnson KC, Eckman MS, Jacks T. Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization. J Biol Chem. 2002 Mar 22;277(12):10394-9
Jakobi R, McCarthy CC, Koeppel MA, Stringer DK. Caspase-activated PAK-2 is regulated by subcellular targeting and proteasomal degradation. J Biol Chem. 2003 Oct 3;278(40):38675-85
Huang Z, Traugh JA, Bishop JM. Negative control of the Myc protein by the stress-responsive kinase Pak2. Mol Cell Biol. 2004 Feb;24(4):1582-94
Orton KC, Ling J, Waskiewicz AJ, Cooper JA, Merrick WC, Korneeva NL, Rhoads RE, Sonenberg N, Traugh JA. Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk. J Biol Chem. 2004 Sep 10;279(37):38649-57
Ling J, Morley SJ, Traugh JA. Inhibition of cap-dependent translation via phosphorylation of eIF4G by protein kinase Pak2. EMBO J. 2005 Dec 7;24(23):4094-105
Coniglio SJ, Zavarella S, Symons MH. Pak1 and Pak2 mediate tumor cell invasion through distinct signaling mechanisms. Mol Cell Biol. 2008 Jun;28(12):4162-72
Hsu YH, Johnson DA, Traugh JA. Analysis of conformational changes during activation of protein kinase Pak2 by amide hydrogen/deuterium exchange. J Biol Chem. 2008 Dec 26;283(52):36397-405
PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2) Hsu YH
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 937
Wilkes MC, Repellin CE, Hong M, Bracamonte M, Penheiter SG, Borg JP, Leof EB. Erbin and the NF2 tumor suppressor Merlin cooperatively regulate cell-type-specific activation of PAK2 by TGF-beta. Dev Cell. 2009 Mar;16(3):433-44
Hsu YH, Traugh JA. Reciprocally coupled residues crucial for protein kinase Pak2 activity calculated by statistical coupling analysis. PLoS One. 2010 Mar 1;5(3):e9455
This article should be referenced as such:
Hsu YH. PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):935-937.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 938
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
TGFBRAP1 (transforming growth factor, beta receptor associated protein 1) Jens U Wurthner
Translational Pharmacology and Discovery Medicine, GlaxoSmithKline, Gunnels Wood Road,
Stevenage, SG1 2NY, USA (JUW)
Published in Atlas Database: April 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/TGFBRAP1ID42542ch2q12.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI TGFBRAP1ID42542ch2q12.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: TRAP-1; TRAP1
HGNC (Hugo): TGFBRAP1
Location: 2q12.1
DNA/RNA
Description
Encoded on the minus strand. 12 exons, exon
number 1 is not depicted in the diagram and
appears to undergo differential splicing, according
to recent NCBI-AceView (accessed 17 Apr 2011).
Transcription
Work by the Wurthner lab in 2003-2005 identified
an 860 aa protein that could be matched with
genomic sequences. Recently predicted proteins
from mRNA variants describe translation products
of 896, 952, 161 and 30 aminino acids (NCBI
AceView, accessed 17 April 2011).
Protein
Description
A fragment of TGFBRAP1 was initially identified
in a Yeast-2-Hybrid screen as a TGF-beta type I
receptor interacting protein (Charng et al., 2002).
Further work by Wurthner et al. demonstrated
binding of the full-length molecule exclusively to
either TGF-beta receptor I and TGF-beta receptor
II, or to Smad4, suggesting TGFBRAP1 to be a
Smad4 chaperone (Wurthner et al., 2001).
Furthermore, receptor activated Smads were shown
to compete for binding of TRAP1 with Smad4,
suggesting only a transient association between
TRAP1 and Smad4. In addition, an interaction of
TRAP1 with 5-lipoxgenase in a yeast two-hybrid
system was described by a different group (Provost
et al., 1999). Gene inactivation of TGFBRAP1
through conventional targeting leads to early
developmental arrest of murine embryos around
day E 6.5 (Messler et al., 2010).
Generated by BlastAnalyser in 2005 (unpublished). Contig: NT_022171.13 (gi: 29789878).
TGFBRAP1 (transforming growth factor, beta receptor associated protein 1)
Wurthner JU
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 939
CNH: Citron Homology Domain; CLH: Clathrin Homology Domain; VPS39: Vesicle Protein Sorting Protein 39 Domain.
Expression
Ubiquitous.
Localisation
Punctate pattern suggestive of endosomal
localisation.
Function
Chaperone for Smad4 in the TGF-beta signal
transduction cascade (Wurthner et al., 2001).
Endosomal trafficking (circumstantial evidence:
domain structure and early embryonic lethality;
Messler et al., 2010).
Homology
hVPS39 (hVam6, hTrap-like-Protein).
References Charng MJ, Zhang D, Kinnunen P, Schneider MD. A novel protein distinguishes between quiescent and activated forms of the type I transforming growth factor beta receptor. J Biol Chem. 1998 Apr 17;273(16):9365-8
Provost P, Samuelsson B, Rådmark O. Interaction of 5-lipoxygenase with cellular proteins. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):1881-5
Wurthner JU, Frank DB, Felici A, Green HM, Cao Z, Schneider MD, McNally JG, Lechleider RJ, Roberts AB. Transforming growth factor-beta receptor-associated protein 1 is a Smad4 chaperone. J Biol Chem. 2001 Jun 1;276(22):19495-502
Felici A, Wurthner JU, Parks WT, Giam LR, Reiss M, Karpova TS, McNally JG, Roberts AB. TLP, a novel modulator of TGF-beta signaling, has opposite effects on Smad2- and Smad3-dependent signaling. EMBO J. 2003 Sep 1;22(17):4465-77
Messler S, Kropp S, Episkopou V, Felici A, Würthner J, Lemke R, Jerabek-Willemsen M, Willecke R, Scheu S, Pfeffer K, Wurthner JU. The TGF-β signaling modulators TRAP1/TGFBRAP1 and VPS39/Vam6/TLP are essential for early embryonic development. Immunobiology. 2011 Mar;216(3):343-50
This article should be referenced as such:
Wurthner JU. TGFBRAP1 (transforming growth factor, beta receptor associated protein 1). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):938-939.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 940
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
AXIN1 (axin 1) Nives Pecina-Slaus, Tamara Nikuseva Martic, Tomislav Kokotovic
Department of Biology, Laboratory for Neurooncology, Croatian Institute for Brain Research,
Medical School University of Zagreb, Salata 12, Zagreb, Croatia (NPS, TN, TK)
Published in Atlas Database: May 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/AXIN1ID379ch16p13.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI AXIN1ID379ch16p13.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: AXIN; MGC52315
HGNC (Hugo): AXIN1
Location: 16p13.3
Note
According to Entrez gene and Ensembl the isoform
a starts at 337440 and ends at 402464 bp with the
total lenght of 65025 bp. The isoform b starts at
338122 and ends at 397025 with the total lenght of
58904 bp. Zeng et al. (1997) renamed the gene that
was originally termed Fu to Axin in order to avoid
confusion with the unrelated Drosophila gene
fused.
DNA/RNA
Description
Axin 1 consists of 11 exons (isoform a). Full gene
transcript product length is 3675 bp. Isoform b
lacks an in-frame exon in the 3' coding region and
is shorter with sequence length of 3567 bp
(Salahshor and Woodgett, 2005) (Figure 1).
Transcription
There are two transcript variants. Variant 1
(encoding for isoform a) represents the longer
transcript (NM 003502.3). Variant 2 (encoding for
isoform b) is shorter compared to variant 1 (NM
181050.2). According to Ensembl there are six
transcripts of AXIN1 of which first two are well
known isoforms a and b and the remaining 4 are
still in research.
Protein
Note
Protein name: Axin 1, Axin, Axis inhibitor, Axis
inhibitor protein 1.
Description
At least two isoforms of protein axin are expressed.
Longer isoform has all eleven exons translated and
consists of 862 aminoacids while shorter has 826
aminoacids translated from ten exons. Axin 1
protein can be recognized primarily by two
domains, the N-terminal RGS domain (regulators of
G-protein signaling) and the C-terminal DIX
domain (dishevelled and axin) (Luo et al., 2005;
Shibata et al., 2007). RGS domain is needed for
APC binding while DIX domain for
homodimerization and heterodimerization
(Ehebauer and Arias, 2009; Noutsou et al., 2011).
There is also a central region of the protein that
binds GSK3beta and beta-catenin. Axin protein has
nuclear localization (NLS) and nuclear export
(NES) sequences as well. It is well known that axin
is a scaffold protein that can shuttle between the
cytoplasm and the nucleus.
Figure 1. Genomic structure of Axin 1. Axin 1 is composed of 10 exons and they encode isoform a, while in isoform b exon 8
is spliced out.
AXIN1 (axin 1) Pecina-Slaus N, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 941
Nucleo-cytoplasmatic shuttling under normal
circumstances suggests existence of possible
"salvage pathway" that would be activated by axin
translocation to the nucleus in order to reduce beta-
catenin oncogenic activity by exporting nuclear
beta-catenin and degrading it in the cytoplasm
(Wiechens et al., 2004). Axin can also undergo
posttranslational modifications. Phosphorilation by
casein kinase 1 (CK1) enhances binding of
GSK3beta and AXIN1. For activation of JNK
pathway axin needs to be SUMOylated (Kim et al.,
2008) (Figure 2).
Figure 2. Two crystallized domains of the Axin 1
protein are shown: (A) RGS and (B) DIX.
Expression
Axin is expressed ubiquitously.
Localisation
Axin is predominantlly expressed in the cytoplasm,
but periplasmic and nuclear localization are also
observed depending on the stimulation of the cells
(Cong and Varmus, 2004; Luo and Lin, 2004). In
nonstimulated cells, axin colocalizes with Smad3.
The subcellular location of axin is not well defined
in the literature. It has been reported that
physiological concentrations of axin is low in
Xenopus egg cells. It has also been shown that it is
located in cytoplasmic puncta in living mammalian
cells. Wang et al. (2009) report that axin 1 is highly
co-localized with beta-catenin in the cytoplasm of
human cumulus cells and that this localization
denotes intact wnt signaling. Pecina-Slaus et al.
(2011) showed the subcellular location of axin in
normal brain white matter and glioblastoma tissue.
The majority of glioblastomas (69.04%) had axin
localized in the cytoplasm. Nevertheless, 9.5% of
glioblastomas samples had axin localized in the
nucleus (Figure 3). Distribution of axin was
reported previously by Anderson et al. (2002) in
neoplastic colon. Altered nuclear expression of axin
seen in colon polyps and carcinomas may be a
consequence of the loss of full-length APC and the
advent of nuclear beta-catenin.
Figure 3. Glioblastoma samples
immunohistochemically stained for protein expression of axin. (A) Cytoplasmic localization of axin and (B) nuclear
localization of axin.
Function
Tumor suppressor protein Axin 1 is an inhibitor of
the Wnt signaling pathway (Polakis, 2000;
Salahshor and Woodgett, 2005). As a scaffold
protein, its main role is binding multiple members
of Wnt signaling and formation of the beta-catenin
destruction complex. It down-regulates beta-
catenin, wnt pathway's main effector signaling
molecule, by facilitating its phosphorylation by
GSK3-beta (Hart et al., 1998). It binds directly to
APC (adenomatous polyposis coli), beta-catenin,
GSK3-beta and dishevelled forming a so called
"beta-catenin destruction complex" in which
phosphorylated beta-catenin is targeted for quick
ubiquitinilation and degradation in the 26S
proteosome (Yamamoto et al., 1999; Logan and
Nusse, 2004). In response to wnt signaling, or
under the circumstances of mutated axin or APC,
beta-catenin is stabilized, accumulates in the
AXIN1 (axin 1) Pecina-Slaus N, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 942
cytoplasm and enters the nucleus, where it finds a
partner, a member of the DNA binding protein
family LEF/TCF. Together they stimulate the
expression of target genes including c-myc, c-jun,
fra-1 and cyclin D1. In developement Axin controls
dorsoventral polarity axis formation (Zeng et al.,
1997; Wodarz and Nusse, 1998) by two
independent mechanisms: downregulation of beta-
catenin, but also by activation of Wnt-independent
JNK signaling activation. Axin has a role in
determining cell's fate upon damage, haematopoetic
stem cells differentiation (Reya et al., 2003) and
transforming growth factor beta signaling
(Furuhashi et al., 2001). Reports indicate that beta-
catenin and axin regulate critical developmental
processes of normal CNS development (Pecina-
Slaus, 2010).
Axin interacts with a number of proteins including:
APC, Axam, Axin, beta-catenin, Ccd1, CKI,
DAXX, DCAP, Diversin, Dvl, gamma-tubulin,
GSK3beta, HIPK2, I-mfa, LRP5/LRP6, MDFIC,
MEKK1, MEKK4, P53, PIAS, Pirh2, PP2A, Rnf11,
Zbed3, Tip60, Smad3, Smad6, and Smad7 (Cliffe et
al., 2003; Chen et al., 2009; Fumoto et al., 2009; Li
et al., 2009; Choi et al., 2010; Kim and Jho, 2010).
Homology
Homologs are found in: Pan troglodytes, Canis
lupus familiaris, Bos taurus, Mus musculus, Rattus
norvegicus, Gallus gallus, Danio rerio.
Mutations
Note
According to HGMD there are 3 missense
mutations reported for AXIN 1 in colorectal
carcinoma. Nikuseva Martic et al. (2010) identified
gross deletions (Loss of Heterozygosity) of AXIN 1
in 6.3% of glioblastomas, in one neuroepithelial
dysembrioplastic tumor and in one
medulloblastoma. In a primary hepatocellular
carcinoma 13 somatic events were reported by
OMIM, a 33-bp deletion in exon 3 of the AXIN1
gene, and 12 missense mutations. OMIM also
reports on hypermethylation of AXIN 1 promotor
region in caudal duplication anomaly.
Implicated in
Hepatocellular carcinoma
Note
In a primary hepatocellular carcinoma (HCC),
Satoh et al. (2000) found a 33-bp deletion in exon 3
of the AXIN1 gene, involving 2 glycogen synthase
kinase-3-beta phosphorylation sites. In addition to
this deletion they found 12 missense mutations, of
which 9 occurred in codons encoding serine or
threonine residues. They confirmed that all 13
mutations found in primary HCCs occurred as
somatic events. Taniguchi et al. (2002) found
AXIN1 mutations in seven (9.6%) HCCs. The
AXIN1 mutations included seven missense
mutations, a 1 bp deletion, and a 12 bp insertion.
Loss of heterozygosity at the AXIN1 locus was
present in four of five informative HCCs with
AXIN1 mutations, suggesting a tumor suppressor
function of this gene. Park et al. (2005) showed that
mutations of AXIN 1 are late events in
hepatocellular carcinogenesis.
Medulloblastoma
Note
To find out if Axin is also involved in the
pathogenesis of sporadic medulloblastomas,
Dahmen et al. (2001) analyzed 86 cases and 11
medulloblastoma cell lines for mutations in the
AXIN1 gene. Using single-strand conformation
polymorphism analysis, screening for large
deletions by reverse transcription-PCR, and
sequencing analysis, a single somatic point
mutation in exon 1 (Pro255Ser) and seven large
deletions (12%) of AXIN1 were detected. Baeza et
al. (2003) screened 39 sporadic cerebellar
medulloblastomas for alterations in the AXIN1
gene. The authors found missense AXIN1
mutations in two tumours, CCC-->TCC at codon
255 (exon 1, Pro-->Ser) and TCT-->TGT at codon
263 (exon 1, Ser-->Cys). Furthermore, the A allele
at the G/A polymorphism at nucleotide 16 in intron
4 was significantly over-represented in
medulloblastomas (39 cases; G 0.76 vs-A 0.24)
compared to healthy individuals (86 cases; G 0.91
vs A 0.09; P=0.0027). Yokota et al. (2002) showed
another AXIN1 mutation in exon 3, corresponding
to GSK-3beta binding site.
Colorectal carcinoma
Note
Hart et al. (1998) report on overexpression of
Axin1 in connection to the downregulation of wild-
type beta-catenin in colon cancer cells. In addition,
Axin1 dramatically facilitated the phosphorylation
of APC and beta-catenin by GSK3 beta in vitro.
Another group (Jin et al., 2003) analyzed 54
colorectal cancer tissues for mutations in AXIN1
gene. They found 3 silent mutations, 6 missense
point mutations in different functionally important
regions. The missense mutation rate was hence
11%, suggesting that Axin 1 deficiency may
contribute to the onset of colorectal tumorigenesis.
Segditsas and Tomlinson (2006) report on
mutations in AXIN1 in microsatellite-unstable
colon cancers. Three AXIN1 missense variants
P312T, R398H, and L445M were detected in 1 of
124 patients with multiple colorectal adenomas.
Three other missense mutations, D545E, G700S,
and R891Q, were found. The overall frequency of
the rare variants was significantly higher in the
patients as compared with the controls (Fearnhead
et al., 2004).
AXIN1 (axin 1) Pecina-Slaus N, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 943
Brain tumors
Note
A sample of 72 neuroepithelial brain tumors was
investigated for AXIN-1 gene changes by Nikuseva
Martic et al. (2010). Polymorphic marker for
AXIN-1, showed loss of heterozygosity in 11.1% of
tumors. Down regulation of axin expression and up
regulation of beta-catenin were detected. Axin was
observed in the cytoplasm in 68.8% of samples, in
28.1% in both the cytoplasm and nucleus and 3.1%
had no expression. Comparison of mean values of
relative increase of axin and beta-catenin showed
that they were significantly reversely proportional
(P=0.014) in a set of neuroepithelial brain tumors.
Pecina-Slaus et al. (2011) also explored axin's
existence at the subcellular level in glioblastomas
and showed that the highest relative quantity of
axin was measured when the protein was in the
nucleus and the lowest relative quantity of axin
when the protein was localized in the cytoplasm.
Ovarian endometroid adenocarcinomas
Note
Wu et al. (2001) report on a nonsense mutation in
one ovarian endometroid adenocarcinoma (OEA).
They also found another missense AXIN1 sequence
alteration in OEA-derived cell lines.
Lung cancer
Note
In 105 lung SCC and adenocarcinoma tissue
samples, the cytoplasmic expression of Axin was
significantly lower than in normal lung tissues.
Western blot analysis also demonstrated that the
relative expression quantity of Axin was
significantly reduced in lung cancer tissues
compared with normal lung tissues. Nuclear
expression of Axin was observed in 21 cases (20%)
of lung cancers (Xu et al., 2011).
Oesophageal squamous cell carcinoma
Note
Nakajima et al. (2003) found reduced expression of
Axin1 in oesophageal squamous cell carcinoma.
Several mutations have also been reported in
oesophageal squamous cell carcinoma.
Cervical cancer
Note
Su et al. (2003) examined AXIN1 in cervical
cancer. Among the 30 tested cervical cancers
mutation analysis of AXIN1 revealed that one
specimen had a heterozygous mutation at codon
740. Six polymorphisms were also found.
Immunohistochemistry showed no relationship
between the protein expression patterns and
mutation of AXIN1.
Prostate cancer
Note
Yardy et al. (2009) reported on AXIN1 mutations
in advanced prostate cancer. They found 7
mutations in prostate cancer cases and 4
polymorphisms in prostate cancer cell lines.
Caudal duplication anomaly
Note
Hypermethylation of the AXIN1 promoter is
associated with the caudal duplication anomalies.
Oates et al. (2006) examined methylation at the
promoter region of the AXIN1 gene in
monozygotic twins. The promoter region of the
AXIN1 gene was significantly more methylated in
the twin with the caudal duplication than in the
unaffected twin.
References Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL 3rd, Lee JJ, Tilghman SM, Gumbiner BM, Costantini F. The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell. 1997 Jul 11;90(1):181-92
Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P. Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol. 1998 May 7;8(10):573-81
Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol. 1998;14:59-88
Yamamoto H, Kishida S, Kishida M, Ikeda S, Takada S, Kikuchi A. Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability. J Biol Chem. 1999 Apr 16;274(16):10681-4
Polakis P. Wnt signaling and cancer. Genes Dev. 2000 Aug 1;14(15):1837-51
Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 2000 Mar;24(3):245-50
Dahmen RP, Koch A, Denkhaus D, Tonn JC, Sörensen N, Berthold F, Behrens J, Birchmeier W, Wiestler OD, Pietsch T. Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. Cancer Res. 2001 Oct 1;61(19):7039-43
Furuhashi M, Yagi K, Yamamoto H, Furukawa Y, Shimada S, Nakamura Y, Kikuchi A, Miyazono K, Kato M. Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway. Mol Cell Biol. 2001 Aug;21(15):5132-41
Wu R, Zhai Y, Fearon ER, Cho KR. Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas. Cancer Res. 2001 Nov 15;61(22):8247-55
Anderson CB, Neufeld KL, White RL. Subcellular distribution of Wnt pathway proteins in normal and neoplastic colon. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8683-8
Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, Nagorney DM, Burgart LJ, Roche PC, Smith DI, Ross JA, Liu W. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene. 2002 Jul 18;21(31):4863-71
AXIN1 (axin 1) Pecina-Slaus N, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 944
Yokota N, Nishizawa S, Ohta S, Date H, Sugimura H, Namba H, Maekawa M. Role of Wnt pathway in medulloblastoma oncogenesis. Int J Cancer. 2002 Sep 10;101(2):198-201
Baeza N, Masuoka J, Kleihues P, Ohgaki H. AXIN1 mutations but not deletions in cerebellar medulloblastomas. Oncogene. 2003 Jan 30;22(4):632-6
Cliffe A, Hamada F, Bienz M. A role of Dishevelled in relocating Axin to the plasma membrane during wingless signaling. Curr Biol. 2003 May 27;13(11):960-6
Jin LH, Shao QJ, Luo W, Ye ZY, Li Q, Lin SC. Detection of point mutations of the Axin1 gene in colorectal cancers. Int J Cancer. 2003 Dec 10;107(5):696-9
Nakajima M, Fukuchi M, Miyazaki T, Masuda N, Kato H, Kuwano H. Reduced expression of Axin correlates with tumour progression of oesophageal squamous cell carcinoma. Br J Cancer. 2003 Jun 2;88(11):1734-9
Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R, Weissman IL. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003 May 22;423(6938):409-14
Su TH, Chang JG, Yeh KT, Lin TH, Lee TP, Chen JC, Lin CC. Mutation analysis of CTNNB1 (beta-catenin) and AXIN1, the components of Wnt pathway, in cervical carcinomas. Oncol Rep. 2003 Sep-Oct;10(5):1195-200
Cong F, Varmus H. Nuclear-cytoplasmic shuttling of Axin regulates subcellular localization of beta-catenin. Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2882-7
Fearnhead NS, Wilding JL, Winney B, Tonks S, Bartlett S, Bicknell DC, Tomlinson IP, Mortensen NJ, Bodmer WF. Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas. Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15992-7
Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781-810
Luo W, Lin SC. Axin: a master scaffold for multiple signaling pathways. Neurosignals. 2004 May-Jun;13(3):99-113
Wiechens N, Heinle K, Englmeier L, Schohl A, Fagotto F. Nucleo-cytoplasmic shuttling of Axin, a negative regulator of the Wnt-beta-catenin Pathway. J Biol Chem. 2004 Feb 13;279(7):5263-7
Luo W, Zou H, Jin L, Lin S, Li Q, Ye Z, Rui H, Lin SC. Axin contains three separable domains that confer intramolecular, homodimeric, and heterodimeric interactions involved in distinct functions. J Biol Chem. 2005 Feb 11;280(6):5054-60
Park JY, Park WS, Nam SW, Kim SY, Lee SH, Yoo NJ, Lee JY, Park CK. Mutations of beta-catenin and AXIN I genes are a late event in human hepatocellular carcinogenesis. Liver Int. 2005 Feb;25(1):70-6
Salahshor S, Woodgett JR. The links between axin and carcinogenesis. J Clin Pathol. 2005 Mar;58(3):225-36
Oates NA, van Vliet J, Duffy DL, Kroes HY, Martin NG, Boomsma DI, Campbell M, Coulthard MG, Whitelaw E, Chong S. Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly. Am J Hum Genet. 2006 Jul;79(1):155-62
Segditsas S, Tomlinson I. Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene. 2006 Dec 4;25(57):7531-7
Shibata N, Tomimoto Y, Hanamura T, Yamamoto R, Ueda M, Ueda Y, Mizuno N, Ogata H, Komori H, Shomura Y, Kataoka M, Shimizu S, Kondo J, Yamamoto H, Kikuchi A, Higuchi Y. Crystallization and preliminary X-ray crystallographic studies of the axin DIX domain. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2007 Jun 1;63(Pt 6):529-31
Kim MJ, Chia IV, Costantini F. SUMOylation target sites at the C terminus protect Axin from ubiquitination and confer protein stability. FASEB J. 2008 Nov;22(11):3785-94
Chen T, Li M, Ding Y, Zhang LS, Xi Y, Pan WJ, Tao DL, Wang JY, Li L. Identification of zinc-finger BED domain-containing 3 (Zbed3) as a novel Axin-interacting protein that activates Wnt/beta-catenin signaling. J Biol Chem. 2009 Mar 13;284(11):6683-9
Ehebauer MT, Arias AM. The structural and functional determinants of the Axin and Dishevelled DIX domains. BMC Struct Biol. 2009 Nov 12;9:70
Fumoto K, Kadono M, Izumi N, Kikuchi A. Axin localizes to the centrosome and is involved in microtubule nucleation. EMBO Rep. 2009 Jun;10(6):606-13
Li Q, Lin S, Wang X, Lian G, Lu Z, Guo H, Ruan K, Wang Y, Ye Z, Han J, Lin SC. Axin determines cell fate by controlling the p53 activation threshold after DNA damage. Nat Cell Biol. 2009 Sep;11(9):1128-34
Wang HX, Tekpetey FR, Kidder GM. Identification of WNT/beta-CATENIN signaling pathway components in human cumulus cells. Mol Hum Reprod. 2009 Jan;15(1):11-7
Yardy GW, Bicknell DC, Wilding JL, Bartlett S, Liu Y, Winney B, Turner GD, Brewster SF, Bodmer WF. Mutations in the AXIN1 gene in advanced prostate cancer. Eur Urol. 2009 Sep;56(3):486-94
Choi SH, Choi KM, Ahn HJ. Coexpression and protein-protein complexing of DIX domains of human Dvl1 and Axin1 protein. BMB Rep. 2010 Sep;43(9):609-13
Kim S, Jho EH. The protein stability of Axin, a negative regulator of Wnt signaling, is regulated by Smad ubiquitination regulatory factor 2 (Smurf2). J Biol Chem. 2010 Nov 19;285(47):36420-6
Nikuseva Martić T, Pećina-Slaus N, Kusec V, Kokotović T, Musinović H, Tomas D, Zeljko M. Changes of AXIN-1 and beta-catenin in neuroepithelial brain tumors. Pathol Oncol Res. 2010 Mar;16(1):75-9
Pećina-Slaus N. Wnt signal transduction pathway and apoptosis: a review. Cancer Cell Int. 2010 Jun 30;10:22
Noutsou M, Duarte AM, Anvarian Z, Didenko T, Minde DP, Kuper I, de Ridder I, Oikonomou C, Friedler A, Boelens R, Rüdiger SG, Maurice MM. Critical scaffolding regions of the tumor suppressor Axin1 are natively unfolded. J Mol Biol. 2011 Jan 21;405(3):773-86
Pećina-Slaus N, Martić TN, Kokotović T, Kusec V, Tomas D, Hrasćan R. AXIN-1 protein expression and localization in glioblastoma. Coll Antropol. 2011 Jan;35 Suppl 1:101-6
Xu HT, Yang LH, Li QC, Liu SL, Liu D, Xie XM, Wang EH. Disabled-2 and Axin are concurrently colocalized and underexpressed in lung cancers. Hum Pathol. 2011 Apr 13;
This article should be referenced as such:
Pecina-Slaus N, Nikuseva Martic T, Kokotovic T. AXIN1 (axin 1). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):940-944.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 945
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
CCR2 (chemokine (C-C motif) receptor 2) Jérôme Moreaux
Institut de Recherche en Biotherapie, INSERM U847, Hopital Saint-Eloi, CHU de Montpellier, 80 av
Augustin Fliche, 34295 Montpellier Cedex 5, France (JM)
Published in Atlas Database: May 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/CCR2ID964ch3p21.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI CCR2ID964ch3p21.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: CC-CKR-2; CCR2A; CCR2B;
CD192; CKR2; CKR2A; CKR2B; CMKBR2;
FLJ78302; MCP-1-R; MGC103828; MGC111760;
MGC168006
HGNC (Hugo): CCR2
Location: 3p21.31
DNA/RNA
Note
CCR2 is a member of the beta chemokine receptor
family. CCR2 is a seven transmembrane protein
similar to G protein-coupled receptors. This gene
encodes two isoforms of a receptor for monocyte
chemoattractant protein-1, a chemokine which
specifically mediates monocyte chemotaxis.
Monocyte chemoattractant protein-1 is involved in
monocyte infiltration in inflammatory diseases such
as rheumatoid arthritis as well as in the
inflammatory response against tumors. The
receptors encoded by this gene mediate agonist-
dependent calcium mobilization and inhibition of
adenylyl cyclase. This gene is located in the
chemokine receptor gene cluster region including
CCR1, CCRL2, CCR3, CCR5 and CCXCR1 on
chromosome 3p.
Description
Size: 7195 bases.
2 isoforms:
- C-C chemokine receptor type 2 isoform A.
CCDS43078.1
- C-C chemokine receptor type 2 isoform B.
CCDS46813.1
Transcription
Homo sapiens chemokine (C-C motif) receptor 2
(CCR2), transcript variant A, mRNA: 2689 bp.
Homo sapiens chemokine (C-C motif) receptor 2
(CCR2), transcript variant B, mRNA: 2335 bp.
Pseudogene
No pseudogenes have been reported for CCR2.
Protein
Note
Chemokine receptors are cytokine receptors found
on the surface of cells, which interact with a type of
cytokine called a chemokine. They have a 7
transmembrane structure and couple to G-protein
for signal transduction within a cell, making them
members of a large protein family of G protein-
coupled receptors. Following interaction with their
specific chemokine ligands, chemokine receptors
trigger a flux in intracellular calcium (Ca2+
) ions
(calcium signaling). This causes cell responses,
including the onset of a process known as
chemotaxis that traffics the cell to a desired location
within the organism.
CCR2 (chemokine (C-C motif) receptor 2) Moreaux J
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 946
Structure of CCR2. The typical serpentine structure is depicted with three extracellular (top) and three intracellular (bottom)
loops and seven transmembrane domains.
Chemokine receptors share many common
structural features; they are composed of about 350
amino acids that are divided into a short and acidic
N-terminal end, seven helical transmembrane
domains with three intracellular and three
extracellular hydrophilic loops, and an intracellular
C-terminus containing serine and threonine residues
that act as phosphorylation sites during receptor
regulation. The first two extracellular loops of
chemokine receptors are linked together by
disulfide bonding between two conserved cysteine
residues. The N-terminal end of a chemokine
receptor binds to chemokine(s) and is important for
ligand specificity. G-proteins couple to the C-
terminal end, which is important for receptor
signaling following ligand binding.
Description
374 amino acids; 41915 Da.
Expression
Peripheral blood monocytes, activated T cells, B
cells and immature dendritic cells.
Localisation
Cell membrane; multi-pass membrane protein.
Function
Receptor for the MCP-1/CCL2, MCP-3/CCL7 and
MCP-4/CCL13 chemokines. Transduces a signal by
increasing the intracellular calcium ions level.
Alternative coreceptor with CD4 for HIV-1
infection.
Homology
CCR2 proteins contains amino acid sequence
homology to other C-C chemokines. CCR1 (56%),
CCR5 (71%), CCR3 (78%), CCR4 (75%).
Implicated in
Multiple myeloma
Prognosis
In a cohort of 80 patients with Multiple Myeloma
(MM), patients with active disease showed
significant lower expression of CCR1, CCR2 and
CXCR4 than patients with non-active disease.
Oncogenesis
CCR1 and CCR2 are overexpressed in myeloma
cells compared to normal B cells. Osteoclasts
express genes coding for CCR2 chemokines
specifically (CCL2, CCL7, CCL8, and CCL13) and
high CCR2 gene expression in myeloma cells is
associated with increased bone lesions in MM
patients. CCR2 is significantly overexpressed in
MM cells compared to normal bone marrow plasma
cells. Osteoclasts can directly recruit MMC by
CCR2 chemokines production, promote MMC
survival, growth, and drug resistance by producing
various growth factors. MMC will promote
osteoclast progenitor recruitment and differentiation
producing CCL3, MIP-1beta, and CXCL12
chemokines, IGF-1, and increasing RANKL
production by stromal cells. Osteoclasts are the
main cells in the BM environment that produce
CCR2 (chemokine (C-C motif) receptor 2) Moreaux J
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 947
various CCR2 chemokines enabling malignant
plasma cells attraction.
Neuroblastoma
Oncogenesis
98 untreated primary neuroblastomas from patients
with metastatic disease were analyzed for tumor-
infiltrating iNKTs (Valpha24-Jalpha18-invariant
natural killer T cells) using RT-PCR and
immunofluorescent microscopy. 53% of tumors
contained iNKTs. CCR2 is more frequently
expressed by iNKT compared to T cells and natural
killer cells from blood. iNKTs migrate toward
neuroblastoma cells in a CCL2-dependent manner,
preferentially infiltrating MYCN nonamplified
proto-oncogene tumors that express CCL2.
Melanoma
Oncogenesis
MCP-1 may play a role in tumor angiogenesis and
early tumor growth of human malignant melanoma
by inducing VEGF and inflammatory cytokines
production (IL-1alpha and TNFalpha by the tumor-
associated macrophages (TAM) and
autocrine/paracrine effects on melanoma cells in a
mouse model.
Prostate cancer
Prognosis
The pleiotropic roles of CCL2 in the development
of prostate cancer are mediated through its receptor,
CCR2. An association between prostate cancer
progression and CCR2 expression was
demonstrated on tissue microarray specimens of
patients. CCR2 mRNA and protein were
significantly overexpressed within prostate cancer
metastatic tissues compared to localized prostate
cancer and benign prostate tissue. CCR2
overexpression was also associated with higher
Gleason score and higher clinical pathologic stages.
Oncogenesis
CCL2 support prostate cancer cell survival via
PI3K/AKT in vitro. CCL2 derived from human
bone marrow endothelial cells induces PC-3 cell
line transendothelial cell migration via activation of
the small GTPase Rac. In a cell co-culture system,
prostate cancer cell-conditioned medium induces
CCL2 overexpression in endothelial cells and
osteoblasts. In osteoblasts, this secretion is
mediated in part by parathyroid hormone-related
protein.
In mouse model, neutralizing antibody against
CCL2 inhibits prostate cancer PC-3 and VCaP
growth in bone. Same results were obtained with
CCL2 knockdown. CCL2 induces surviving
expression in prostate cancer cells and protect them
from autophagic death.
Breast cancer
Prognosis
Overexpression of the chemokine CCL2 is
frequently associated with advanced tumor stage
and metastatic relapse in breast cancer.
Oncogenesis
Overexpression of CCL2 promotes breast cancer
metastasis to both lung and bone in mice. Blocking
CCL2 with a neutralizing antibody reduced lung
and bone metastases. The enhancement of lung
metastases by CCL2 was associated with increased
macrophage infiltration. In bone, it was associated
with osteoclast differentiation. CCL2 produced by
breast tumor cells activates CCR2 positive stromal
cells of monocytic origin (including macrophages
and preosteoclasts) leading to metastases in lung
and bone.
Esophageal carcinoma
Oncogenesis
CCL2 is expressed by tumor cells of esophageal
squamous cell carcinoma. CCL2 produced by
tumor cell and CCR2 expressed on vascular
endothelial cells may participate in esophageal
carcinoma tumor angiogenesis.
Gastric cancer
Oncogenesis
CCL2 produced by human gastric carcinoma cells
is involved in angiogenesis via macrophage
recruitment and activation via CCR2. CCL2
produced by gastric carcinoma cells induces tumor
growth in ectopic xenografts and increased
tumorigenicity and induced lymph node metastases
and ascites in orthotopic xenografts.
References De Vos J, Couderc G, Tarte K, Jourdan M, Requirand G, Delteil MC, Rossi JF, Mechti N, Klein B. Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays. Blood. 2001 Aug 1;98(3):771-80
Ohta M, Kitadai Y, Tanaka S, Yoshihara M, Yasui W, Mukaida N, Haruma K, Chayama K. Monocyte chemoattractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human gastric carcinomas. Int J Oncol. 2003 Apr;22(4):773-8
Koide N, Nishio A, Sato T, Sugiyama A, Miyagawa S. Significance of macrophage chemoattractant protein-1 expression and macrophage infiltration in squamous cell carcinoma of the esophagus. Am J Gastroenterol. 2004 Sep;99(9):1667-74
Metelitsa LS, Wu HW, Wang H, Yang Y, Warsi Z, Asgharzadeh S, Groshen S, Wilson SB, Seeger RC. Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2. J Exp Med. 2004 May 3;199(9):1213-21
Kuroda T, Kitadai Y, Tanaka S, Yang X, Mukaida N, Yoshihara M, Chayama K. Monocyte chemoattractant protein-1 transfection induces angiogenesis and tumorigenesis of gastric carcinoma in nude mice via macrophage recruitment. Clin Cancer Res. 2005 Nov 1;11(21):7629-36
Vande Broek I, Leleu X, Schots R, Facon T, Vanderkerken K, Van Camp B, Van Riet I. Clinical significance of
CCR2 (chemokine (C-C motif) receptor 2) Moreaux J
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 948
chemokine receptor (CCR1, CCR2 and CXCR4) expression in human myeloma cells: the association with disease activity and survival. Haematologica. 2006 Feb;91(2):200-6
Chavey C, Bibeau F, Gourgou-Bourgade S, Burlinchon S, Boissière F, Laune D, Roques S, Lazennec G. Oestrogen receptor negative breast cancers exhibit high cytokine content. Breast Cancer Res. 2007;9(1):R15
Koga M, Kai H, Egami K, Murohara T, Ikeda A, Yasuoka S, Egashira K, Matsuishi T, Kai M, Kataoka Y, Kuwano M, Imaizumi T. Mutant MCP-1 therapy inhibits tumor angiogenesis and growth of malignant melanoma in mice. Biochem Biophys Res Commun. 2008 Jan 11;365(2):279-84
Soria G, Ben-Baruch A. The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett. 2008 Aug 28;267(2):271-85
Lu X, Kang Y. Chemokine (C-C motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast
cancer metastasis to lung and bone. J Biol Chem. 2009 Oct 16;284(42):29087-96
Zhang J, Lu Y, Pienta KJ. Multiple roles of chemokine (C-C motif) ligand 2 in promoting prostate cancer growth. J Natl Cancer Inst. 2010 Apr 21;102(8):522-8
Zhang J, Patel L, Pienta KJ. CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis. Cytokine Growth Factor Rev. 2010 Feb;21(1):41-8
Moreaux J, Hose D, Kassambara A, Reme T, Moine P, Requirand G, Goldschmidt H, Klein B. Osteoclast-gene expression profiling reveals osteoclast-derived CCR2 chemokines promoting myeloma cell migration. Blood. 2011 Jan 27;117(4):1280-90
This article should be referenced as such:
Moreaux J. CCR2 (chemokine (C-C motif) receptor 2). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):945-948.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 949
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase)) Dimitra Florou, Andreas Scorilas, Dido Vassilacopoulou, Emmanuel G Fragoulis
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens 15701,
Panepistimiopolis, Athens, Greece (DF, AS, DV, EGF)
Published in Atlas Database: May 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/DDCID50590ch7p12.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI DDCID50590ch7p12.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: AADC
HGNC (Hugo): DDC
Location: 7p12.1
Local order: Centromere to telomere.
DNA/RNA
Note
The complete nucleotide structure of the human
DDC gene has been determined from tissues of
neural and non-neural origin (Sumi-Ichinose et al.,
1992; Ichinose et al., 1992). The full DDC cDNA
sequence has been cloned from human cells, such
as pheochromocytoma (Ichinose et al., 1989), liver
(Ichinose et al., 1992), hepatoma cells (Scherer et
al., 1992), placenta (Siaterli et al., 2003), peripheral
leukocytes (Kokkinou et al., 2009b), as well as
from several human cell lines, such as, U937
macrophage cells (Kokkinou et al., 2009a), SH-
SY5Y, HTB-14 and HeLa cells (Chalatsa et al.,
2011).
Description
The human DDC gene exists as a single-copy in the
haploid genome. It is composed of 15 exons and 14
introns, spanning for more than 85 kbs (Sumi-
Ichinose et al., 1992). The size of the exons was
found to range from 20 to 406 bps (Sumi-Ichinose
et al., 1992), whereas the size of the introns ranged
from 927 to 24077 bps (Sumi-Ichinose et al., 1992;
Yu et al., 2006). The DDC gene is located in close
proximity to the epidermal growth factor (EGF)
gene (Craig et al., 1992).
Transcription
Alternative splicing events are responsible for the
production of two distinct DDC mRNAs, termed
neural and non-neural, which differ in their 5'
untranslated region (UTR). The neural-type
transcript includes exon N1 (83 bps) that is located
17.8 kbs upstream of exon two. The non-neural
type DDC mRNA bears exon L1 (200 bps), which is
located 4.2 kbs upstream to the location of exon N1.
The second exon contains the translation start site
and is located 22 kbs downstream from the non-
neural (L1) exon (Ichinose et al., 1992). The
transcription of the gene starts at position -111
(Sumi-Ichinose et al., 1992).
It has been reported that the two alternative DDC
transcripts share identical coding regions and that
their production is a result of alternative splicing
and alternative promoter usage (Ichinose et al.,
1992; Sumi-Ichinose et al., 1995). Neural and non-
neural promoters have been identified 5' to the
flanking region of the respective exon 1 (Le Van
Thai et al., 1993; Sumi-Ichinose et al., 1995;
Chatelin et al., 2001; Dugast-Darzacq et al., 2004).
The generation of the two alternative DDC mRNAs
is not a mutually exclusive and tissue-specific event
as previously thought (Siaterli et al., 2003;
Vassilacopoulou et al., 2004; Kokkinou et al.,
2009a; Kokkinou et al., 2009b; Chalatsa et al.,
2011).
An alternative splicing event has been described
within the coding region of DDC mRNA, leading to
the formation of a shorter transcript lacking exon 3
(O'Malley et al., 1995; Chang et al., 1996).
DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase))
Florou D, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 950
Table 1. Expression of DDC mRNA transcripts in human tissues, cells and cancer cell lines.
It must be noted that the above authors did not
specify the nature, neural or non-neural, of this
shorter transcript. Recent evidence have revealed
the neural nature of this alternative transcript in
humans (Kokkinou et al., 2009a; Kokkinou et al.,
2009b; Chalatsa et al., 2011).
A novel DDC mRNA coding region splice-variant,
resulting in the formation of a truncated DDC
mRNA has been also identified. This human DDC
mRNA (1.8 kbs), termed as Alt-DDC, lacks exons
10-15 of the full-length transcript, but includes an
alternative exon 10 (Vassilacopoulou et al., 2004).
The Alt-DDC exon 10 (358 bps) was found within
intron 9 of the DDC gene. Although Alt-DDC
mRNA was detected in human placenta, high
expression levels of this alternative transcript were
found in human kidney (Vassilacopoulou et al.,
2004).
The notion that transcription of the human DDC
gene leads to the production of multiple mRNA
isoforms, which are expressed in a non-mutually
exclusive and tissue-specific manner, underlines the
complexity of the expression patterns of this gene
(table 1).
Pseudogene
None has been identified yet.
Protein
Note
Although, it was initially suggested that the DDC
gene encoded for a single protein product (Sumi-
Ichinose et al., 1992), evidence that demonstrated
the expression of additional DDC protein isoforms
in humans, argue against it (O'Malley et al., 1995;
Chang et al., 1996; Vassilacopoulou et al., 2004).
Description
The DDC enzyme (EC 4.1.1.28) was initially
purified and characterized from pig kidney
(Christenson et al., 1970) as well as from the
insects Calliphora vicina (Fragoulis and Sekeris,
1975) and Ceratitis capitata (Mappouras and
Fragoulis, 1988; Bossinakou and Fragoulis, 1996).
DDC is a homodimer of 100-110 kDa, with a
subunit molecular mass of 50-55 kDa (Voltattorni
et al., 1979; Mappouras et al., 1990; Bossinakou
and Fragoulis, 1996). The full-length protein
molecule consists of 480 amino acids (Ichinose et
al., 1989). DDC is a pyridoxal-5-phosphate (PLP)-
dependent enzyme possessing a single binding-site
for PLP per subunit (Voltattorni et al., 1982;
Ichinose et al., 1989; Burkhard et al., 2001).
Expression of the DDC gene, in humans, results in
the production of additional protein isoforms
(O'Malley et al., 1995; Chang et al., 1996;
Vassilacopoulou et al., 2004). O'Malley et al.
(1995) identified of a new DDC protein isoform
(O'Malley et al., 1995). The truncated DDC protein
isoform (Mr; 50 kDa) consists of 442 amino acid
residues (DDC442). This isoform was found to be
inactive towards the decarboxylation of both L-
Dopa to Dopamine and 5-Hydroxytryptophan (5-
HTP) to serotonin (O'Malley et al., 1995). As
mentioned above, the translation of Alt-DDC
mRNA resulted in the synthesis of a truncated 338
amino acid long polypeptide, termed as Alt-DDC
(Mr; 37 kDa). This isoform was identical to the
full-length DDC protein up to amino acid residue
315. The remaining 23 amino acids of the C-
terminal sequence are encoded by the alternative
DDC exon 10 and are not incorporated in the full-
length DDC protein sequence (Vassilacopoulou et
al., 2004).
Although previous data had suggested that DDC
was a rather unregulated molecule, several findings
have indicated that DDC activity can be modulated
by many factors, such as D1, DA receptor
antagonists (Rossetti et al., 1990), a2-adrenergic
receptor antagonists (Rossetti et al., 1989), D1, D2
receptor antagonists (Zhu et al., 1992;
Hadjiconstantinou et al., 1993), DA receptor
DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase))
Florou D, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 951
Table 2. Human DDC identity.
agonists (Zhu et al., 1993), PK-A and PK-C
mediated pathways (Young et al., 1993; Young et
al., 1994) and by endogenous inhibitors isolated
from human serum (Vassiliou et al., 2005) and
placenta (Vassiliou et al., 2009).
Expression
DDC has been detected throughout the length of the
gastrointestinal tract (Eisenhofer et al., 1997) and in
blood plasma (Boomsma et al., 1986). DDC is
expressed in normal human kidney and placenta
(Mappouras et al., 1990; Siaterli et al., 2003). DDC
expression was observed in normal peripheral
leukocytes and T-lymphocytes (Kokkinou et al.,
2009b). Furthermore, DDC is expressed in the
human cancer cell lines U937 (Kokkinou et al.,
2009a), SH-SY5Y, HeLa and HTB-14 (Chalatsa et
al., 2011). Interestingly, the expression of the
alternative DDC isoform (Alt-DDC) was also
demonstrated in peripheral leukocytes (Kokkinou et
al., 2009b), U937 (Kokkinou et al., 2009a), SH-
SY5Y and HeLa cell lines (Chalatsa et al., 2011).
In the central nervous system, increased DDC
enzymatic activity is detected in the hypothalamus,
epiphysis, striatum, locus ceruleus, olfactory bulb
and retina (Park et al., 1986). Elevated enzymatic
DDC activity is also detected in peripheral organs
such as liver, pancreas, kidney, lungs, spleen,
stomach, salivary glands, as well as in the
endothelial cells of blood vessels (Lovenberg et al.,
1962; Rahman et al., 1981; Lindström and Sehlin,
1983).
Localisation
DDC was considered to be a cytosolic molecule
(Lovenberg et al., 1962; Sims et al., 1973).
Nevertheless, additional experimental findings have
demonstrated that a population of enzymatically
active DDC molecules is associated with the
cellular membrane fraction in the mammalian CNS
(Poulikakos et al., 2001). Membrane-associated,
enzymatically active DDC subpopulations were
detected in the highly hydrophobic fractions of
normal human leukocytes and U937 cancer cells
(Kokkinou et al., 2009a; Kokkinou et al., 2009b).
Function
In terms of substrate specificity, the DDC molecule
purified from insects demonstrated a remarkably
high affinity towards the decarboxylation of L-
Dopa to dopamine (Fragoulis and Sekeris, 1975;
Mappouras and Fragoulis, 1988; Bossinakou and
Fragoulis, 1996). However, work by Mappouras et
al. (1990) in the normal human kidney has
suggested that the enzyme is capable of also
decarboxylating L-5-Hydroxytryptophan to
serotonin, although the decarboxylation activity
towards L-5-Hydroxytryptophan was found to be
considerably lower than the one observed for L-
Dopa (Mappouras et al., 1990). Since DDC
expression results in the production of multiple
protein isoforms, it is conceivable that these
different protein molecules could be responsible for
the decarboxylation of other aromatic L-amino
acids.
Homology
Comparison of the amino acid sequence of DDC
from different species, suggested that the enzyme is
an evolutionarily conserved molecule. The amino
acid sequence around the coenzyme binding lysine
is also evolutionarily conserved (Bossa et al., 1977;
Ichinose et al., 1989). The conserved amino acids
are residues 267-317, which surround the PLP-
binding site (Ichinose et al., 1989), as well as, the
extended regions of amino acids 64-155 and 182-
204, which according to Maras et al. (1991) are
important for the enzyme's catalytic function
(Maras et al., 1991). Table 2 shows the percentage
of human DDC amino acid identity to other species
(Maras et al., 1991; Mantzouridis et al., 1997).
Mutations
Table 3. The mutations of the DDC gene in the AADC
disorder.
DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase))
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Germinal
Such mutations have not been identified so far.
Somatic
Aromatic L-amino acid decarboxylase (AADC)
deficiency, a rare autosomaly-recessive inherited
defect, is associated with mutations of the DDC
gene. This disorder leads to profound modifications
in the homeostasis of central and peripheral nervous
system (Hyland et al., 1992). In their majority, such
mutations are missense and are listed above (table
3). Other mutations of the human DDC gene that
are related to AADC-deficiency are also included
(Fiumara et al., 2002; Chang et al., 2004; Pons et
al., 2004; Tay et al., 2007; Lee et al., 2009).
Implicated in
Prostate cancer
Note
Neuroendocrine differentiation features have been
identified in prostatic adenocarcinoma.
Aggressiveness of the disease is increased as the
cells reach the androgen-independent phase
(Speights et al., 1997; Nelson et al., 2002). L-Dopa
decarboxylase has been identified as a novel
androgen receptor (AR) coactivator protein (Wafa
et al., 2003). Recent evidence have shown that the
expression of DDC mRNA could serve as a
potential novel biomarker in prostate cancer
(Avgeris et al., 2008). Wafa et al. (2007) have
indicated by immunohistochemistry that DDC was
found to be a putative neuroendocrine marker for
prostate cancer. In certain NE tumor cells of the
prostate gland, DDC was found to be co-expressed
with AR. DDC expression was increased after
hormone-ablation therapy, as well as, in metastatic
tumors that have progressed to the androgen-
independent phenotypes (Wafa et al., 2007).
Disease
Increased DDC mRNA and/or elevated protein
expression levels were detected in the LnCaP cell
line following synthetic androgen treatment. DDC
protein was found to be enzymatically active in the
androgen-treated LnCaP cells as compared to the
untreated controls. In treated LnCaP cells, DDC
was up-regulated during AR-activation, while DDC
expression was down-regulated following AR-
inhibition. These findings support a coactivator role
for DDC in AR activation (Shao et al., 2007). DDC
over-expression affects the gene expression profile
of the androgen-dependent prostate cancer cell line,
LnCaP, as revealed by microarray analysis
(Margiotti et al., 2007).
Prognosis
Statistically significant elevated DDC mRNA levels
were observed in prostate cancer tissue specimens
when compared to benign hyperplasia human
samples.
Multivariate survival analysis indicated that the
expression of the DDC gene could be used as an
independent marker for the differential diagnosis
between prostate cancer and benign hyperplasia
patients, using tissue biopsies. DDC mRNA
expression was also shown to be associated with
advanced tumor stage and higher Gleason score.
This finding suggested an unfavorable prognostic
value for DDC expression in patients with tumors
in their prostate glands (Avgeris et al., 2008).
Colorectal carcinoma
Note
High L-Dopa decarboxylase activity has been
detected in almost half of the original colorectal
carcinomas examined, as well as, in the majority of
cultured cell lines, established from human primary
and metastatic tumors (Park et al., 1987). Other
data have shown that most solid colorectal tumors
exhibited DDC activity at lower levels when
compared to the enzymatic DDC activity displayed
by the NE tumors (Gazdar et al., 1988). DDC
mRNA expression was found to be elevated in
well-differentiated (grade I) intestinal
adenocarcinomas as compared to more aggressive
tumors (Kontos et al., 2010).
Prognosis
Increased DDC mRNA levels were observed in
grade I colorectal adenocarcinomas. Survival
analysis revealed a significantly lower risk of
disease recurrence and longer overall survival for
patients with DDC-positive colorectal neoplasms.
These results indicate that DDC mRNA expression
might represent a possible future biomarker for the
prognosis of colorectal cancer patients (Kontos et
al., 2010).
Gastric cancer
Note
Advanced gastric cancer is characterized by
peritoneal dissemination, the most common disease
relapse, which is caused by the dispersal of free
gastric cancer cells into the peritoneal cavity (Baba
et al., 1989; Abe et al., 1995).
Disease
It has been proposed that increased DDC mRNA
expression could be an accurate tool for the
detection of gastric cancer micrometastases in the
peritoneal cavity. According to Sakakura et al.
(2004), DDC expression levels were equivalent to
the degree of dissemination potential of gastric
cancer cells.
Pheochromocytomas
Note
Pheochromocytomas are characterized by over-
production of catecholamines (Eisenhofer et al.,
2001).
DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase))
Florou D, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 953
Disease
These non-innervated tumors originate, in most
cases, from adrenal medullary cells which are
capable for catecholamine biosynthesis (Yanase et
al., 1986). Catecholamine release by these cells is
not initiated by nerve impulses. Elevated DDC
mRNA levels have been detected in
pheochromocytoma tissues as compared to normal
adrenal medullary cells. Isobe et al. (1998)
suggested that high DDC expression could lead to
the development or growth of pheochromocytomas
(Isobe et al., 1998).
Neuroblastomas
Note
In the neuroblastoma cell line, the SH-SY5Y cells,
both neural full-length DDC mRNA and the neural
mRNA isoform lacking exon 3, were detected
(Chalatsa et al., 2011).
Disease
Neuroblastomas, the most common extracranial
solid neoplasms in children, originate from
sympathetic neural crest cells and their
characteristic is the production of catecholamines
and their metabolites (Boomsma et al., 1989).
Neuroblastomas are categorized as small round-cell
tumors of the childhood (Gilbert et al., 1999). In the
active untreated state, plasma L-Dopa values and/or
DDC enzymatic activity levels have been found to
be elevated. Interestingly, following chemotherapy
treatment, DDC enzymatic activity levels fall
within the physiological range. Elevated levels of
plasma L-Dopa and especially DDC enzyme
activity are observed during disease relapse
(Boomsma et al., 1989).
It is noted that conventional light microscopy
cannot clearly differentiate between neuroblastoma
and other small round-cell tumors of the childhood.
Co-expression of DDC and Tyrosine Hydroxylase
(TH) has been used for the differential diagnosis of
these types of tumors (Gilbert et al., 1999).
Prognosis
Elevated levels of plasma L-Dopa, in
neuroblastoma patients, could provide an indication
for residual tumor. These findings could be
associated with dismal prognosis for neuroblastoma
patients. Furthermore, a sharp increase in plasma
DDC enzymatic activity could be related to disease
reccurence (Boomsma et al., 1989). DDC mRNA
was detected in all bone marrow and peripheral
blood samples obtained from neuroblastoma
patients at relapse. Given these results, Bozzi et al.
(2004) have suggested that DDC mRNA expression
could represent a specific molecular marker for
monitoring bone marrow and peripheral blood
neuroblastoma metastases (Bozzi et al., 2004).
Furthermore, DDC mRNA levels could be used as a
sensitive indicator to predict minimal residual
disease as well as the outcome for patients (Träger
et al., 2008).
Lung carcinomas
Note
Elevated DDC enzymatic activity was observed in
small-cell lung carcinoma (SCLC) as compared to
normal lung epithelia (Nagatsu et al., 1985). The
majority of non-SCLC (NSCLC) exhibited low
levels or no DDC enzyme activity (Gazdar et al.,
1981; Bepler et al., 1988). It is noted that in some
NSCLC cases, high DDC activity values have been
reported (Baylin et al., 1980), although in these
lung lesions the detection of DDC activity was
restricted to large-cell carcinomas and
adenocarcinomas, while squamous cell carcinomas
did not exhibit any enzymatic activity (Gazdar et
al., 1988).
Disease
DDC activity appears to be a valuable
neuroendocrine marker for identifying SCLC tumor
cells in culture (Baylin et al., 1980). DDC
enzymatic activity is highest during the exponential
cellular growth phase and/or when the cells are
during the transition from G2 to the M phase of the
cell cycle (Francis et al., 1983). DDC activity has
been also used as a useful biomarker for the
distinction of SCLC from NSCLC. Furthermore,
DDC activity has been used for the differentiation
between the classical SCLC cell lines (SCLC-C),
which express high DDC activity levels, from the
variant subtype of the SCLC (SCLC-V), which
does not express the enzyme (Carney et al., 1985;
Gazdar et al., 1985).
Prognosis
The elevated DDC enzymatic activity, which is
observed in patients harboring SCLC tumors, seems
to be associated with disease differentiation grade.
High DDC activity has been associated with better
prognosis and patient's outcome (Bepler et al.,
1987).
Medullary thyroid carcinoma
Note
The expression of L-Dopa decarboxylase has been
detected in medullary carcinoma of the thyroid
gland (Pearse, 1969; Atkins et al., 1973).
Disease
Medullary thyroid carcinoma (MTC) originates
from the calcitonin (CT)-secreting thyroid C cells
and is a unique malignancy of endocrine origin
(Tashjian and Melvin, 1968). Malignancy
progression could be monitored, in patients with the
virulent phenotype of the disease, using the
simultaneous increased levels of DDC and
histaminase (Trump et al., 1979; Lippman et al.,
1982). It has been proposed that increased DDC
enzymatic activity might represent an early
differentiation marker in the virulent form of this
neoplasm (Berger et al., 1984).
DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase))
Florou D, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 954
Neuroendocrine tumors (NETs): bronchial, liver and ileal carcinoids, gastric / pancreatic / pulmonary tumors
Note
DDC enzymatic activity constitutes an excellent
cellular marker for identifying tumors of the
neuroendocrine (NE) origin. The majority of NE
tumors tested were found to express relatively high
DDC enzymatic activity (Gazdar et al., 1988). DDC
expression and/or activity have been reported in
NETs, particularly in SCLC. For these reasons,
DDC has been considered as a general endocrine
marker (Gazdar et al., 1988; Jensen et al., 1990).
Disease
Strikingly higher DDC mRNA expression levels
were revealed in all bronchial carcinoids and
pulmonary NETs when compared to their normal
corresponding types of tissues.
Immunohistochemical data have confirmed DDC
protein expression in all of these tumors. In the
gastroenteropancreatic NETs examined, the
detected DDC mRNA levels were comparable to
those of normal gastric, ileal and pancreatic tissues.
Almost half of the pancreatic and stomach NETs
and all ileal carcinoids were found to be DDC
immunoreactive (Uccella et al., 2006).
Interestingly, hepatic carcinoid tumors
demonstrated a 20-fold increase in DDC activity as
compared with normal surrounding liver tissues
(Gilbert et al., 1995).
Hybrid/Mutated gene
Not yet discovered.
References LOVENBERG W, WEISSBACH H, UDENFRIEND S. Aromatic L-amino acid decarboxylase. J Biol Chem. 1962 Jan;237:89-93
Tashjian AH Jr, Melvin EW. Medullary carcinoma of the thyroid gland. Studies of thyrocalcitonin in plasma and tumor extracts. N Engl J Med. 1968 Aug 8;279(6):279-83
Pearse AG. The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series and the embryologic, physiologic and pathologic implications of the concept. J Histochem Cytochem. 1969 May;17(5):303-13
Christenson JG, Dairman W, Udenfriend S. Preparation and properties of a homogeneous aromatic L-amino acid decarboxylase from hog kidney. Arch Biochem Biophys. 1970 Nov;141(1):356-67
Atkins FL, Beaven MA, Keiser HR. Dopa decarboxylase in medullary carcinoma of the thyroid. N Engl J Med. 1973 Sep 13;289(11):545-8
Sims KL, Davis GA, Bloom FE. Activities of 3,4-dihydroxy-L-phenylalanine and 5-hydroxy-L-tryptophan decarboxylases in rat brain: assay characteristics and distribution. J Neurochem. 1973 Feb;20(2):449-64
Fragoulis EG, Sekeris CE. Purification and characteristics of DOPA-decarboxylase from the integument of Calliphora
vicina larve. Arch Biochem Biophys. 1975 May;168(1):15-25
Bossa F, Martini F, Barra D, Voltattorni CB, Minelli A, Turano C. The chymotryptic phosphopyridoxyl peptide of DOPA decarboxylase from pig kidney. Biochem Biophys Res Commun. 1977 Sep 9;78(1):177-84
Trump DL, Mendelsohn G, Baylin SB. Discordance between plasma calcitonin and tumor-cell mass in medullary thyroid carcinoma. N Engl J Med. 1979 Aug 2;301(5):253-5
Voltattorni CB, Minelli A, Vecchini P, Fiori A, Turano C. Purification and characterization of 3,4-dihydroxyphenylalanine decarboxyase from pig kidney. Eur J Biochem. 1979 Jan 2;93(1):181-8
Baylin SB, Abeloff MD, Goodwin G, Carney DN, Gazdar AF. Activities of L-dopa decarboxylase and diamine oxidase (histaminase) in human lung cancers and decarboxylase as a marker for small (oat) cell cancer in cell culture. Cancer Res. 1980 Jun;40(6):1990-4
Gazdar AF, Zweig MH, Carney DN, Van Steirteghen AC, Baylin SB, Minna JD. Levels of creatine kinase and its BB isoenzyme in lung cancer specimens and cultures. Cancer Res. 1981 Jul;41(7):2773-7
Rahman MK, Nagatsu T, Kato T. Aromatic L-amino acid decarboxylase activity in central and peripheral tissues and serum of rats with L-DOPA and L-5-hydroxytryptophan as substrates. Biochem Pharmacol. 1981 Mar 15;30(6):645-9
Lippman SM, Mendelsohn G, Trump DL, Wells SA Jr, Baylin SB. The prognostic and biological significance of cellular heterogeneity in medullary thyroid carcinoma: a study of calcitonin, L-dopa decarboxylase, and histaminase. J Clin Endocrinol Metab. 1982 Feb;54(2):233-40
Voltattorni CB, Minelli A, Cirotto C, Barra D, Turano C. Subunit structure of 3, 4-dihydroxyphenylalanine decarboxylase from pig kidney. Arch Biochem Biophys. 1982 Aug;217(1):58-64
Francis J, Thompson R, Bernal SD, Luk GD, Baylin SB. Effects of dibutyryl cyclic adenosine 3':5'-monophosphate on the growth of cultured human small-cell lung carcinoma and the specific cellular activity of L-dopa decarboxylase. Cancer Res. 1983 Feb;43(2):639-45
Lindström P, Sehlin J. Mechanisms underlying the effects of 5-hydroxytryptamine and 5-hydroxytryptophan in pancreatic islets. A proposed role for L-aromatic amino acid decarboxylase. Endocrinology. 1983 Apr;112(4):1524-9
Berger CL, de Bustros A, Roos BA, Leong SS, Mendelsohn G, Gesell MS, Baylin SB. Human medullary thyroid carcinoma in culture provides a model relating growth dynamics, endocrine cell differentiation, and tumor progression. J Clin Endocrinol Metab. 1984 Aug;59(2):338-43
Carney DN, Gazdar AF, Bepler G, Guccion JG, Marangos PJ, Moody TW, Zweig MH, Minna JD. Establishment and identification of small cell lung cancer cell lines having classic and variant features. Cancer Res. 1985 Jun;45(6):2913-23
Gazdar AF, Carney DN, Nau MM, Minna JD. Characterization of variant subclasses of cell lines derived from small cell lung cancer having distinctive biochemical, morphological, and growth properties. Cancer Res. 1985 Jun;45(6):2924-30
Nagatsu T, Ichinose H, Kojima K, Kameya T, Shimase J, Kodama T, Shimosato Y. Aromatic L-amino acid decarboxylase activities in human lung tissues:
DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase))
Florou D, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 955
comparison between normal lung and lung carcinomas. Biochem Med. 1985 Aug;34(1):52-9
Boomsma F, van der Hoorn FA, Schalekamp MA. Determination of aromatic-L-amino acid decarboxylase in human plasma. Clin Chim Acta. 1986 Sep 15;159(2):173-83
Park DH, Teitelman G, Evinger MJ, Woo JI, Ruggiero DA, Albert VR, Baetge EE, Pickel VM, Reis DJ, Joh TH. Phenylethanolamine N-methyltransferase-containing neurons in rat retina: immunohistochemistry, immunochemistry, and molecular biology. J Neurosci. 1986 Apr;6(4):1108-13
Yanase T, Nawata H, Kato K, Ibayashi H. Catecholamines and opioid peptides in human phaeochromocytomas. Acta Endocrinol (Copenh). 1986 Nov;113(3):378-84
Bepler G, Jaques G, Koehler A, Gropp C, Havemann K. Markers and characteristics of human SCLC cell lines. Neuroendocrine markers, classical tumor markers, and chromosomal characteristics of permanent human small cell lung cancer cell lines. J Cancer Res Clin Oncol. 1987;113(3):253-9
Park JG, Oie HK, Sugarbaker PH, Henslee JG, Chen TR, Johnson BE, Gazdar A. Characteristics of cell lines established from human colorectal carcinoma. Cancer Res. 1987 Dec 15;47(24 Pt 1):6710-8
Bepler G, Koehler A, Kiefer P, Havemann K, Beisenherz K, Jaques G, Gropp C, Haeder M. Characterization of the state of differentiation of six newly established human non-small-cell lung cancer cell lines. Differentiation. 1988;37(2):158-71
Gazdar AF, Helman LJ, Israel MA, Russell EK, Linnoila RI, Mulshine JL, Schuller HM, Park JG. Expression of neuroendocrine cell markers L-dopa decarboxylase, chromogranin A, and dense core granules in human tumors of endocrine and nonendocrine origin. Cancer Res. 1988 Jul 15;48(14):4078-82
Mappouras DG, Fragoulis EG.. Purification and characterization of L-DOPA decarboxylase from the white puparia of Ceratitis capitata. Insect Biochem. 1988 Jan;18(4):369-376.
Baba H, Korenaga D, Okamura T, Saito A, Sugimachi K.. Prognostic factors in gastric cancer with serosal invasion. Univariate and multivariate analyses. Arch Surg. 1989 Sep;124(9):1061-4.
Boomsma F, Ausema L, Hakvoort-Cammel FG, Oosterom R, Man in't Veld AJ, Krenning EP, Hahlen K, Schalekamp MA.. Combined measurements of plasma aromatic L-amino acid decarboxylase and DOPA as tumour markers in diagnosis and follow-up of neuroblastoma. Eur J Cancer Clin Oncol. 1989 Jul;25(7):1045-52.
Ichinose H, Kurosawa Y, Titani K, Fujita K, Nagatsu T.. Isolation and characterization of a cDNA clone encoding human aromatic L-amino acid decarboxylase. Biochem Biophys Res Commun. 1989 Nov 15;164(3):1024-30.
Rossetti Z, Krajnc D, Neff NH, Hadjiconstantinou M.. Modulation of retinal aromatic L-amino acid decarboxylase via alpha 2 adrenoceptors. J Neurochem. 1989 Feb;52(2):647-52.
Jensen SM, Gazdar AF, Cuttitta F, Russell EK, Linnoila RI.. A comparison of synaptophysin, chromogranin, and L-dopa decarboxylase as markers for neuroendocrine differentiation in lung cancer cell lines. Cancer Res. 1990 Sep 15;50(18):6068-74.
Mappouras DG, Stiakakis J, Fragoulis EG.. Purification and characterization of L-dopa decarboxylase from human kidney. Mol Cell Biochem. 1990 May 10;94(2):147-56.
Rossetti ZL, Silvia CP, Krajnc D, Neff NH, Hadjiconstantinou M.. Aromatic L-amino acid decarboxylase is modulated by D1 dopamine receptors in rat retina. J Neurochem. 1990 Mar;54(3):787-91.
Maras B, Dominici P, Barra D, Bossa F, Voltattorni CB.. Pig kidney 3,4-dihydroxyphenylalanine (dopa) decarboxylase. Primary structure and relationships to other amino acid decarboxylases. Eur J Biochem. 1991 Oct 15;201(2):385-91.
Craig SP, Thai AL, Weber M, Craig IW.. Localisation of the gene for human aromatic L-amino acid decarboxylase (DDC) to chromosome 7p13-->p11 by in situ hybridisation. Cytogenet Cell Genet. 1992;61(2):114-6.
Hyland K, Surtees RA, Rodeck C, Clayton PT.. Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology. 1992 Oct;42(10):1980-8.
Ichinose H, Sumi-Ichinose C, Ohye T, Hagino Y, Fujita K, Nagatsu T.. Tissue-specific alternative splicing of the first exon generates two types of mRNAs in human aromatic L-amino acid decarboxylase. Biochemistry. 1992 Nov 24;31(46):11546-50.
Scherer LJ, McPherson JD, Wasmuth JJ, Marsh JL.. Human dopa decarboxylase: localization to human chromosome 7p11 and characterization of hepatic cDNAs. Genomics. 1992 Jun;13(2):469-71.
Sumi-Ichinose C, Ichinose H, Takahashi E, Hori T, Nagatsu T.. Molecular cloning of genomic DNA and chromosomal assignment of the gene for human aromatic L-amino acid decarboxylase, the enzyme for catecholamine and serotonin biosynthesis. Biochemistry. 1992 Mar 3;31(8):2229-38.
Zhu MY, Juorio AV, Paterson IA, Boulton AA.. Regulation of aromatic L-amino acid decarboxylase by dopamine receptors in the rat brain. J Neurochem. 1992 Feb;58(2):636-41.
Hadjiconstantinou M, Wemlinger TA, Sylvia CP, Hubble JP, Neff NH.. Aromatic L-amino acid decarboxylase activity of mouse striatum is modulated via dopamine receptors. J Neurochem. 1993 Jun;60(6):2175-80.
Le Van Thai A, Coste E, Allen JM, Palmiter RD, Weber MJ.. Identification of a neuron-specific promoter of human aromatic L-amino acid decarboxylase gene. Brain Res Mol Brain Res. 1993 Mar;17(3-4):227-38.
Young EA, Neff NH, Hadjiconstantinou M.. Evidence for cyclic AMP-mediated increase of aromatic L-amino acid decarboxylase activity in the striatum and midbrain. J Neurochem. 1993 Jun;60(6):2331-3.
Zhu MY, Juorio AV, Paterson IA, Boulton AA.. Regulation of striatal aromatic L-amino acid decarboxylase: effects of blockade or activation of dopamine receptors. Eur J Pharmacol. 1993 Jul 20;238(2-3):157-64.
Young EA, Neff NH, Hadjiconstantinou M.. Phorbol ester administration transiently increases aromatic L-amino acid decarboxylase activity of the mouse striatum and midbrain. J Neurochem. 1994 Aug;63(2):694-7.
Abe S, Yoshimura H, Tabara H, Tachibana M, Monden N, Nakamura T, Nagaoka S.. Curative resection of gastric cancer: limitation of peritoneal lavage cytology in predicting the outcome. J Surg Oncol. 1995 Aug;59(4):226-9.
Gilbert JA, Bates LA, Ames MM.. Elevated aromatic-L-amino acid decarboxylase in human carcinoid tumors. Biochem Pharmacol. 1995 Sep 7;50(6):845-50.
O'Malley KL, Harmon S, Moffat M, Uhland-Smith A, Wong S.. The human aromatic L-amino acid decarboxylase gene
DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase))
Florou D, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 956
can be alternatively spliced to generate unique protein isoforms. J Neurochem. 1995 Dec;65(6):2409-16.
Sumi-Ichinose C, Hasegawa S, Ichinose H, Sawada H, Kobayashi K, Sakai M, Fujii T, Nomura H, Nomura T, Nagatsu I, et al.. Analysis of the alternative promoters that regulate tissue-specific expression of human aromatic L-amino acid decarboxylase. J Neurochem. 1995 Feb;64(2):514-24.
Bossinakou KS, Fragoulis EG.. Purification and characterisation of L-DOPA decarboxylase from pharate pupae of Ceratitis capitata. A comparison with the enzyme purified from the white prepupae. Comp Biochem Physiol B Biochem Mol Biol. 1996 Feb;113(2):213-20.
Chang YT, Mues G, Hyland K.. Alternative splicing in the coding region of human aromatic L-amino acid decarboxylase mRNA. Neurosci Lett. 1996 Jan 5;202(3):157-60.
Eisenhofer G, Aneman A, Friberg P, Hooper D, Fandriks L, Lonroth H, Hunyady B, Mezey E.. Substantial production of dopamine in the human gastrointestinal tract. J Clin Endocrinol Metab. 1997 Nov;82(11):3864-71.
Mantzouridis TD, Sideris DC, Fragoulis EG.. cDNA cloning of L-dopa decarboxylase from the eclosion stage of the insect Ceratitis capitata. Evolutionary relationship to other species decarboxylases. Gene. 1997 Dec 19;204(1-2):85-9.
Speights VO Jr, Cohen MK, Riggs MW, Coffield KS, Keegan G, Arber DA.. Neuroendocrine stains and proliferative indices of prostatic adenocarcinomas in transurethral resection samples. Br J Urol. 1997 Aug;80(2):281-6.
Isobe K, Nakai T, Yukimasa N, Nanmoku T, Takekoshi K, Nomura F.. Expression of mRNA coding for four catecholamine-synthesizing enzymes in human adrenal pheochromocytomas. Eur J Endocrinol. 1998 Apr;138(4):383-7.
Gilbert J, Haber M, Bordow SB, Marshall GM, Norris MD.. Use of tumor-specific gene expression for the differential diagnosis of neuroblastoma from other pediatric small round-cell malignancies. Am J Pathol. 1999 Jul;155(1):17-21.
Burkhard P, Dominici P, Borri-Voltattorni C, Jansonius JN, Malashkevich VN.. Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase. Nat Struct Biol. 2001 Nov;8(11):963-7.
Chatelin S, Wehrle R, Mercier P, Morello D, Sotelo C, Weber MJ.. Neuronal promoter of human aromatic L-amino acid decarboxylase gene directs transgene expression to the adult floor plate and aminergic nuclei induced by the isthmus. Brain Res Mol Brain Res. 2001 Dec 30;97(2):149-60.
Eisenhofer G, Huynh TT, Hiroi M, Pacak K.. Understanding catecholamine metabolism as a guide to the biochemical diagnosis of pheochromocytoma. Rev Endocr Metab Disord. 2001 Aug;2(3):297-311. (REVIEW)
Poulikakos P, Vassilacopoulou D, Fragoulis EG.. L-DOPA decarboxylase association with membranes in mouse brain. Neurochem Res. 2001 May;26(5):479-85.
Fiumara A, Brautigam C, Hyland K, Sharma R, Lagae L, Stoltenborg B, Hoffmann GF, Jaeken J, Wevers RA.. Aromatic L-amino acid decarboxylase deficiency with hyperdopaminuria. Clinical and laboratory findings in response to different therapies. Neuropediatrics. 2002 Aug;33(4):203-8.
Nelson PS, Clegg N, Arnold H, Ferguson C, Bonham M, White J, Hood L, Lin B.. The program of androgen-
responsive genes in neoplastic prostate epithelium. Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11890-5. Epub 2002 Aug 16.
Siaterli MZ, Vassilacopoulou D, Fragoulis EG.. Cloning and expression of human placental L-Dopa decarboxylase. Neurochem Res. 2003 Jun;28(6):797-803.
Wafa LA, Cheng H, Rao MA, Nelson CC, Cox M, Hirst M, Sadowski I, Rennie PS.. Isolation and identification of L-dopa decarboxylase as a protein that binds to and enhances transcriptional activity of the androgen receptor using the repressed transactivator yeast two-hybrid system. Biochem J. 2003 Oct 15;375(Pt 2):373-83.
Bozzi F, Luksch R, Collini P, Gambirasio F, Barzano E, Polastri D, Podda M, Brando B, Fossati-Bellani F.. Molecular detection of dopamine decarboxylase expression by means of reverse transcriptase and polymerase chain reaction in bone marrow and peripheral blood: utility as a tumor marker for neuroblastoma. Diagn Mol Pathol. 2004 Sep;13(3):135-43.
Chang YT, Sharma R, Marsh JL, McPherson JD, Bedell JA, Knust A, Brautigam C, Hoffmann GF, Hyland K.. Levodopa-responsive aromatic L-amino acid decarboxylase deficiency. Ann Neurol. 2004 Mar;55(3):435-8.
Dugast-Darzacq C, Egloff S, Weber MJ.. Cooperative dimerization of the POU domain protein Brn-2 on a new motif activates the neuronal promoter of the human aromatic L-amino acid decarboxylase gene. Brain Res Mol Brain Res. 2004 Jan 5;120(2):151-63.
Pons R, Ford B, Chiriboga CA, Clayton PT, Hinton V, Hyland K, Sharma R, De Vivo DC.. Aromatic L-amino acid decarboxylase deficiency: clinical features, treatment, and prognosis. Neurology. 2004 Apr 13;62(7):1058-65. (REVIEW)
Sakakura C, Takemura M, Hagiwara A, Shimomura K, Miyagawa K, Nakashima S, Yoshikawa T, Takagi T, Kin S, Nakase Y, Fujiyama J, Hayasizaki Y, Okazaki Y, Yamagishi H.. Overexpression of dopa decarboxylase in peritoneal dissemination of gastric cancer and its potential as a novel marker for the detection of peritoneal micrometastases with real-time RT-PCR. Br J Cancer. 2004 Feb 9;90(3):665-71.
Vassilacopoulou D, Sideris DC, Vassiliou AG, Fragoulis EG.. Identification and characterization of a novel form of the human L-dopa decarboxylase mRNA. Neurochem Res. 2004 Oct;29(10):1817-23.
Vassiliou AG, Vassilacopoulou D, Fragoulis EG.. Purification of an endogenous inhibitor of L-Dopa decarboxylase activity from human serum. Neurochem Res. 2005 May;30(5):641-9.
Uccella S, Cerutti R, Vigetti D, Furlan D, Oldrini R, Carnevali I, Pelosi G, La Rosa S, Passi A, Capella C.. Histidine decarboxylase, DOPA decarboxylase, and vesicular monoamine transporter 2 expression in neuroendocrine tumors: immunohistochemical study and gene expression analysis. J Histochem Cytochem. 2006 Aug;54(8):863-75. Epub 2006 Mar 3.
Yu Y, Panhuysen C, Kranzler HR, Hesselbrock V, Rounsaville B, Weiss R, Brady K, Farrer LA, Gelernter J.. Intronic variants in the dopa decarboxylase (DDC) gene are associated with smoking behavior in European-Americans and African-Americans. Hum Mol Genet. 2006 Jul 15;15(14):2192-9. Epub 2006 Jun 1.
Margiotti K, Wafa LA, Cheng H, Novelli G, Nelson CC, Rennie PS.. Androgen-regulated genes differentially modulated by the androgen receptor coactivator L-dopa decarboxylase in human prostate cancer cells. Mol Cancer. 2007 Jun 6;6:38.
DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase))
Florou D, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 957
Tay SK, Poh KS, Hyland K, Pang YW, Ong HT, Low PS, Goh DL.. Unusually mild phenotype of AADC deficiency in 2 siblings. Mol Genet Metab. 2007 Aug;91(4):374-8. Epub 2007 May 29.
Shao C, Wang Y, Yue HH, Zhang YT, Shi CH, Liu F, Bao TY, Yang ZY, Yuan JL, Shao GX.. Biphasic effect of androgens on prostate cancer cells and its correlation with androgen receptor coactivator dopa decarboxylase. J Androl. 2007 Nov-Dec;28(6):804-12. Epub 2007 Jun 20.
Wafa LA, Palmer J, Fazli L, Hurtado-Coll A, Bell RH, Nelson CC, Gleave ME, Cox ME, Rennie PS.. Comprehensive expression analysis of L-dopa decarboxylase and established neuroendocrine markers in neoadjuvant hormone-treated versus varying Gleason grade prostate tumors. Hum Pathol. 2007 Jan;38(1):161-70. Epub 2006 Sep 25.
Avgeris M, Koutalellis G, Fragoulis EG, Scorilas A.. Expression analysis and clinical utility of L-Dopa decarboxylase (DDC) in prostate cancer. Clin Biochem. 2008 Oct;41(14-15):1140-9. Epub 2008 Jun 10.
Trager C, Vernby A, Kullman A, Ora I, Kogner P, Kagedal B.. mRNAs of tyrosine hydroxylase and dopa decarboxylase but not of GD2 synthase are specific for neuroblastoma minimal disease and predicts outcome for children with high-risk disease when measured at diagnosis. Int J Cancer. 2008 Dec 15;123(12):2849-55.
Kokkinou I, Fragoulis EG, Vassilacopoulou D.. The U937 macrophage cell line expresses enzymatically active L-Dopa decarboxylase. J Neuroimmunol. 2009a Nov 30;216(1-2):51-8. Epub 2009 Oct 1.
Kokkinou I, Nikolouzou E, Hatzimanolis A, Fragoulis EG, Vassilacopoulou D.. Expression of enzymatically active L-DOPA decarboxylase in human peripheral leukocytes. Blood Cells Mol Dis. 2009b Jan-Feb;42(1):92-8. Epub 2008 Nov 28.
Lee HF, Tsai CR, Chi CS, Chang TM, Lee HJ.. Aromatic L-amino acid decarboxylase deficiency in Taiwan. Eur J Paediatr Neurol. 2009 Mar;13(2):135-40. Epub 2008 Jun 24.
Vassiliou AG, Fragoulis EG, Vassilacopoulou D.. Detection, purification and identification of an endogenous inhibitor of L-Dopa decarboxylase activity from human placenta. Neurochem Res. 2009 Jun;34(6):1089-100. Epub 2008 Nov 13.
Kontos CK, Papadopoulos IN, Fragoulis EG, Scorilas A.. Quantitative expression analysis and prognostic significance of L-DOPA decarboxylase in colorectal adenocarcinoma. Br J Cancer. 2010 Apr 27;102(9):1384-90.
Chalatsa I, Nikolouzou E, Fragoulis EG, Vassilacopoulou D.. L-Dopa decarboxylase expression profile in human cancer cells. Mol Biol Rep. 2011 Feb;38(2):1005-11. Epub 2010 Jun 11.
This article should be referenced as such:
Florou D, Scorilas A, Vassilacopoulou D, Fragoulis EG. DDC (dopa decarboxylase (aromatic L-amino acid decarboxylase)). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):949-957.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 958
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
DDR1 (discoidin domain receptor tyrosine kinase 1) Barbara Roig, Elisabet Vilella
Hospital Psiquiatic Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, C/Sant Llorenc
21, 43201 REUS, Spain (BR, EV)
Published in Atlas Database: May 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/DDR1ID40280ch6p21.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI DDR1ID40280ch6p21.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: CAK; CD167; DDR; EDDR1;
HGK2; MCK10; NEP; NTRK4; PTK3; PTK3A;
RTK6; TRKE
HGNC (Hugo): DDR1
Location: 6p21.33
DNA/RNA
Description
The DDR1 gene comprises 17 exons and spans 12
kb of the genomic sequence on chromosome 6
(from position 30851861 bp to 30867933 bp in the
positive strand orientation).
Transcription
The 3840-bp mRNA is transcribed in a centromeric
to telomeric orientation. Alternative splicing can
occur, and 5 named isoforms (DDR1a-e) are
recognised.
Pseudogene
No pseudogene has been described.
Genomic organisation of the DDR1 gene on chromosome 6. Exons that are implicated in the alternative splicing process of
the DDR1 gene are represented by open boxes. The alternative splicing process of exon 10 to exon 14 generates 5 DDR1 isoforms, which are affixed a-e.
DDR1 (discoidin domain receptor tyrosine kinase 1) Roig B, Vilella E
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 959
Protein
Schematic diagram of the DDR1 protein and
localization of the DDR1 Tyrosine phosphorylated sites at intracellular domain.
Description
DDR1 belongs to the DDRs subfamily of tyrosine
kinase receptors. This subfamily is composed of
only two members, DDR1 and DDR2, and it is
distinguished by an extracellular domain that is
homologous to the carbohydrate-binding lectin
discoidin-I in Dictyostelium discoideum. The
Discoidin domain is essential for the ability of
DDRs to bind ligands. To-date, collagen is the only
unique DDR1 ligand that has been identified. Five
isoforms of DDR1 that are generated by alternative
splicing have been described. The longest DDR1
transcript codes for the full-length receptor (DDR1c
isoform) and is composed of 919 amino acids.
DDR1a and DDR1b isoforms lack 37 amino acids
in the juxtamembrane domain or 6 amino acids in
the kinase domain. DDR1d and DDR1e isoforms
are C-terminally truncated receptors. DDR1d lacks
exons 11 and 12 causing a frame-shift mutation that
generates a stop codon and premature termination
of transcription. Finally, DDR1e lacks exons 11 and
12 as well as the first half of exon 10 (Alves et al.,
1995).
Expression
DDR1 is ubiquitously expressed in a variety of
epithelial tissues (Alves et al., 1995; Curat and
Vogel, 2002; Ferri et al., 2004; Hou et al., 2001;
Mohan et al., 2001; Sakamoto et al., 2001; Tanaka
et al., 1998). DDR1 is also expressed in endothelial
blood capillary cells and oligodendrocytes in the
human brain (Franco-Pons et al., 2009; Roig et al.,
2010). DDR1 is significantly overexpressed in
several human cancers (Barker et al., 1995; Colas et
al., 2011; Ford et al., 2007; Hajdu et al., 2010;
Heinzelmann-Schwarz et al., 2004; Laval et al.,
1994; Nemoto et al., 1997; Park et al., 2007; Tun et
al., 2011; Weiner et al., 1996; Weiner et al., 2000;
Yamanaka et al., 2006; Yoshida et al., 2007) and
carcinoma cell lines (Alves et al., 1995; Gu et al.,
2011; Park et al., 2007; Sakuma et al., 1996).
Localisation
Transmembrane.
Function
Receptor tyrosine kinases are key components of
several signal transduction pathways. These kinases
control multiple cellular processes, including
motility, proliferation, differentiation, metabolism
and survival.
DDR1 is actively involved in tumorigenesis and
promotes the proliferation of neoplasic cells. The
interaction of DDR1 and Notch1 displays a
prosurvival effect (Kim et al., 2011). DDR1
participates in the collective migration of cancer
cells by coordinating the cell polarity regulators
Par3 and Par6 (Hidalgo-Carcedo et al., 2011).
Homology
- P. troglodytes, discoidin domain receptor tyrosine
kinase 1, DDR1
- C. lupus, discoidin domain receptor tyrosine
kinase 1, DDR1
- M. musculus, discoidin domain receptor family
member 1, Ddr1
- R. norvegicus, discoidin domain receptor tyrosine
kinase 1
- D. rerio, discoidin domain receptor family
member 1
Mutations
Note
Few somatic mutations have been described. Four
mutations (G1486T, A496S, CC2469/2470TT,
R824W) have been identified in a cohort of 26
primary lung neoplasms (Davies et al., 2005). One
somatic mutation (A803V) was found in 4 acute
myeloid leukaemia patients (Tomasson et al.,
2008).
DDR1 (discoidin domain receptor tyrosine kinase 1) Roig B, Vilella E
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 960
Implicated in
Breast cancer
Note
DDR1 overexpression was observed in human
primary breast tumours samples compared to that in
normal breast tissues (Barker et al., 1995). In
addition, invasive ductal and lobular carcinomas
showed differential expression of DDR1. DDR1
was downregulated in lobular carcinomas
(Turashvili et al., 2007a; Turashvili et al., 2007b).
Osteosarcoma
Note
The DDR1 promoter presents a potential p53
binding-site. A previous study has shown that p53
expression upregulated the mRNA expression
levels of DDR1 in human osteosarcoma cells
(Sakuma et al., 1996).
Oesophageal cancer
Note
The overexpression of DDR1 was reported in 12
carcinomatous oesophageal tissues compared to
that in normal tissues. Furthermore, a positive
correlation was identified between DDR1 mRNA
expression and the proliferative activity of the
tumoural cells (Nemoto et al., 1997).
Ovarian cancer
Note
DDR1 was highly expressed in 158 histological
subtypes of primary epithelial ovarian cancers
(EOC) compared to that in normal ovarian surface
epithelium samples (Heinzelmann-Schwarz et al.,
2004).
Endometrial cancer
Note
DDR1 has been implicated as a potential molecular
marker of endometrial cancer (Colas et al., 2011;
Domenyuk et al., 2007). A gene expression
screening of 52 carcinomas samples showed
differential expression of several genes, including
the DDR1 gene. These data were also demonstrated
in 50 tumoural and non-tumoural uterine aspirates
(Colas et al., 2011).
Brain tumours
Note
DDR1 was originally isolated in malignant
childhood brain tumours, which overexpressed
DDR1 (Weiner et al., 1996). Replicable findings
were found in metastatic brain neoplasms and
glioma cells (Yamanaka et al., 2006; Weiner et al.,
2000). In glioma cells, DDR1 was involved in cell
proliferation and invasion via cell interactions with
the extracellular matrix (Ram et al., 2005;
Yamanaka et al., 2006). Moreover, a study on
DDR1a and DDR1b isoforms overexpression in
glioma cells has identified distinct roles for each
DDR1 isoforms in the cell attachment process,
which is mediated by collagen I (Ram et al., 2005).
The analysis of the expression profile in mice that
had PDGF-induced glioma showed overexpression
of DDR1 (Johansson et al., 2005).
Primary central nervous system lymphoma (PCNSL)
Note
A PCNSL pathway analysis revealed upregulation
of DDR1 expression in the extracellular matrix and
the adhesion-related pathways (Tun et al., 2011).
Pituitary adenoma
Note
In different subtypes of pituitary adenoma, DDR1
expression was related to the hormonal background.
DDR1 was more highly expressed in
macroadenomas, compared to microadenomas, and
in PRL- and GH-producing adenomas (Yoshida et
al., 2007).
Lung cancer
Note
DDR1 was upregulated in tumour lung tissue
compared to that in normal tissue and was an
independent favourable predictor for prognosis
(Ford et al., 2007). Similarly, DDR1 was highly
phosphorylated in non-small cell lung cancer
(NSCLC) (Rikova et al., 2007).
DDR1 (discoidin domain receptor tyrosine kinase 1) Roig B, Vilella E
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 961
One study described the presence of DDR1 somatic
mutations in lung cancer (Davies et al., 2005).
However, no mutations were detected in another
lung cancer study (Ford et al., 2007).
Liver cancer
Note
DDR1a and DDR1b isoforms were overexpressed
in hepatocellular carcinoma cell lines HLE and
Huh-7. DDR1 isoform overexpression enhanced the
migration and invasion of the hepatocellular
carcinoma cell lines in association with the matrix
metalloproteinases MMP2 and MMP9 (Park et al.,
2007).
The downregulation of miR-199a-5p, which is a
direct target of DDR1, deregulated DDR1
functionality and increased cell invasion in human
hepatocellular carcinoma (HCC) (Shen et al., 2010).
Finally, a profiling study on receptor tyrosine
kinase phosphorylation in cholangiocarcinoma
patients showed high levels of phosphorylation of
DDR1 and other tyrosine kinases in tumour tissues
in comparison to para-tumour tissues (Gu et al.,
2011).
Mesenchymal neoplasm
Note
Solitary fibrous tumour (SFT) expression profiling
of 23 samples showed an over-expression of several
receptor tyrosine kinase genes, including DDR1.
However, no mutations were identified using
cDNA sequencing (Hajdu et al., 2010).
References Alves F, Vogel W, Mossie K, Millauer B, Höfler H, Ullrich A. Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer. Oncogene. 1995 Feb 2;10(3):609-18
Barker KT, Martindale JE, Mitchell PJ, Kamalati T, Page MJ, Phippard DJ, Dale TC, Gusterson BA, Crompton MR. Expression patterns of the novel receptor-like tyrosine kinase, DDR, in human breast tumours. Oncogene. 1995 Feb 2;10(3):569-75
Perez JL, Jing SQ, Wong TW. Identification of two isoforms of the Cak receptor kinase that are coexpressed in breast tumor cell lines. Oncogene. 1996 Apr 4;12(7):1469-77
Sakuma S, Saya H, Tada M, Nakao M, Fujiwara T, Roth JA, Sawamura Y, Shinohe Y, Abe H. Receptor protein tyrosine kinase DDR is up-regulated by p53 protein. FEBS Lett. 1996 Dec 2;398(2-3):165-9
Weiner HL, Rothman M, Miller DC, Ziff EB. Pediatric brain tumors express multiple receptor tyrosine kinases including novel cell adhesion kinases. Pediatr Neurosurg. 1996 Aug;25(2):64-71; discussion 71-2
Nemoto T, Ohashi K, Akashi T, Johnson JD, Hirokawa K. Overexpression of protein tyrosine kinases in human esophageal cancer. Pathobiology. 1997;65(4):195-203
Weiner HL, Huang H, Zagzag D, Boyce H, Lichtenbaum R, Ziff EB. Consistent and selective expression of the discoidin domain receptor-1 tyrosine kinase in human brain tumors. Neurosurgery. 2000 Dec;47(6):1400-9
Alves F, Saupe S, Ledwon M, Schaub F, Hiddemann W, Vogel WF. Identification of two novel, kinase-deficient variants of discoidin domain receptor 1: differential expression in human colon cancer cell lines. FASEB J. 2001 May;15(7):1321-3
Curat CA, Vogel WF. Discoidin domain receptor 1 controls growth and adhesion of mesangial cells. J Am Soc Nephrol. 2002 Nov;13(11):2648-56
Ferri N, Carragher NO, Raines EW. Role of discoidin domain receptors 1 and 2 in human smooth muscle cell-mediated collagen remodeling: potential implications in atherosclerosis and lymphangioleiomyomatosis. Am J Pathol. 2004 May;164(5):1575-85
Heinzelmann-Schwarz VA, Gardiner-Garden M, Henshall SM, Scurry J, Scolyer RA, Davies MJ, Heinzelmann M, Kalish LH, Bali A, Kench JG, Edwards LS, Vanden Bergh PM, Hacker NF, Sutherland RL, O'Brien PM. Overexpression of the cell adhesion molecules DDR1, Claudin 3, and Ep-CAM in metaplastic ovarian epithelium and ovarian cancer. Clin Cancer Res. 2004 Jul 1;10(13):4427-36
Davies H, Hunter C, Smith R, Stephens P, Greenman C, Bignell G, Teague J, Butler A, Edkins S, Stevens C, Parker A, O'Meara S, Avis T, Barthorpe S, Brackenbury L, Buck G, Clements J, Cole J, Dicks E, Edwards K, Forbes S, Gorton M, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Raine K, Shepherd R, Small A, Solomon H, Stephens Y, Tofts C, Varian J, Webb A, West S, Widaa S, Yates A, Brasseur F, Cooper CS, Flanagan AM, Green A, Knowles M, Leung SY, Looijenga LH, Malkowicz B, Pierotti MA, Teh BT, Yuen ST, Lakhani SR, Easton DF, Weber BL, Goldstraw P, Nicholson AG, Wooster R, Stratton MR, Futreal PA. Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res. 2005 Sep 1;65(17):7591-5
Johansson FK, Göransson H, Westermark B. Expression analysis of genes involved in brain tumor progression driven by retroviral insertional mutagenesis in mice. Oncogene. 2005 Jun 2;24(24):3896-905
Ram R, Lorente G, Nikolich K, Urfer R, Foehr E, Nagavarapu U. Discoidin domain receptor-1a (DDR1a) promotes glioma cell invasion and adhesion in association with matrix metalloproteinase-2. J Neurooncol. 2006 Feb;76(3):239-48
Yamanaka R, Arao T, Yajima N, Tsuchiya N, Homma J, Tanaka R, Sano M, Oide A, Sekijima M, Nishio K. Identification of expressed genes characterizing long-term survival in malignant glioma patients. Oncogene. 2006 Sep 28;25(44):5994-6002
Domenyuk VP, Litovkin KV, Verbitskaya TG, Dubinina VG, Bubnov VV. Identification of new DNA markers of endometrial cancer in patients from the Ukrainian population. Exp Oncol. 2007 Jun;29(2):152-5
Ford CE, Lau SK, Zhu CQ, Andersson T, Tsao MS, Vogel WF. Expression and mutation analysis of the discoidin domain receptors 1 and 2 in non-small cell lung carcinoma. Br J Cancer. 2007 Mar 12;96(5):808-14
Park HS, Kim KR, Lee HJ, Choi HN, Kim DK, Kim BT, Moon WS. Overexpression of discoidin domain receptor 1 increases the migration and invasion of hepatocellular carcinoma cells in association with matrix metalloproteinase. Oncol Rep. 2007 Dec;18(6):1435-41
Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb
DDR1 (discoidin domain receptor tyrosine kinase 1) Roig B, Vilella E
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 962
MJ. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007 Dec 14;131(6):1190-203
Turashvili G, Bouchal J, Baumforth K, Wei W, Dziechciarkova M, Ehrmann J, Klein J, Fridman E, Skarda J, Srovnal J, Hajduch M, Murray P, Kolar Z. Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis. BMC Cancer. 2007a Mar 27;7:55
Turashvili G, Bouchal J, Ehrmann J, Fridman E, Skarda J, Kolar Z. Novel immunohistochemical markers for the differentiation of lobular and ductal invasive breast carcinomas. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2007b Jun;151(1):59-64
Yoshida D, Teramoto A. Enhancement of pituitary adenoma cell invasion and adhesion is mediated by discoidin domain receptor-1. J Neurooncol. 2007 Mar;82(1):29-40
Tomasson MH, Xiang Z, Walgren R, Zhao Y, Kasai Y, Miner T, Ries RE, Lubman O, Fremont DH, McLellan MD, Payton JE, Westervelt P, DiPersio JF, Link DC, Walter MJ, Graubert TA, Watson M, Baty J, Heath S, Shannon WD, Nagarajan R, Bloomfield CD, Mardis ER, Wilson RK, Ley TJ. Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood. 2008 May 1;111(9):4797-808
Tun HW, Personett D, Baskerville KA, Menke DM, Jaeckle KA, Kreinest P, Edenfield B, Zubair AC, O'Neill BP, Lai WR, Park PJ, McKinney M. Pathway analysis of primary central nervous system lymphoma. Blood. 2008 Mar 15;111(6):3200-10
Franco-Pons N, Tomàs J, Roig B, Auladell C, Martorell L, Vilella E. Discoidin domain receptor 1, a tyrosine kinase receptor, is upregulated in an experimental model of remyelination and during oligodendrocyte differentiation in vitro. J Mol Neurosci. 2009 May;38(1):2-11
Hajdu M, Singer S, Maki RG, Schwartz GK, Keohan ML, Antonescu CR. IGF2 over-expression in solitary fibrous tumours is independent of anatomical location and is related to loss of imprinting. J Pathol. 2010 Jul;221(3):300-7
Shen Q, Cicinnati VR, Zhang X, Iacob S, Weber F, Sotiropoulos GC, Radtke A, Lu M, Paul A, Gerken G, Beckebaum S. Role of microRNA-199a-5p and discoidin domain receptor 1 in human hepatocellular carcinoma invasion. Mol Cancer. 2010 Aug 27;9:227
Colas E, Perez C, Cabrera S, Pedrola N, Monge M, Castellvi J, Eyzaguirre F, Gregorio J, Ruiz A, Llaurado M, Rigau M, Garcia M, Ertekin T, Montes M, Lopez-Lopez R, Carreras R, Xercavins J, Ortega A, Maes T, Rosell E, Doll A, Abal M, Reventos J, Gil-Moreno A. Molecular markers of endometrial carcinoma detected in uterine aspirates. Int J Cancer. 2011 Jan 4;
Gu TL, Deng X, Huang F, Tucker M, Crosby K, Rimkunas V, Wang Y, Deng G, Zhu L, Tan Z, Hu Y, Wu C, Nardone J, MacNeill J, Ren J, Reeves C, Innocenti G, Norris B, Yuan J, Yu J, Haack H, Shen B, Peng C, Li H, Zhou X, Liu X, Rush J, Comb MJ. Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS One. 2011 Jan 6;6(1):e15640
Hidalgo-Carcedo C, Hooper S, Chaudhry SI, Williamson P, Harrington K, Leitinger B, Sahai E. Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6. Nat Cell Biol. 2011 Jan;13(1):49-58
Kim HG, Hwang SY, Aaronson SA, Mandinova A, Lee SW. DDR1 receptor tyrosine kinase promotes prosurvival pathway through Notch1 activation. J Biol Chem. 2011 May 20;286(20):17672-81
This article should be referenced as such:
Roig B, Vilella E. DDR1 (discoidin domain receptor tyrosine kinase 1). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):958-962.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 963
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)) Luca Braccioli, Marilena V Iorio, Patrizia Casalini
Molecular Targeting Unit, Experimenatal Oncology Department, Fondazione IRCCS Istituto
Nazionale dei Tumori, Via Amadeo, 42, 20133 Milano, Italy (LB, MVI, PC)
Published in Atlas Database: May 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/ERBB2ID162ch17q11.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI ERBB2ID162ch17q11.txt This article is an update of : Casalini P, Iorio MV. ERBB2 (erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) ). Atlas Genet Cytogenet Oncol Haematol 2005;9(1) This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: CD340; HER2; HER-2; HER-2/neu;
MLN 19; NEU; NGL; TKR1
Location: 17q12
Probe(s) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics.
Note
Tyrosine-kinase receptor (RTK). The HER family
of RTKs consists of four receptors: epidermal
growth factor receptor (EGFR, also called HER-1
or erbB-1), HER-2 (also called erbB-2 or Neu),
HER-3 and HER-4 (also called erbB-3 and erbB-4,
respectively).
DNA/RNA
Description
Sequence length: 40522; CDS: 3678. 30 exons, 26
coding exons; total exon length: 4816, max exon
length: 969, min exon length: 48. Number of SNPs:
17.
Polymorphisms: allelic variations at amino acid
positions 654 and 655 of isoform (a) (positions 624
and 625 of isoform (b)) have been reported, with
the most common allele B1 (Ile-654/Ile-655); allele
B2 (Ile-654/Val-655); allele B3 (Val-654/Val-655).
This nucleotide polymorphism could be associated
with development of gastric carcinoma and with
breast cancer risk, particularly among younger
women.
Transcription
Alternative splicing results in several additional
transcript variants, some encoding different
isoforms and others that have not been fully
characterized.
- mRNA transcript variant: this variant (1)
represents the shorter transcript but encodes the
longer isoform (a) (protein: erbB-2 isoform (a)).
- mRNA transcript variant: this variant (2)
(protein: erbB-2 isoform (b)) contains additional
exons at its 5' end and lacks an alternate 5'
noncoding exon, compared to variant (1). These
differences result in translation initiation at an in-
frame, downstream AUG and an isoform (b) with a
shorter N-terminus compared to isoform (a).
- mRNA transcript variant: herstatin HER2-ECD
1300 bp alternative erbB-2 transcript that retains
intron 8. This alternative transcript specifies 340
residues identical to subdomains I and II from the
extracellular domain of p185erbB-2 followed by a
unique C-terminal sequence of 79 aa encoded by
ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian))
Braccioli L, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 964
intron 8. The herstatin mRNA is expressed in
normal human fetal kidney and liver, but is at
reduced levels relative to p185erbB-2 mRNA in
carcinoma cells that contain an amplified erbB-2
gene.
- mRNA transcript variant: an alternative
transcript form of the human homologous gene
erbB-2, containing an in-frame deletion
encompassing exon 19, has been detected in human
breast carcinomas.
- mRNA transcript variant: an alternative
transcript form of the human homologous gene
erbB-2, called HER2Δ16, has been detected in
human breast carcinomas. This splicing variant,
contains an in-frame deletion and encodes a
receptor lacking exon 16, which immediately
precedes the transmembrane domain containing two
cysteines. The loss of these cysteine residues might
induce a change in the conformation of HER2
receptor extracellular domain that promotes
intermolecular disulfide bonding and, in turn,
homodimers capable of transforming cells. Ectopic
expression of HER2Δ16 promotes receptor
dimerization, cell invasion, and trastuzumab
resistant tumor cell lines. The potential metastatic
and oncogenic properties of HER2Δ16 were
mediated through direct coupling of HER2Δ16 to
Src kinase.
Protein
Description
erbB2 encodes a 185-kDa, 1255 amino acids,
orphan receptor tyrosine kinase, and displays potent
oncogenic activity when overexpressed. The proto-
oncogene consists of three domains: a single
transmembrane domain that separates an
intracellular kinase domain from an extracellular
ligand-binding domain. An aberrant form of HER2,
missing the extracellular domain, so-called
HER2p95, has been found in some breast cancers.
HER2p95 is constitutively active because the
external domain of these receptors acts as an
inhibitor until they are bound by ligand. This
isoform can cause resistance to trastuzumab, an
antibody that works by binding to a domain in the
external domain of HER2. HER2p95 fragments
arise through at least 2 different mechanisms:
proteolytic shedding of the extracellular domain of
the full-length receptor and translation of the
mRNA encoding HER2 from internal initiation
codons. Shedding of the ectodomain of HER2
generates a 95- to 100-kDa HER2 p95 membrane-
anchored fragment. Translation of the mRNA
encoding HER2 can be initiated from the AUG
codon that gives rise to the full-length protein of
1255 amino acids or, alternatively, from 2 internal
initiation codons at positions 611 and 678, located
upstream and downstream of the transmembrane
domain, respectively.
Expression
HER2 protein is expressed in several human organs
and tissues: normal epithelium, endometrium and
ovarian epithelium and at neuromuscular level;
prostate, pancreas, lung, kidney, liver, heart,
hematopoietic cells. HER2 expression is low in
mononuclear cells from bone marrow, peripheral
blood (PB) and mobilized PB. The higher
expression has been found in cord blood-derived
cells. Quiescent CD34+ progenitor cells from all
blood sources and resting lymphocytes are HER2
negative, but the expression of this receptor is up-
regulated during cell-cycle recruitment of
progenitor cells. Similarly, it increases in mature,
hematopoietic proliferating cells, underlying the
correlation between HER2 and the proliferating
status of hematopoietic cells.
Localisation
Plasma membrane.
HER2 protein: schematic representation. Receptor tyrosin-kinases (RTKs) are cell surface allosteric enzymes consisting of:
an extracellular ligand-binding domain (blue); a single transmembrane (TM) domain has an extensive homology to the epidermal grow factor receptor (brown); a cytoplasmic domain with catalityc activity (green).
ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian))
Braccioli L, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 965
Function
Activation and interactions
For the other member of the HER family, ligand
binding induces receptor homo- or
heterodimerization, which is essential for TKs
activation and subsequent recruitment of target
proteins, in turn initiating a complex signaling
cascade that leads into distinct transcriptional
programs. There are several HER-specific ligands.
HER2, which apparently has no direct or specific
ligand, plays a major coordinating role in the HER
network because of its ability to enhance and
stabilize the dimerization: each receptor with a
specific ligand appears in fact to prefer HER-2 as
its heterodimeric partner. HER-2-containing
heterodimers are characterized by extremely high
signaling potency because HER-2 dramatically
reduces the rate of ligand dissociation, allowing
strong and prolonged activation of downstream
signaling pathways.
Signaling and cellular
The most important intracellular pathways activated
by HER2 are those involving mitogen activated
protein kinase (MAPK) and phosphatidylinositol-3
kinase (PI3K). HER2 expression in cancer, besides
its role in proliferation, enhances and prolongs
survivals signals, associating up-regulation of this
receptor to the malignant phenotype. At the same
time, and depending on cellular status, the role of
this receptor in controlling cell fate can also lead to
differentiation and apoptosis.
Physiological
Role in development and differentiation:
- HER2 has several non-oncogenic roles in
regulating growth, differentiation, apoptosis and/or
remodeling in normal mammary glands. Dominant-
negative forms of HER2 have significant defects in
mammary development and lactation.
- HER2 has an important role in development and
function of heart. Cre-Lox technology to mutate
erbB-2 specifically in ventricular cardiomyocytes
leads to a severe cardiomyopathy. This is inferred
also by the adverse cardiac side effects observed in
breast cancer patients treated with the monoclonal
anti-HER2 Ab Trastuzumab.
- HER2 has a role in control of Schwann cell
myelination and it has been demonstrated that
HER2 signaling is also critical for oligodendrocyte
differentiation in vivo.
- HER2 has a dual role in both muscle spindle
maintenance and survival of myoblasts. Muscle-
specific HER2 KO results in fact in viable mice
with a progressive defect in proprioception due to
loss of muscles spindles.
Homology
Homolog to avian erythroblastic leukemia viral (v-
erb-b) oncogen 2.
Mutations
Somatic
The Cancer Genome Project and Collaborative
Group sequenced the erbB-2 gene from 120
primary lung tumors and identified 4% that had
mutations within the kinase domain; in the
adenocarcinoma subtype of lung cancer, 10% of
cases had mutations.
In non small cell lung cancer (adenocarcinoma) the
following erbB-2 mutations were found:
insertion/duplication of GCATACGTGATG at
nucleotide 2322 of the erbB-2 gene, resulting in a
4-amino acid insertion (AYVM) at codon 774.
Insertion of CTGTGGGCT at nucleotide 2335 of
the erbB-2 gene, resulting in a 3-amino acid
insertion (VGS) starting at codon 779; a 2-bp
substitution in the erbB-2 gene, TT-CC at
nucleotides 2263 and 2264, resulting in a leu755-to-
pro (L755P) substitution.
In lung cancer a C44645G transition in the erbB-2
gene that caused a pro1170-to-ala substitution
(P1170A).
In a glioblastoma a 2740G-A transition in the erbB-
2 gene that caused a glu914-to-lys substitution
(E914K).
In a gastric tumor a 2326G-A transition in the erbB-
2 gene that caused a gly776-to-ser (G776S)
substitution.
In an ovarian tumor, a 2570A-G transition in the
erbB-2 gene that caused an asn857-to-ser (N857S)
substitution.
Implicated in
Hematological malignancies
Disease
HER2 expression can be detected in blast cells from
patients with hematological malignancies including
acute lymphoblastic leukemia (ALL). It could be
used as a potential target for the application of
HER2-directed treatment strategies in ALL
including vaccination approaches.
Bladder cancer
Prognosis
HER2 is overexpressed in 25% to 40% of several
human tumors and associated with the malignancy
of the disease, high mitotic index and a shorter
survival time for the patient. Overexpression of
ErbB-2 is also associated with transitional cell
carcinoma of the bladder. HER2 overexpression
occurs in muscle-invasive urothelial carcinomas of
the bladder and is associated with worse survival;
amplifications of erbB-2 gene are also frequently
linked to alterations of the TOP2A gene in bladder
cancer. Furthermore, HER2 overexpression and
amplification in urothelial carcinoma of the bladder
is found associated with MYC co-amplification.
ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian))
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Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 966
Breast carcinoma
Prognosis
Normal tissues have a low content of HER2
membrane protein. Overexpression of HER2 is seen
in 20% of breast and it confers worse biological
behavior and clinical aggressiveness in breast
cancer. Breast cancers can have up to 25 to 50
copies of the HER2 gene and up to a 40- to 100-
fold increase in HER2 protein resulting in 2 million
receptors expressed at the tumor cell surface. The
differential HER2 expression between normal
tissues and tumors helps to define HER2 as an ideal
treatment target. Trastuzumab, the first treatment
targeting HER2, is well tolerated in patients and has
little toxicity because its effects are relatively
specific for cancer cells overexpressing HER2.
HER2 amplification is a relatively early event in
human breast tumorigenesis, occurring in almost
50% of in situ carcinomas. HER2 status is
maintained during progression to invasive disease
and to nodal and distant metastasis. The fact that
only 20% of invasive breast cancers are HER2
amplified suggests that many HER2-amplified in
situ cancers never progress to the invasive stage.
HER2 amplification defines a subtype of breast
cancer with a unique signature of genes and this is
maintained during progression. Some tumors lose
HER2 expression following treatment with
trastuzumab, presumably by selection of a HER2-
negative clone not killed by treatment. Conversely,
HER2 may become positive in some initially
negative tumors over time, especially after
endocrine therapy targeting ER. Indeed, estrogen
receptor has been shown to downregulate HER2
and, conversely, HER2 is able to downregulate ER
expression. Therefore, it is not surprising that
blocking ER might upregulate HER2 and that
blocking HER2 might upregulate ER. HER2-
amplified breast cancers have unique biological and
clinical characteristics. They have increased
sensitivity to certain cytotoxic agents such as
doxorubicin, relative resistance to hormonal agents,
and propensity to metastasize to the brain and
viscera. HER2-amplified tumors have an increased
sensitivity to doxorubicin possibly due to
coamplification of the topoisomerase-2 gene, which
is near the HER2 locus on chromosome 17 and is
the target of the drug. Half of HER2-positive breast
cancers are ER positive but they generally have
lower ER levels, and many have p53 alterations.
These tumors have higher proliferation rates and
more aneuploidy and are associated with poorer
patient prognosis. The poor outcome is dramatically
improved with appropriate chemotherapy combined
with the HER2-targeting drug trastuzumab.
Overexpression of the erbB-2 gene is associated
with tumor aggressiveness, and with patient
responsiveness to doxorubicin, cyclophosphamide,
methotrexate, fluorouracil (CMF), and to paclitaxel,
whereas tamoxifen was found to be ineffective and
even detrimental in patients with HER2-positive
tumors. In Paget's disease of breast, HER2 protein
overexpression is caused by amplification of the
erbB-2 gene. HER2 has a role in this disease of the
breast, where the epidermis of the nipple is
infiltrated by large neoplastic cells of glandular
origin. It seems that binding of heregulin-alpha to
the receptor complex on Paget cells results in
chemotaxis of these breast cancer cells. The
isoforms HER2p95 and HER2Δ16 are found in
some breast cancers and the expression of these
hyperactive forms of HER2 may contribute to the
malignant progression.
Cervical cancer
Prognosis
HER2 may be activated in the early stage of
pathogenesis of cervical carcinoma in geriatric
patients and is frequently amplified in squamous
cell carcinoma of the uterine cervix.
Childhood medulloblastoma
Prognosis
Overexpression of HER2 in medulloblastoma is
associated with poor prognosis and metastasis and
HER2-HER4 receptor heterodimerization is of
particular biological significance in this disease.
Colorectal cancer
Prognosis
Overexpression of HER2 occurs in a significant
number of colorectal cancers. It was significantly
associated with poor survival and related to tumor
progression in colorectal cancer.
Oral squamous cell carcinoma
Prognosis
E6/E7 proteins of HPV type 16 and HER2
cooperate to induce neoplastic transformation of
primary normal oral epithelial cells. Overexpression
of HER2 receptor is a frequent event in oral
squamous cell carcinoma and is correlated with
poor survival.
Gastric cancer
Prognosis
HER2 amplification/overexpression does not seem
to play a role in the molecular pathogenesis of most
gastrinomas. However, mild gene amplification
occurs in a subset of them, and overexpression of
this receptor is associated with aggressiveness of
the disease. HER2 overexpression in patients with
gastric cancer, and it has been solidly correlated to
poor outcomes and a more aggressive disease. The
overall HER2 positive rate is about 22%. HER2
overexpression rate in gastric cancer varies
according to the site of the tumor. A higher
overexpression rate (36%) was shown in
gastroesophageal junction (GEJ) tumors in
comparison to 21% in gastric tumors.
ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian))
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Germ-cell testicular tumor
Prognosis
A significant correlation was observed between
HER2 overexpression and clinical outcome in
germ-cell testicular tumors.
Cholangiocarcinoma
Prognosis
Data are still controversial about HER2 role in this
carcinoma. Increased HER2 expression contributes
to the development of cholangiocarcinogenesis into
an advanced stage associated with tumor
metastasis. In addition, overexpression of HER2
and COX-2 correlated directly with tumor
differentiation. However, other studies report that
HER2 expression is associated with more favorable
clinical features, such as a polypoid macroscopic
type and absence of other organ involvement, and
has been reported that the proportion of HER2-
positive cases in papillary adenocarcinoma is higher
than in other histological types and is associated
with an early disease stage. HER2 is preferentially
expressed in well differentiated component, and it
is also expressed in dedifferentiated components in
progressive cases.
Lung cancer
Prognosis
HER2 is overexpressed in less than 20% of patients
with non-small cell lung cancer (NSCLC) and
studies have shown that overexpression of this
receptor is correlated with a poor prognosis in both
resected and advanced NSCLC. HER2
overexpression has an important function in the
biology of NSCLC and may have a prognostic
value for patients with metastatic NSCLC.
Osteosarcoma
Prognosis
Higher frequency of HER2 expression has been
observed in samples from patients with metastatic
disease at presentation and at the time of relapse,
and it correlates with worse histologic response and
decreased event-free survival. HER2 could be an
effective target for the immunotherapy of
osteosarcoma, especially the type with high
metastatic potential.
Ovarian cancer
Prognosis
HER2 overexpression varies from 9% to 32% of all
cases of ovarian cancer and its overexpression is
more frequent in advanced stage of ovarian cancer.
Overexpression of HER2 in ovarian cancer cells
leads to faster cell growth, higher abilities in DNA
repair and colony formation. A cross-talk between
HER2 and estrogen receptor (ER) was identified in
ovarian cancer cells. Estrogen has been proven to
induce the phosphorylation of HER2, and initiate
the HER2's signaling pathway.
Pancreatic adenocarcinoma
Prognosis
Overexpression of HER-2 in pancreatic
adenocarcinoma seems to be a result of increased
transcription rather than gene amplification. The
coexpression of HER2 oncogene protein, epidermal
growth factor receptor, and TGF-beta1 in pancreatic
ductal adenocarcinoma is related to the
histopathological grades and clinical stages of
tumors. The blockade of HER2 inhibits the growth
of pancreatic cancer cells in vitro. HER2
overexpression was reported to accumulate in well
differentiated pancreas adenocarcinomas whereas it
is only infrequently found in poorly differentiated
or undifferentiated tumors, in vivo and in vitro
analyses have suggested that targeting HER2 might
increase treatment effects of conventional
chemotherapies of pancreas adenocarcinoma.
However, unlike in breast cancer, the application of
antibodies directed against HER2 has not yet
become an established therapy for pancreas
adenocarcinoma.
Prostate cancer
Prognosis
HER2 plays pivotal roles in prostate cancer. Studies
have shown that 25% of untreated primary tumors,
59% of localized tumors after neoadjuvant hormone
therapy, and 78% of metastatic tumors
overexpressed HER2. Several lines of evidence
have implicated HER2 as a key mediator in the
recurrence of prostate cancer to a hormone-
refractory, androgen-independent tumor, which is
the hallmark of prostate cancer progress. The
driving force for prostate cancer recurrence is the
reactivation of androgen receptor (AR), which is a
type of nuclear receptors, activated by steroid
hormone but ablated in hormonal therapy.
Phosphorylation and reactivation of AR stimulate
cancer cell growth and trigger tumor progression. It
has been observed that overexpression of HER2
kinase enhanced AR function and hormone-
independent growth in prostate tumor cells. HER2
activated AR through the MAPK pathway.
Additionally, the HER2/HER3 dimmer increases
AR protein stability and promotes the binding of
AR to the promoter region of its target genes,
resulting in AR activation in an androgen-depleted
environment.
Salivary gland tumor
Prognosis
Several results demonstrated significant positive
staining of HER2 in the salivary tumorigenic tissue
but not in the surrounding non-tumorigenic tissue,
pointing to a biological role in the tumorigenic
process. HER2 amplification is present
predominantly in tumors with high HER2
expression and seems to be the dominant
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mechanism for HER2 overexpression in this tumor
type.
To be noted
Note
Possible therapeutic strategies: 1) growth inhibitory
antibodies (like Trastuzumab), used alone or in
combination with standard chemotherapeutics; 2)
tyrosin kinase inhibitors (TKI); 3) active
immunotherapy, because HER2 oncoprotein is
immunogenic in some breast carcinoma patients; 4)
dimerization inhibitor antibodies, like Pertuzumab:
its binding to HER2 inhibits the dimerization of
HER2 with other HER receptors.
References Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987 Jan 9;235(4785):177-82
Di Fiore PP, Segatto O, Taylor WG, Aaronson SA, Pierce JH. EGF receptor and erbB-2 tyrosine kinase domains confer cell specificity for mitogenic signaling. Science. 1990 Apr 6;248(4951):79-83
Papewalis J, Nikitin AYu, Rajewsky MF. G to A polymorphism at amino acid codon 655 of the human erbB-2/HER2 gene. Nucleic Acids Res. 1991 Oct 11;19(19):5452
Tateishi M, Toda T, Minamisono Y, Nagasaki S. Clinicopathological significance of c-erbB-2 protein expression in human gastric carcinoma. J Surg Oncol. 1992 Apr;49(4):209-12
Kolodziejczyk P, Yao T, Oya M, Nakamura S, Utsunomiya T, Ishikawa T, Tsuneyoshi M. Long-term follow-up study of patients with gastric adenomas with malignant transformation. An immunohistochemical and histochemical analysis. Cancer. 1994 Dec 1;74(11):2896-907
Mitra AB, Murty VV, Pratap M, Sodhani P, Chaganti RS. ERBB2 (HER2/neu) oncogene is frequently amplified in squamous cell carcinoma of the uterine cervix. Cancer Res. 1994 Feb 1;54(3):637-9
Motojima K, Furui J, Kohara N, Izawa K, Kanematsu T, Shiku H. erbB-2 expression in well-differentiated adenocarcinoma of the stomach predicts shorter survival after curative resection. Surgery. 1994 Mar;115(3):349-54
Beerli RR, Graus-Porta D, Woods-Cook K, Chen X, Yarden Y, Hynes NE. Neu differentiation factor activation of ErbB-3 and ErbB-4 is cell specific and displays a differential requirement for ErbB-2. Mol Cell Biol. 1995 Dec;15(12):6496-505
Bühring HJ, Sures I, Jallal B, Weiss FU, Busch FW, Ludwig WD, Handgretinger R, Waller HD, Ullrich A. The receptor tyrosine kinase p185HER2 is expressed on a subset of B-lymphoid blasts from patients with acute lymphoblastic leukemia and chronic myelogenous leukemia. Blood. 1995 Sep 1;86(5):1916-23
Gilbertson RJ, Pearson AD, Perry RH, Jaros E, Kelly PJ. Prognostic significance of the c-erbB-2 oncogene product in childhood medulloblastoma. Br J Cancer. 1995 Mar;71(3):473-7
Horan T, Wen J, Arakawa T, Liu N, Brankow D, Hu S, Ratzkin B, Philo JS. Binding of Neu differentiation factor
with the extracellular domain of Her2 and Her3. J Biol Chem. 1995 Oct 13;270(41):24604-8
Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature. 1995 Nov 23;378(6555):394-8
Carlomagno C, Perrone F, Gallo C, De Laurentiis M, Lauria R, Morabito A, Pettinato G, Panico L, D'Antonio A, Bianco AR, De Placido S. c-erb B2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary lymph node metastases. J Clin Oncol. 1996 Oct;14(10):2702-8
Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ, Yarden Y. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol. 1996 Oct;16(10):5276-87
Gilbertson RJ, Perry RH, Kelly PJ, Pearson AD, Lunec J. Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma. Cancer Res. 1997 Aug 1;57(15):3272-80
Graus-Porta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 1997 Apr 1;16(7):1647-55
Xia W, Lau YK, Zhang HZ, Liu AR, Li L, Kiyokawa N, Clayman GL, Katz RL, Hung MC. Strong correlation between c-erbB-2 overexpression and overall survival of patients with oral squamous cell carcinoma. Clin Cancer Res. 1997 Jan;3(1):3-9
Giani C, Casalini P, Pupa SM, De Vecchi R, Ardini E, Colnaghi MI, Giordano A, Ménard S. Increased expression of c-erbB-2 in hormone-dependent breast cancer cells inhibits cell growth and induces differentiation. Oncogene. 1998 Jul 30;17(4):425-32
Kwong KY, Hung MC. A novel splice variant of HER2 with increased transformation activity. Mol Carcinog. 1998 Oct;23(2):62-8
Olayioye MA, Graus-Porta D, Beerli RR, Rohrer J, Gay B, Hynes NE. ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner. Mol Cell Biol. 1998 Sep;18(9):5042-51
Balsari A, Casalini P, Tagliabue E, Greco M, Pilotti S, Agresti R, Giovanazzi R, Alasio L, Rumio C, Cascinelli N, Colnaghi MI, Ménard S. Fluctuation of HER2 expression in breast carcinomas during the menstrual cycle. Am J Pathol. 1999 Nov;155(5):1543-7
Doherty JK, Bond C, Jardim A, Adelman JP, Clinton GM. The HER-2/neu receptor tyrosine kinase gene encodes a secreted autoinhibitor. Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10869-74
Ménard S, Casalini P, Tomasic G, Pilotti S, Cascinelli N, Bufalino R, Perrone F, Longhi C, Rilke F, Colnaghi MI. Pathobiologic identification of two distinct breast carcinoma subsets with diverging clinical behaviors. Breast Cancer Res Treat. 1999 May;55(2):169-77
Nezu M, Sasaki H, Kuwahara Y, Ochiya T, Yamada Y, Sakamoto H, Tashiro H, Yamazaki M, Ikeuchi T, Saito Y, Terada M. Identification of a novel promoter and exons of the c-ERBB-2 gene. Biochem Biophys Res Commun. 1999 May 19;258(3):499-505
Rabczyński JK, Kochman AT. Primary cancer of the fallopian tube with transitional differentiation. Clinical and pathological assessment of 6 cases. Neoplasma. 1999;46(2):128-31
ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian))
Braccioli L, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 969
Chung TK, Cheung TH, To KF, Wong YF. Overexpression of p53 and HER-2/neu and c-myc in primary fallopian tube carcinoma. Gynecol Obstet Invest. 2000;49(1):47-51
Garratt AN, Voiculescu O, Topilko P, Charnay P, Birchmeier C. A dual role of erbB2 in myelination and in expansion of the schwann cell precursor pool. J Cell Biol. 2000 Mar 6;148(5):1035-46
Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000 Jul 3;19(13):3159-67
Schelfhout VR, Coene ED, Delaey B, Thys S, Page DL, De Potter CR. Pathogenesis of Paget's disease: epidermal heregulin-alpha, motility factor, and the HER receptor family. J Natl Cancer Inst. 2000 Apr 19;92(8):622-8
Xie D, Shu XO, Deng Z, Wen WQ, Creek KE, Dai Q, Gao YT, Jin F, Zheng W. Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk. J Natl Cancer Inst. 2000 Mar 1;92(5):412-7
Casalini P, Botta L, Menard S. Role of p53 in HER2-induced proliferation or apoptosis. J Biol Chem. 2001 Apr 13;276(15):12449-53
Kim YS, Konoplev SN, Montemurro F, Hoy E, Smith TL, Rondón G, Champlin RE, Sahin AA, Ueno NT. HER-2/neu overexpression as a poor prognostic factor for patients with metastatic breast cancer undergoing high-dose chemotherapy with autologous stem cell transplantation. Clin Cancer Res. 2001 Dec;7(12):4008-12
Ménard S, Valagussa P, Pilotti S, Gianni L, Biganzoli E, Boracchi P, Tomasic G, Casalini P, Marubini E, Colnaghi MI, Cascinelli N, Bonadonna G. Response to cyclophosphamide, methotrexate, and fluorouracil in lymph node-positive breast cancer according to HER2 overexpression and other tumor biologic variables. J Clin Oncol. 2001 Jan 15;19(2):329-35
Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
Aishima SI, Taguchi KI, Sugimachi K, Shimada M, Sugimachi K, Tsuneyoshi M. c-erbB-2 and c-Met expression relates to cholangiocarcinogenesis and progression of intrahepatic cholangiocarcinoma. Histopathology. 2002 Mar;40(3):269-78
Andrechek ER, Hardy WR, Girgis-Gabardo AA, Perry RL, Butler R, Graham FL, Kahn RC, Rudnicki MA, Muller WJ. ErbB2 is required for muscle spindle and myoblast cell survival. Mol Cell Biol. 2002 Jul;22(13):4714-22
Endo K, Yoon BI, Pairojkul C, Demetris AJ, Sirica AE. ERBB-2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditions. Hepatology. 2002 Aug;36(2):439-50
Gandour-Edwards R, Lara PN Jr, Folkins AK, LaSalle JM, Beckett L, Li Y, Meyers FJ, DeVere-White R. Does HER2/neu expression provide prognostic information in patients with advanced urothelial carcinoma? Cancer. 2002 Sep 1;95(5):1009-15
Goebel SU, Iwamoto M, Raffeld M, Gibril F, Hou W, Serrano J, Jensen RT. Her-2/neu expression and gene amplification in gastrinomas: correlations with tumor biology, growth, and aggressiveness. Cancer Res. 2002 Jul 1;62(13):3702-10
Hirsch FR, Varella-Garcia M, Franklin WA, Veve R, Chen L, Helfrich B, Zeng C, Baron A, Bunn PA Jr. Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas. Br J Cancer. 2002 May 6;86(9):1449-56
Huang YW, Li MD, Wu QL, Liu FY. [Expression and clinical significance of p53 and c-erbB2 in geriatric women with cervical carcinoma]. Ai Zheng. 2002 Mar;21(3):297-300
Khan AJ, King BL, Smith BD, Smith GL, DiGiovanna MP, Carter D, Haffty BG. Characterization of the HER-2/neu oncogene by immunohistochemical and fluorescence in situ hybridization analysis in oral and oropharyngeal squamous cell carcinoma. Clin Cancer Res. 2002 Feb;8(2):540-8
Knösel T, Yu Y, Stein U, Schwabe H, Schlüns K, Schlag PM, Dietel M, Petersen I. Overexpression of c-erbB-2 protein correlates with chromosomal gain at the c-erbB-2 locus and patient survival in advanced colorectal carcinomas. Clin Exp Metastasis. 2002;19(5):401-7
Ménard S, Balsari A, Casalini P, Tagliabue E, Campiglio M, Bufalino R, Cascinelli N. HER-2-positive breast carcinomas as a particular subset with peculiar clinical behaviors. Clin Cancer Res. 2002 Feb;8(2):520-5
Ozcelik C, Erdmann B, Pilz B, Wettschureck N, Britsch S, Hübner N, Chien KR, Birchmeier C, Garratt AN. Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8880-5
Savinainen KJ, Saramäki OR, Linja MJ, Bratt O, Tammela TL, Isola JJ, Visakorpi T. Expression and gene copy number analysis of ERBB2 oncogene in prostate cancer. Am J Pathol. 2002 Jan;160(1):339-45
Zhang L, Yuan SZ. Expression of c-erbB-2 oncogene protein, epidermal growth factor receptor, and TGF-beta1 in human pancreatic ductal adenocarcinoma. Hepatobiliary Pancreat Dis Int. 2002 Nov;1(4):620-3
Delektorskaya VV, Perevoshchikov AG, Kushlinskii NE. Immunohistological study of NM 23 and C-erbB-2 expression in primary tumor and metastases of colorectal adenocarcinoma. Bull Exp Biol Med. 2003 May;135(5):489-94
Junttila TT, Laato M, Vahlberg T, Söderström KO, Visakorpi T, Isola J, Elenius K. Identification of patients with transitional cell carcinoma of the bladder overexpressing ErbB2, ErbB3, or specific ErbB4 isoforms: real-time reverse transcription-PCR analysis in estimation of ErbB receptor status from cancer patients. Clin Cancer Res. 2003 Nov 1;9(14):5346-57
Kim JY, Sun Q, Oglesbee M, Yoon SO. The role of ErbB2 signaling in the onset of terminal differentiation of oligodendrocytes in vivo. J Neurosci. 2003 Jul 2;23(13):5561-71
Kuraoka K, Matsumura S, Hamai Y, Nakachi K, Imai K, Matsusaki K, Oue N, Ito R, Nakayama H, Yasui W. A single nucleotide polymorphism in the transmembrane domain coding region of HER-2 is associated with development and malignant phenotype of gastric cancer. Int J Cancer. 2003 Nov 20;107(4):593-6
Latif Z, Watters AD, Dunn I, Grigor KM, Underwood MA, Bartlett JM. HER2/neu overexpression in the development of muscle-invasive transitional cell carcinoma of the bladder. Br J Cancer. 2003 Oct 6;89(7):1305-9
Moliterni A, Ménard S, Valagussa P, Biganzoli E, Boracchi P, Balsari A, Casalini P, Tomasic G, Marubini E, Pilotti S, Bonadonna G. HER2 overexpression and doxorubicin in adjuvant chemotherapy for resectable breast cancer. J Clin Oncol. 2003 Feb 1;21(3):458-62
Müller MR, Grünebach F, Kayser K, Vogel W, Nencioni A, Brugger W, Kanz L, Brossart P. Expression of her-2/neu on acute lymphoblastic leukemias: implications for the development of immunotherapeutic approaches. Clin Cancer Res. 2003 Aug 15;9(9):3448-53
ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian))
Braccioli L, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 970
Nagler RM, Kerner H, Ben-Eliezer S, Minkov I, Ben-Itzhak O. Prognostic role of apoptotic, Bcl-2, c-erbB-2 and p53 tumor markers in salivary gland malignancies. Oncology. 2003;64(4):389-98
Nakamura H, Saji H, Ogata A, Hosaka M, Hagiwara M, Kawasaki N, Kato H. Correlation between encoded protein overexpression and copy number of the HER2 gene with survival in non-small cell lung cancer. Int J Cancer. 2003 Jan 1;103(1):61-6
Nuciforo PG, Pellegrini C, Fasani R, Maggioni M, Coggi G, Parafioriti A, Bosari S. Molecular and immunohistochemical analysis of HER2/neu oncogene in synovial sarcoma. Hum Pathol. 2003 Jul;34(7):639-45
Simon R, Atefy R, Wagner U, Forster T, Fijan A, Bruderer J, Wilber K, Mihatsch MJ, Gasser T, Sauter G. HER-2 and TOP2A coamplification in urinary bladder cancer. Int J Cancer. 2003 Dec 10;107(5):764-72
Tan D, Deeb G, Wang J, Slocum HK, Winston J, Wiseman S, Beck A, Sait S, Anderson T, Nwogu C, Ramnath N, Loewen G. HER-2/neu protein expression and gene alteration in stage I-IIIA non-small-cell lung cancer: a study of 140 cases using a combination of high throughput tissue microarray, immunohistochemistry, and fluorescent in situ hybridization. Diagn Mol Pathol. 2003 Dec;12(4):201-11
Zhou H, Randall RL, Brothman AR, Maxwell T, Coffin CM, Goldsby RE. Her-2/neu expression in osteosarcoma increases risk of lung metastasis and can be associated with gene amplification. J Pediatr Hematol Oncol. 2003 Jan;25(1):27-32
Al Moustafa AE, Foulkes WD, Benlimame N, Wong A, Yen L, Bergeron J, Batist G, Alpert L, Alaoui-Jamali MA. E6/E7 proteins of HPV type 16 and ErbB-2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells. Oncogene. 2004 Jan 15;23(2):350-8
Bernard C, Corzo G, Adachi-Akahane S, Foures G, Kanemaru K, Furukawa Y, Nakajima T, Darbon H. Solution structure of ADO1, a toxin extracted from the saliva of the assassin bug, Agriosphodrus dohrni. Proteins. 2004 Feb 1;54(2):195-205
Camilleri-Broët S, Hardy-Bessard AC, Le Tourneau A, Paraiso D, Levrel O, Leduc B, Bain S, Orfeuvre H, Audouin J, Pujade-Lauraine E. HER-2 overexpression is an independent marker of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group. Ann Oncol. 2004 Jan;15(1):104-12
Casalini P, Iorio MV, Galmozzi E, Ménard S. Role of HER receptors family in development and differentiation. J Cell Physiol. 2004 Sep;200(3):343-50
Chung GG, Zerkowski MP, Ocal IT, Dolled-Filhart M, Kang JY, Psyrri A, Camp RL, Rimm DL. beta-Catenin and p53 analyses of a breast carcinoma tissue microarray. Cancer. 2004 May 15;100(10):2084-92
Cianciulli A, Cosimelli M, Marzano R, Merola R, Piperno G, Sperduti I, de la Iglesia F, Leonardo G, Graziano F, Mancini R, Guadagni F. Genetic and pathologic significance of 1p, 17p, and 18q aneusomy and the ERBB2 gene in colorectal cancer and related normal colonic mucosa. Cancer Genet Cytogenet. 2004 May;151(1):52-9
Essapen S, Thomas H, Green M, De Vries C, Cook MG, Marks C, Topham C, Modjtahedi H. The expression and prognostic significance of HER-2 in colorectal cancer and its relationship with clinicopathological parameters. Int J Oncol. 2004 Feb;24(2):241-8
Hermanová M, Lukás Z, Nenutil R, Brázdil J, Kroupová I, Kren L, Pazourková M, Růzicka M, Díte P. Amplification and overexpression of HER-2/neu in invasive ductal
carcinomas of the pancreas and pancreatic intraepithelial neoplasms and the relationship to the expression of p21(WAF1/CIP1). Neoplasma. 2004;51(2):77-83
Hirsch FR, Langer CJ. The role of HER2/neu expression and trastuzumab in non-small cell lung cancer. Semin Oncol. 2004 Feb;31(1 Suppl 1):75-82
Hughes DP, Thomas DG, Giordano TJ, Baker LH, McDonagh KT. Cell surface expression of epidermal growth factor receptor and Her-2 with nuclear expression of Her-4 in primary osteosarcoma. Cancer Res. 2004 Mar 15;64(6):2047-53
Konecny GE, Thomssen C, Lück HJ, Untch M, Wang HJ, Kuhn W, Eidtmann H, du Bois A, Olbricht S, Steinfeld D, Möbus V, von Minckwitz G, Dandekar S, Ramos L, Pauletti G, Pegram MD, Jänicke F, Slamon DJ. Her-2/neu gene amplification and response to paclitaxel in patients with metastatic breast cancer. J Natl Cancer Inst. 2004 Aug 4;96(15):1141-51
Lassus H, Leminen A, Vayrynen A, Cheng G, Gustafsson JA, Isola J, Butzow R. ERBB2 amplification is superior to protein expression status in predicting patient outcome in serous ovarian carcinoma. Gynecol Oncol. 2004 Jan;92(1):31-9
Mándoky L, Géczi L, Bodrogi I, Tóth J, Csuka O, Kásler M, Bak M. Clinical relevance of HER-2/neu expression in germ-cell testicular tumors. Anticancer Res. 2004 Jul-Aug;24(4):2219-24
Onn A, Correa AM, Gilcrease M, Isobe T, Massarelli E, Bucana CD, O'Reilly MS, Hong WK, Fidler IJ, Putnam JB, Herbst RS. Synchronous overexpression of epidermal growth factor receptor and HER2-neu protein is a predictor of poor outcome in patients with stage I non-small cell lung cancer. Clin Cancer Res. 2004 Jan 1;10(1 Pt 1):136-43
Riener EK, Arnold N, Kommoss F, Lauinger S, Pfisterer J. The prognostic and predictive value of immunohistochemically detected HER-2/neu overexpression in 361 patients with ovarian cancer: a multicenter study. Gynecol Oncol. 2004 Oct;95(1):89-94
Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, Stevens C, O'Meara S, Smith R, Parker A, Barthorpe A, Blow M, Brackenbury L, Butler A, Clarke O, Cole J, Dicks E, Dike A, Drozd A, Edwards K, Forbes S, Foster R, Gray K, Greenman C, Halliday K, Hills K, Kosmidou V, Lugg R, Menzies A, Perry J, Petty R, Raine K, Ratford L, Shepherd R, Small A, Stephens Y, Tofts C, Varian J, West S, Widaa S, Yates A, Brasseur F, Cooper CS, Flanagan AM, Knowles M, Leung SY, Louis DN, Looijenga LH, Malkowicz B, Pierotti MA, Teh B, Chenevix-Trench G, Weber BL, Yuen ST, Harris G, Goldstraw P, Nicholson AG, Futreal PA, Wooster R, Stratton MR. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature. 2004 Sep 30;431(7008):525-6
Castiglioni F, Tagliabue E, Campiglio M, Pupa SM, Balsari A, Ménard S. Role of exon-16-deleted HER2 in breast carcinomas. Endocr Relat Cancer. 2006 Mar;13(1):221-32
Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008 Sep;19(9):1523-9
Hansel DE, Swain E, Dreicer R, Tubbs RR. HER2 overexpression and amplification in urothelial carcinoma of the bladder is associated with MYC coamplification in a subset of cases. Am J Clin Pathol. 2008 Aug;130(2):274-81
Jo UH, Han SG, Seo JH, Park KH, Lee JW, Lee HJ, Ryu JS, Kim YH. The genetic polymorphisms of HER-2 and the risk of lung cancer in a Korean population. BMC Cancer. 2008 Dec 4;8:359
ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian))
Braccioli L, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 971
Yoshikawa D, Ojima H, Iwasaki M, Hiraoka N, Kosuge T, Kasai S, Hirohashi S, Shibata T. Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer. 2008 Jan 29;98(2):418-25
Hirsch FR, Varella-Garcia M, Cappuzzo F. Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer. Oncogene. 2009 Aug;28 Suppl 1:S32-7
Mitra D, Brumlik MJ, Okamgba SU, Zhu Y, Duplessis TT, Parvani JG, Lesko SM, Brogi E, Jones FE. An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance. Mol Cancer Ther. 2009 Aug;8(8):2152-62
Higa GM, Singh V, Abraham J. Biological considerations and clinical applications of new HER2-targeted agents. Expert Rev Anticancer Ther. 2010 Sep;10(9):1497-509
Kimple RJ, Vaseva AV, Cox AD, Baerman KM, Calvo BF, Tepper JE, Shields JM, Sartor CI. Radiosensitization of epidermal growth factor receptor/HER2-positive pancreatic cancer is mediated by inhibition of Akt independent of ras mutational status. Clin Cancer Res. 2010 Feb 1;16(3):912-23
Tai W, Mahato R, Cheng K. The role of HER2 in cancer therapy and targeted drug delivery. J Control Release. 2010 Sep 15;146(3):264-75
Williams MD, Roberts DB, Kies MS, Mao L, Weber RS, El-Naggar AK. Genetic and expression analysis of HER-2 and EGFR genes in salivary duct carcinoma: empirical and therapeutic significance. Clin Cancer Res. 2010 Apr 15;16(8):2266-74
Arribas J, Baselga J, Pedersen K, Parra-Palau JL. p95HER2 and breast cancer. Cancer Res. 2011 Mar 1;71(5):1515-9
Gutierrez C, Schiff R. HER2: biology, detection, and clinical implications. Arch Pathol Lab Med. 2011 Jan;135(1):55-62
Shan LQ, Ma S, Qiu XC, Wang T, Yu SB, Ma BA, Zhou Y, Fan QY, Yang AG. A novel recombinant immuno-tBid with a furin site effectively suppresses the growth of HER2-positive osteosarcoma cells in vitro. Oncol Rep. 2011 Feb;25(2):325-31
This article should be referenced as such:
Braccioli L, Iorio MV, Casalini P. ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):963-971.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 972
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
KIAA0101 (KIAA0101) Shannon Joseph, Lingbo Hu, Fiona Simpson
University of Queensland Diamantina Institute, University of Queensland, Brisbane, Australia (SJ,
LH, FS)
Published in Atlas Database: May 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/KIAA0101ID41058ch15q22.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI KIAA0101ID41058ch15q22.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: FLJ58702; NS5ATP9; OEATC-1;
OEATC1; PAF; p15(PAF); p15PAF
HGNC (Hugo): KIAA0101
Location: 15q22.31
DNA/RNA
Note
Murine gene embryonic expression shows highly
restricted expression of KIAA0101 in facial
prominences, limbs, somites, brain, spinal cord and
hair follicles. It has a suggested role in embryonic
development (van Beuren et al., 2007).
Description
The gene is composed of 4 exons.
Transcription
One transcript. RNA was expressed as a 1.1 kb
message in liver, pancreas and placenta at high
levels (Yu et al., 2001). RNA profiling shows it is
highly expressed in a number of tumors,
specifically in esophageal tumors, anaplastic
thyroid carcinomas, pancreatic cancer and non-
small-cell lung cancer lines (Yu et al., 2001;
Hosokawa et al., 2007). KIAA0101 was also
reported to be down-regulated in colon cancer cells
(Simpson et al., 2006) and human hepatocellular
carcinoma (Guo et al., 2006). Nuclear protein NF-
kappaB (p50) (Li et al., 2008), the Hepatitis C virus
protein non-structural protein 5A (NS5A) (Shi et
al., 2008) and ATF3 (Turchi et al., 2009) bind to
the promoter region upstream of the KIAA0101
transcription initiation site promoting transcription
in response to DNA damage.
Pseudogene
None.
Protein
Note
NS5ATP9, Hepatitis C virus NS5A-transactivated
protein 9, HCV NS5A-transactivated protein 9,
Overexpressed in anaplastic thyroid carcinoma-1,
OEATC-1, OEATC1, p15(PAF), L5.
Description
The KIAA0101 gene encodes for a 111 amino acid
15 kDa protein. It contains a conserved
proliferating cell nuclear antigen (PCNA)-binding
motif (Yu et al., 2001).
DNA diagram. KIAA0101 9768 chr: 62444265-62460755. One transcript, 4 exons.
KIAA0101 (KIAA0101) Joseph S, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 973
Protein diagram. 111 aa in length, single transcript,
mutation I-A at position 65 and mutation F-A at position 68 results in loss of PCNA binding.
Expression
Predominant expression in liver, pancreas and
brain. Not detected in heart or liver (Yu et al.,
2001). The KIAA0101 protein was down-regulated
in human hepatocellular carcinoma (Guo et al.,
2006; Yuan et al., 2007). Increased protein levels
have been detected in pancreatic cancer cells
(Hosokawa et al., 2007).
Localisation
Nucleus, mitochondrion (Yu et al., 2001; Guo et al.,
2006; Simpson et al., 2006; Yuan et al., 2007).
Function
The KIAA0101 protein binds to PCNA through a
conserved PCNA binding domain. PCNA is
required for DNA replication or repair as a
supplementary factor for DNA polymerase
(Paunesku et al., 2001). Proteins bound to PCNA
can prevent its binding to DNA polymerase, in turn
leading to inhibition of DNA synthesis, cell cycle
progression and G1 cell cycle arrest (Yuan et al.,
2007). PCNA binding proteins also interact with
each other to modulate this regulation. For
example, KIAA0101 also interacts in a complex
with p33ING1 isoform 2, another PCNA binding
protein which is a potential tumor suppressor and
regulator of p53 (Simpson et al., 2006). UV
irradiation caused increased association of
KIAA0101 with PCNA suggesting that this
association occurs in response to DNA damage.
KIAA0101 also competes with p21WAF for
binding to PCNA (Yu et al., 2001). KIAA0101
most recently been shown to act in concert with
ATF3 to control genomic integrity after UV stress
(Turchi et al., 2009). KIAA0101 expression levels
are also regulated by NF-kappaB, this protein
family having significant roles in apoptosis, cell
cycle regulation and onocgenesis (Hosokawa et al.,
2007; Li et al., 2008). Together this data suggests a
likely role for KIAA0101 in DNA repair and in
protection from UV-induced cell death.
Mutations
Note
Experimentally mutation I-A at position 65 and F-A
at position 68 result in loss of PCNA binding (Yu et
al., 2001). No other mutations have been described.
Screening of colon tumour samples identified a
polymorphism in the intronic region just prior to the
start of exon 2 (982-15delT) (Simpson et al., 2006).
Implicated in
Hepatocellular carcinoma
Disease
KIAA0101 expression was proposed to promote
growth advantage and hypoxic insult resistance and
be associated with promoting cell proliferation
(Yuan et al., 2007). KIAA0101 overexpression was
associated with concomitant p53 mutation and
vascular invasion (Yuan et al., 2007). This study
suggested that high expression in hepatocellular
carcinoma was indicative of tumour recurrence,
metastatic potential and poor prognosis (Yuan et
al., 2007). KIAA0101 was also reported to be
downregulated in hepatocellular carcinoma (Guo et
al., 2006). This study suggested that KIAA0101 had
a growth inhibitory effect.
Astrocytomas
Disease
Grade IV (glioblastoma multiforme) astrocytomas
had 5 times higher expression levels when
compared to Grade I (pilocytic) astrocyomas
suggesting that KIAA0101 abundance correlates
with malignancy grade in human astrocytes (Marie
et al., 2008).
Pancreatic cancer
Disease
Pancreatic cells overexpress KIAA0101 both at
cDNA and protein level. Knock down of
KIAA0101 by siRNA attenuated proliferation and
DNA replication whereas overexpression enhanced
cell growth in pancreatic cancer cell lines
(Hosokawa et al., 2007).
Anaplastic thyroid carcinoma
Disease
Anaplastic thyroid carcinoma cell lines had
significant overexpression of KIAA0101. Cell
growth was inhibited by silencing KIAA0101
expression using siRNA. KIAA0101 may be
oncogenic or cell growth-promoting but the
mechanism for this is not understood (Mizutani et
al., 2005).
Follicular lymphoma
Disease
High expression of KIAA0101 (along with CCNB1
(cyclin B1), CDC2, CDKN3A, CKS1B, ANP32E)
was associated with better survival/response rate in
a univariate analysis following CHOP
(cyclophosphamide, vincristine, doxorubicin,
prednisone) chemotherapy for follicular lymphoma
treatment. Identification of these proteins aims to
develop a follicular lymphoma international
prognostic index to aid in informing a successful
treatment strategy (Bjorck et al., 2005).
KIAA0101 (KIAA0101) Joseph S, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 974
Oncogenesis
This gene is thought to be oncogenic through
modulation of DNA repair pathways via interaction
with PCNA.
References Nagase T, Miyajima N, Tanaka A, Sazuka T, Seki N, Sato S, Tabata S, Ishikawa K, Kawarabayasi Y, Kotani H. Prediction of the coding sequences of unidentified human genes. III. The coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 1995;2(1):37-43
Paunesku T, Mittal S, Protić M, Oryhon J, Korolev SV, Joachimiak A, Woloschak GE. Proliferating cell nuclear antigen (PCNA): ringmaster of the genome. Int J Radiat Biol. 2001 Oct;77(10):1007-21
Yu P, Huang B, Shen M, Lau C, Chan E, Michel J, Xiong Y, Payan DG, Luo Y. p15(PAF), a novel PCNA associated factor with increased expression in tumor tissues. Oncogene. 2001 Jan 25;20(4):484-9
Björck E, Ek S, Landgren O, Jerkeman M, Ehinger M, Björkholm M, Borrebaeck CA, Porwit-MacDonald A, Nordenskjöld M. High expression of cyclin B1 predicts a favorable outcome in patients with follicular lymphoma. Blood. 2005 Apr 1;105(7):2908-15
Mizutani K, Onda M, Asaka S, Akaishi J, Miyamoto S, Yoshida A, Nagahama M, Ito K, Emi M. Overexpressed in anaplastic thyroid carcinoma-1 (OEATC-1) as a novel gene responsible for anaplastic thyroid carcinoma. Cancer. 2005 May 1;103(9):1785-90
Guo M, Li J, Wan D, Gu J. KIAA0101 (OEACT-1), an expressionally down-regulated and growth-inhibitory gene in human hepatocellular carcinoma. BMC Cancer. 2006 Apr 29;6:109
Simpson F, Lammerts van Bueren K, Butterfield N, Bennetts JS, Bowles J, Adolphe C, Simms LA, Young J, Walsh MD, Leggett B, Fowles LF, Wicking C. The PCNA-associated factor KIAA0101/p15(PAF) binds the potential tumor suppressor product p33ING1b. Exp Cell Res. 2006 Jan 1;312(1):73-85
Collado M, Garcia V, Garcia JM, Alonso I, Lombardia L, Diaz-Uriarte R, Fernández LA, Zaballos A, Bonilla F, Serrano M. Genomic profiling of circulating plasma RNA
for the analysis of cancer. Clin Chem. 2007 Oct;53(10):1860-3
Hosokawa M, Takehara A, Matsuda K, Eguchi H, Ohigashi H, Ishikawa O, Shinomura Y, Imai K, Nakamura Y, Nakagawa H. Oncogenic role of KIAA0101 interacting with proliferating cell nuclear antigen in pancreatic cancer. Cancer Res. 2007 Mar 15;67(6):2568-76
van Bueren KL, Bennetts JS, Fowles LF, Berkman JL, Simpson F, Wicking C. Murine embryonic expression of the gene for the UV-responsive protein p15(PAF). Gene Expr Patterns. 2007 Jan;7(1-2):47-50
Yuan RH, Jeng YM, Pan HW, Hu FC, Lai PL, Lee PH, Hsu HC. Overexpression of KIAA0101 predicts high stage, early tumor recurrence, and poor prognosis of hepatocellular carcinoma. Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5368-76
Li K, Ma Q, Shi L, Dang C, Hong Y, Wang Q, Li Y, Fan W, Zhang L, Cheng J. NS5ATP9 gene regulated by NF-kappaB signal pathway. Arch Biochem Biophys. 2008 Nov 1;479(1):15-9
Marie SK, Okamoto OK, Uno M, Hasegawa AP, Oba-Shinjo SM, Cohen T, Camargo AA, Kosoy A, Carlotti CG Jr, Toledo S, Moreira-Filho CA, Zago MA, Simpson AJ, Caballero OL. Maternal embryonic leucine zipper kinase transcript abundance correlates with malignancy grade in human astrocytomas. Int J Cancer. 2008 Feb 15;122(4):807-15
Shi L, Zhang SL, Li K, Hong Y, Wang Q, Li Y, Guo J, Fan WH, Zhang L, Cheng J. NS5ATP9, a gene up-regulated by HCV NS5A protein. Cancer Lett. 2008 Feb 8;259(2):192-7
Turchi L, Fareh M, Aberdam E, Kitajima S, Simpson F, Wicking C, Aberdam D, Virolle T. ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress. Cell Death Differ. 2009 May;16(5):728-37
Miller WR, Larionov A. Changes in expression of oestrogen regulated and proliferation genes with neoadjuvant treatment highlight heterogeneity of clinical resistance to the aromatase inhibitor, letrozole. Breast Cancer Res. 2010;12(4):R52
This article should be referenced as such:
Joseph S, Hu L, Simpson F. KIAA0101 (KIAA0101). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):972-974.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 975
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8) Nikki Minnebo, Nele Van Dessel, Monique Beullens, Aleyde van Eynde, Mathieu Bollen
Laboratory of Biosignaling & Therapeutics, Dept Molecular Cell Biology, University of Leuven,
Herestraat 49 box 901, 3000 Leuven, Belgium (NM, NV, MB, Av, MB)
Published in Atlas Database: May 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/PPP1R8ID41811ch1p35.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI PPP1R8ID41811ch1p35.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: ARD-1; ARD1; NIPP-1; NIPP1;
PRO2047
HGNC (Hugo): PPP1R8
Location: 1p35.3
DNA/RNA
Note
ARD1 is a frequently used alias for NIPP1,
however, this name actually corresponds to an
alternative transcript (NIPP1gamma), which
encodes a truncated form of NIPP1 encompassing
residues 225-351 only. This transcript has been
shown to restore endoribonuclease activity to E.
coli rne gene mutants (Wang and Cohen, 1994;
Claverie-Martin et al., 1997; Chang et al., 1999; Jin
et al., 1999; Van Eynde et al., 1999). Moreover,
note that the name ARD1 is also used for a
completely unrelated protein, TRIM23 (Mishima et
al., 1993).
Description
The entire PPP1R8 gene spans 20.9 kb on the
forward strand of the long arm on chromosome 1.
The gene contains 7 exons of which exon 1 has 5'-
alternative splice sites.
Transcription
The PPP1R8 gene contains 7 exons which give rise
to 5 alternative splice products (see diagram above).
Genomic organization of the PPP1R8 gene and the alternative splice variants with their corresponding coding sequences (black
line). Exons and alternative splice sites are indicated by different colors.
PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8)
Minnebo N, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 976
When speaking about NIPP1, one usually refers to
the NIPP1alpha isoform (39 kDa, 351 residues)
which is by far the most abundant isoform in all
examined mammalian tissues. When visualized by
immunoblotting with C-terminal antibodies (which
recognize all isoforms except NIPP1epsilon), also
smaller polypeptides are visualized albeit at a much
lower intensity as compared to the alpha-isoform.
However, it is not clear yet whether these represent
some of the other NIPP1 isoforms or simply
degradation products of NIPP1alpha (Van Eynde et
al., 1999; Chang et al., 1999; Fardilha et al., 2004).
Pseudogene
A processed pseudogene, termed PPP1R8P, has
been mapped to chromosome 1p33-32 (48790762-
48791795 bp from pter according to hg19 - Feb
2009). Consistent with this notion, it is only 1034
bp in size, contains no introns and encodes an
incomplete NIPP1-transcript due to the presence of
various premature stop codons (Van Eynde et al.,
1999).
Protein
Note
Nuclear Inhibitor of PP1 (NIPP1) was first
identified in bovine thymus nuclei as a potent
inhibitor of the protein Ser/Thr phosphatase PP1
(Beullens et al., 1992; Beullens et al., 1993). Later
on, it became clear that NIPP1 exerts various
functions in the eukaryotic cell by serving as a kind
of scaffold protein onto which a variety of proteins
can bind. These interaction partners range from
protein kinase MELK, protein phosphatase PP1
(PPP1C-a/PPP1C-b/PPP1C-c), the pre-mRNA
splicing factors SAP155 (SF3B1) and CDC5L to
the chromatin modifiers EED and EZH2.
Description
NIPP1 consists of 351 amino acids and has a
molecular mass of 39 kDa. However, it migrates at
a size of about 45 kDa on SDS-PAGE. NIPP1
contains an N-terminal ForkHead Associated
(FHA) domain.
Via this established phosphothreonine-binding
domain, NIPP1 interacts with protein kinase
MELK, the splicing factors SAP155 and CDC5L
and the histone methyltransferase EZH2. Moreover,
it was shown that the NIPP1 FHA-domain binds to
its ligands via phosphorylated TP-dipeptide motifs,
present in the interacting proteins (Boudrez et al.,
2000; Boudrez et al., 2002; Vulsteke et al., 2004;
Nuytten et al., 2008).
Two additional interactors, PP1 and EED, have two
separate binding sites on NIPP1: one in the central
domain and the other at the C-terminus. In the
central domain, the binding of NIPP1 to PP1 is
mediated by a so called RVXF-motif, which is
present in about two thirds of all known PP1
interacting proteins (Beullens et al., 1999; Beullens
et al., 2000; Hendrickx et al., 2009). In addition, the
C-terminal 22 residues can interact with nucleic
acids (Jin et al., 1999).
Expression
NIPP1 is ubiquitously expressed (Van Eynde et al.,
1995).
Localisation
NIPP1 is a nuclear protein and is enriched in
splicing factor storage sites called speckles
(Trinkle-Mulcahy et al., 1999; Jagiello et al., 2000).
Although largely nuclear, some data suggest that
there also exists a cytoplasmic pool of NIPP1
(Boudrez et al., 1999; Jagiello et al., 1997).
Function
NIPP1 is a scaffold protein and exerts its functions
via its interacting proteins. NIPP1 was discovered
as a potent inhibitor and a major nuclear interactor
of the phosphatase PP1 (Beullens et al., 1999). PP1
functions as a holoenzyme in which the interacting
proteins confine substrate specificity, activity
and/or localization of PP1 (Bollen et al., 2010). For
NIPP1, it has been shown that it acts as a
physiological PP1 inhibitor for some substrates,
while functioning as an activator towards other
substrates (Parker et al., 2002; Lesage et al., 2004;
Comerford et al., 2006; Shi and Manley, 2007).
A schematic representation of the domain structure of NIPP1 and its interactor binding sites. The FHA-domain (red) binds the
indicated interactors via a phosphorylated TP dipeptide motif. NIPP1 binds PP1 via the indicated RVXF-motif and via a C-terminal binding site (green). EED and RNA binding sites are colored blue and orange, respectively. Known phosphorylation
sites are indicated in black (in vivo validated) or grey (in vitro data).
PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8)
Minnebo N, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 977
Also, the interaction between NIPP1 and PP1 can
be regulated by phosphorylation (Beullens et al.,
1993; Van Eynde et al., 1994; Jagiello et al., 1995;
Vulsteke et al., 1997; Beullens et al., 1999). NIPP1
is also involved in 3 other major cellular processes:
splicing, transcription and development. Firstly,
NIPP1 is associated with spliceosomes and splicing
factor storage sites called "speckles", probably
mediated by its interaction with the splicing factors
CDC5L and SAP155 (Boudrez et al., 2000; Deckert
et al., 2006). Pre-mRNA splicing assays showed
that NIPP1 is required for late stage spliceosome
formation (Beullens and Bollen, 2002). Recently it
was published that NIPP1 directs associated PP1 to
dephosphorylate SAP155 (Tanuma et al., 2008).
Secondly, NIPP1 is a transcriptional repressor via
its interaction with EED and EZH2 (Jin et al., 2003;
Roy et al., 2007), two core components of the
Polycomb repressive complex 2 (PRC2). Through
its interaction with PRC2, NIPP1 directs it to a
subset of Polycomb target genes, where the
methyltransferase EZH2 will mark genes proned for
silencing by trimethylating histone 3 on lysine 27
(Nuytten et al, 2008). In 2010, Van Dessel et al.
showed that this targeting function of NIPP1 is
dependent on associated PP1. Finally, NIPP1 is
essential for embryonic development as a NIPP1
knock out mouse is embryonically lethal at the
onset of gastrulation (Van Eynde et al., 2004).
The splice variant NIPP1gamma or ARD1 displays
a site-specific Mg2+
-dependent endoribonuclease
activity, in contrast to the NIPP1alpha isoform,
which does not possess this function (Wang and
Cohen, 1994; Claverie-Martin et al., 1997; Chang et
al., 1999; Jin et al., 1999; Van Eynde et al., 1999).
Homology
NIPP1 is highly conserved in all multicellular
organisms.
Implicated in
Hepatoma
Disease
Cancer.
Prognosis
An increase in NIPP1 mRNA is correlated with a
malignant phenotype in rats (Kim et al., 2000).
References Beullens M, Van Eynde A, Stalmans W, Bollen M. The isolation of novel inhibitory polypeptides of protein phosphatase 1 from bovine thymus nuclei. J Biol Chem. 1992 Aug 15;267(23):16538-44
Mishima K, Tsuchiya M, Nightingale MS, Moss J, Vaughan M. ARD 1, a 64-kDa guanine nucleotide-binding protein with a carboxyl-terminal ADP-ribosylation factor domain. J Biol Chem. 1993 Apr 25;268(12):8801-7
Beullens M, Van Eynde A, Bollen M, Stalmans W. Inactivation of nuclear inhibitory polypeptides of protein
phosphatase-1 (NIPP-1) by protein kinase A. J Biol Chem. 1993 Jun 25;268(18):13172-7
Van Eynde A, Beullens M, Stalmans W, Bollen M. Full activation of a nuclear species of protein phosphatase-1 by phosphorylation with protein kinase A and casein kinase-2. Biochem J. 1994 Feb 1;297 ( Pt 3):447-9
Wang M, Cohen SN. ard-1: a human gene that reverses the effects of temperature-sensitive and deletion mutations in the Escherichia coli rne gene and encodes an activity producing RNase E-like cleavages. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10591-5
Jagiello I, Beullens M, Stalmans W, Bollen M. Subunit structure and regulation of protein phosphatase-1 in rat liver nuclei. J Biol Chem. 1995 Jul 21;270(29):17257-63
Van Eynde A, Wera S, Beullens M, Torrekens S, Van Leuven F, Stalmans W, Bollen M. Molecular cloning of NIPP-1, a nuclear inhibitor of protein phosphatase-1, reveals homology with polypeptides involved in RNA processing. J Biol Chem. 1995 Nov 24;270(47):28068-74
Claverie-Martin F, Wang M, Cohen SN. ARD-1 cDNA from human cells encodes a site-specific single-strand endoribonuclease that functionally resembles Escherichia coli RNase E. J Biol Chem. 1997 May 23;272(21):13823-8
Jagiello I, Beullens M, Vulsteke V, Wera S, Sohlberg B, Stalmans W, von Gabain A, Bollen M. NIPP-1, a nuclear inhibitory subunit of protein phosphatase-1, has RNA-binding properties. J Biol Chem. 1997 Aug 29;272(35):22067-71
Vulsteke V, Beullens M, Waelkens E, Stalmans W, Bollen M. Properties and phosphorylation sites of baculovirus-expressed nuclear inhibitor of protein phosphatase-1 (NIPP-1). J Biol Chem. 1997 Dec 26;272(52):32972-8
Beullens M, Van Eynde A, Vulsteke V, Connor J, Shenolikar S, Stalmans W, Bollen M. Molecular determinants of nuclear protein phosphatase-1 regulation by NIPP-1. J Biol Chem. 1999 May 14;274(20):14053-61
Boudrez A, Evens K, Beullens M, Waelkens E, Stalmans W, Bollen M. Identification of MYPT1 and NIPP1 as subunits of protein phosphatase 1 in rat liver cytosol. FEBS Lett. 1999 Jul 16;455(1-2):175-8
Chang AC, Sohlberg B, Trinkle-Mulcahy L, Claverie-Martin F, Cohen P, Cohen SN. Alternative splicing regulates the production of ARD-1 endoribonuclease and NIPP-1, an inhibitor of protein phosphatase-1, as isoforms encoded by the same gene. Gene. 1999 Nov 15;240(1):45-55
Jin Q, Beullens M, Jagiello I, Van Eynde A, Vulsteke V, Stalmans W, Bollen M. Mapping of the RNA-binding and endoribonuclease domains of NIPP1, a nuclear targeting subunit of protein phosphatase 1. Biochem J. 1999 Aug 15;342 ( Pt 1):13-9
Trinkle-Mulcahy L, Ajuh P, Prescott A, Claverie-Martin F, Cohen S, Lamond AI, Cohen P. Nuclear organisation of NIPP1, a regulatory subunit of protein phosphatase 1 that associates with pre-mRNA splicing factors. J Cell Sci. 1999 Jan;112 ( Pt 2):157-68
Van Eynde A, Pérez-Callejón E, Schoenmakers E, Jacquemin M, Stalmans W, Bollen M. Organization and alternate splice products of the gene encoding nuclear inhibitor of protein phosphatase-1 (NIPP-1). Eur J Biochem. 1999 Apr;261(1):291-300
Beullens M, Vulsteke V, Van Eynde A, Jagiello I, Stalmans W, Bollen M. The C-terminus of NIPP1 (nuclear inhibitor of protein phosphatase-1) contains a novel binding site for protein phosphatase-1 that is controlled by tyrosine phosphorylation and RNA binding. Biochem J. 2000 Dec 15;352 Pt 3:651-8
PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8)
Minnebo N, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 978
Boudrez A, Beullens M, Groenen P, Van Eynde A, Vulsteke V, Jagiello I, Murray M, Krainer AR, Stalmans W, Bollen M. NIPP1-mediated interaction of protein phosphatase-1 with CDC5L, a regulator of pre-mRNA splicing and mitotic entry. J Biol Chem. 2000 Aug 18;275(33):25411-7
Kim SE, Ishita A, Shima H, Nakamura K, Yamada Y, Ogawa K, Kikuchi K. Increased expression of NIPP-1 mRNA correlates positively with malignant phenotype in rat hepatomas. Int J Oncol. 2000 Apr;16(4):751-5
Beullens M, Bollen M. The protein phosphatase-1 regulator NIPP1 is also a splicing factor involved in a late step of spliceosome assembly. J Biol Chem. 2002 May 31;277(22):19855-60
Boudrez A, Beullens M, Waelkens E, Stalmans W, Bollen M. Phosphorylation-dependent interaction between the splicing factors SAP155 and NIPP1. J Biol Chem. 2002 Aug 30;277(35):31834-41
Parker L, Gross S, Beullens M, Bollen M, Bennett D, Alphey L. Functional interaction between nuclear inhibitor of protein phosphatase type 1 (NIPP1) and protein phosphatase type 1 (PP1) in Drosophila: consequences of over-expression of NIPP1 in flies and suppression by co-expression of PP1. Biochem J. 2002 Dec 15;368(Pt 3):789-97
Jin Q, van Eynde A, Beullens M, Roy N, Thiel G, Stalmans W, Bollen M. The protein phosphatase-1 (PP1) regulator, nuclear inhibitor of PP1 (NIPP1), interacts with the polycomb group protein, embryonic ectoderm development (EED), and functions as a transcriptional repressor. J Biol Chem. 2003 Aug 15;278(33):30677-85
Fardilha M, Wu W, Sá R, Fidalgo S, Sousa C, Mota C, da Cruz e Silva OA, da Cruz e Silva EF. Alternatively spliced protein variants as potential therapeutic targets for male infertility and contraception. Ann N Y Acad Sci. 2004 Dec;1030:468-78
Lesage B, Beullens M, Nuytten M, Van Eynde A, Keppens S, Himpens B, Bollen M. Interactor-mediated nuclear translocation and retention of protein phosphatase-1. J Biol Chem. 2004 Dec 31;279(53):55978-84
Van Eynde A, Nuytten M, Dewerchin M, Schoonjans L, Keppens S, Beullens M, Moons L, Carmeliet P, Stalmans W, Bollen M. The nuclear scaffold protein NIPP1 is essential for early embryonic development and cell proliferation. Mol Cell Biol. 2004 Jul;24(13):5863-74
Vulsteke V, Beullens M, Boudrez A, Keppens S, Van Eynde A, Rider MH, Stalmans W, Bollen M. Inhibition of spliceosome assembly by the cell cycle-regulated protein kinase MELK and involvement of splicing factor NIPP1. J Biol Chem. 2004 Mar 5;279(10):8642-7
Comerford KM, Leonard MO, Cummins EP, Fitzgerald KT, Beullens M, Bollen M, Taylor CT. Regulation of protein phosphatase 1gamma activity in hypoxia through increased interaction with NIPP1: implications for cellular metabolism. J Cell Physiol. 2006 Oct;209(1):211-8
Deckert J, Hartmuth K, Boehringer D, Behzadnia N, Will CL, Kastner B, Stark H, Urlaub H, Lührmann R. Protein composition and electron microscopy structure of affinity-purified human spliceosomal B complexes isolated under physiological conditions. Mol Cell Biol. 2006 Jul;26(14):5528-43
Roy N, Van Eynde A, Beke L, Nuytten M, Bollen M. The transcriptional repression by NIPP1 is mediated by Polycomb group proteins. Biochim Biophys Acta. 2007 Sep-Oct;1769(9-10):541-5
Shi Y, Manley JL. A complex signaling pathway regulates SRp38 phosphorylation and pre-mRNA splicing in response to heat shock. Mol Cell. 2007 Oct 12;28(1):79-90
Nuytten M, Beke L, Van Eynde A, Ceulemans H, Beullens M, Van Hummelen P, Fuks F, Bollen M. The transcriptional repressor NIPP1 is an essential player in EZH2-mediated gene silencing. Oncogene. 2008 Feb 28;27(10):1449-60
Tanuma N, Kim SE, Beullens M, Tsubaki Y, Mitsuhashi S, Nomura M, Kawamura T, Isono K, Koseki H, Sato M, Bollen M, Kikuchi K, Shima H. Nuclear inhibitor of protein phosphatase-1 (NIPP1) directs protein phosphatase-1 (PP1) to dephosphorylate the U2 small nuclear ribonucleoprotein particle (snRNP) component, spliceosome-associated protein 155 (Sap155). J Biol Chem. 2008 Dec 19;283(51):35805-14
Hendrickx A, Beullens M, Ceulemans H, Den Abt T, Van Eynde A, Nicolaescu E, Lesage B, Bollen M. Docking motif-guided mapping of the interactome of protein phosphatase-1. Chem Biol. 2009 Apr 24;16(4):365-71
Bollen M, Peti W, Ragusa MJ, Beullens M. The extended PP1 toolkit: designed to create specificity. Trends Biochem Sci. 2010 Aug;35(8):450-8
Van Dessel N, Beke L, Görnemann J, Minnebo N, Beullens M, Tanuma N, Shima H, Van Eynde A, Bollen M. The phosphatase interactor NIPP1 regulates the occupancy of the histone methyltransferase EZH2 at Polycomb targets. Nucleic Acids Res. 2010 Nov;38(21):7500-12
This article should be referenced as such:
Minnebo N, Van Dessel N, Beullens M, van Eynde A, Bollen M. PPP1R8 (protein phosphatase 1, regulatory (inhibitor) subunit 8). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):975-978.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 979
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
SMYD2 (SET and MYND domain containing 2) Hitoshi Tsuda, Shuhei Komatsu
Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
(HT), Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of
Medicine, Kyoto, Japan (SK)
Published in Atlas Database: May 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/SMYD2ID47098ch1q32.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI SMYD2ID47098ch1q32.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: HSKM-B; KMT3C; MGC119305;
ZMYND14
HGNC (Hugo): SMYD2
Location: 1q32.3
DNA/RNA
Description
55913 bp, 12 exons.
Transcription
1689 bp mRNA.
Protein
Description
433 amino acids. The protein contains SET domain,
MYND domain/zinc-finger motif, and cysteine-rich
post-SET domain. The SET domain is split into two
segments by a MYND domain.
Expression
Wide, highly expressed in heart, brain, liver,
kidney, thymus, ovary, embryonic tissues (heart,
hypothalamus) (Brown et al., 2006).
Localisation
Cytoplasmic and nucleus (Brown et al., 2006).
Function
Regulation of transcription as a lysine
methyltransferase for histone 3, lysine 36 (H3K36)
and inhibition of p53's transactivation activity as a
lysine methyltransferase for lysine 370 (K370) of
p53 through the SET domain (Brown et al., 2006;
Huang et al., 2006). Possibly promotion of cell
proliferation and/or differentiation through its
overexpression/activation-induced inhibition of
p53's transactivation activity. Methylation of
retinoblastoma (RB) tumor suppressor at lysine
860, that is regulated during cell cycle progression,
cellular differentiation ,and in response to DNA
damage (Saddic et al., 2010). RB monomethylation
at lysine 860 provides a direct binding site for the
transcription repressor L3MBTL1. Through
interaction with HSP90alpha, SMYD2 histone
methyltransferase activity and specificity for
histone H3 at lysine 4 (H3K4) are enhanced in vitro
(Abu-Farha et al., 2008). SMYD2 gain of function
is correlated with the upregulation of 37 and down
regulation of 4 genes, the majority of which are
involved in the cell cycle, chromatin remodelling,
and transcriptional regulation (Abu-Farha et al.,
2008).
SMYD2 (SET and MYND domain containing 2) Tsuda H, Komatsu S
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 980
Homology
Xenopus laevis, Zebrafish, Chicken, Gray short-
tailed opossum, Mouse, Rat, Rabbit, Pig, Horse,
Cattle, Dog, White-tufted-ear marmoset, Rhesus
monkey, Sumatran orangutan, Chimpanzee.
Mutations
Note
Not found.
Implicated in
Esophageal squamous cell carcinoma (ESCC)
Note
Frequent overexpression of SMYD2 mRNA and
protein was observed in KYSE150 cells with
remarkable amplification at 1q32-q41.1 and other
ESCC cell lines (11/43 lines, 25.6%).
Overexpression of SMYD2 protein was frequently
detected in primary tumor samples of ESCC
(117/153 cases, 76.5%) as well and significantly
correlated with gender, venous invasion, the pT
category in the tumor-lymph node-metastasis
classification and status of recurrence. Patients with
SMYD2-overexpressing tumors had a worse overall
rate of survival than those with non-expressing
tumors. Knockdown of SMYD2 expression
inhibited and ectopic overexpression of SMYD2
promoted the proliferation of ESCC cells in a TP53
mutation-independent but SMYD2 expression
dependent manner (Komatsu et al., 2009).
Thyroid carcinoma and benign thyroid nodule
Note
Using differential display-polymerase chain
reaction method, the gene expression differences
between benign thyroid nodules (BTNs) and
follicular and classic variants of papillary thyroid
carcinoma (PTC) were evaluated in a group of 42
patients (15 BTNs, 14 follicular variant of PTC and
13 classic variant of PTC). SMYD2 had lower
expression in both carcinoma groups than in BTNs
(Igci et al., 2011).
Breast cancer
Note
Expression of a group of three genes (MTSS1,
RPL37, and SMYD2) evaluated by real-time PCR
was shown to be a potential candidate to predict
response to neoadjuvant chemotherapy (4 cycles of
doxorubicin and cyclophosphamide) in breast
cancer patients (Barros Filho et al., 2010).
References Brown MA, Sims RJ 3rd, Gottlieb PD, Tucker PW. Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex. Mol Cancer. 2006 Jun 28;5:26
Huang J, Perez-Burgos L, Placek BJ, Sengupta R, Richter M, Dorsey JA, Kubicek S, Opravil S, Jenuwein T, Berger SL. Repression of p53 activity by Smyd2-mediated methylation. Nature. 2006 Nov 30;444(7119):629-32
Abu-Farha M, Lambert JP, Al-Madhoun AS, Elisma F, Skerjanc IS, Figeys D. The tale of two domains: proteomics and genomics analysis of SMYD2, a new histone methyltransferase. Mol Cell Proteomics. 2008 Mar;7(3):560-72
Komatsu S, Imoto I, Tsuda H, Kozaki KI, Muramatsu T, Shimada Y, Aiko S, Yoshizumi Y, Ichikawa D, Otsuji E, Inazawa J. Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma. Carcinogenesis. 2009 Jul;30(7):1139-46
Barros Filho MC, Katayama ML, Brentani H, Abreu AP, Barbosa EM, Oliveira CT, Góes JC, Brentani MM, Folgueira MA. Gene trio signatures as molecular markers to predict response to doxorubicin cyclophosphamide neoadjuvant chemotherapy in breast cancer patients. Braz J Med Biol Res. 2010 Dec;43(12):1225-31
Saddic LA, West LE, Aslanian A, Yates JR 3rd, Rubin SM, Gozani O, Sage J. Methylation of the retinoblastoma tumor suppressor by SMYD2. J Biol Chem. 2010 Nov 26;285(48):37733-40
Igci YZ, Arslan A, Akarsu E, Erkilic S, Igci M, Oztuzcu S, Cengiz B, Gogebakan B, Cakmak EA, Demiryurek AT. Differential expression of a set of genes in follicular and classic variants of papillary thyroid carcinoma. Endocr Pathol. 2011 Jun;22(2):86-96
This article should be referenced as such:
Tsuda H, Komatsu S. SMYD2 (SET and MYND domain containing 2). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):979-980.
Leukaemia Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 981
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
t(1;9)(p34;q34) Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers,
France (JLH)
Published in Atlas Database: May 2011
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0109p34q34ID2143.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI t0109p34q34ID2143.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Disease
B cell progenitor acute lymphoid leukemia (B-
ALL)
Epidemiology
Only one case to date, a 22-year-old male patient
(Hidalgo-Curtis et al., 2008).
Prognosis
Complete remission was obtained, a relapse
occured. The patient was in complete remission 6
years after diagnosis.
Cytogenetics
Cytogenetics morphological
The translocation was found solely in the main
clone, and a subclone also showed a +21.
Genes involved and proteins
SFPQ
Location
1p34.3
Protein
DNA- and RNA binding protein; pre-mRNA
splicing factor; binds specifically to intronic
polypyrimidine tracts.
Role in transcription and RNA splicing: SFPQ,
often called PSF, is a coactivator of Fox proteins,
which bind the RNA element UGCAUG and
regulate alternative pre-mRNA splicing. SFPQ and
NONO are part of a large complex with all the
snRNPs. SFPQ is phosphorylated by GSK3, which
prevents SFPQ from binding PTPRC (CD45
antigen) pre-mRNA. The association of HNRNPL
and SFPQ drives the change in PTPRC (CD45)
splicing (CD45 undergoes alternative splicing in
response to T-cell activation).
DNA damage: DNA double-strand breaks are
repaired via nonhomologous DNA end joining and
homologous recombination. The SFPQ/NONO
heterodimer enhances DNA strand break rejoining.
SFPQ has homologous recombination and non-
homologous end joining activities. SFPQ is
associated with the RAD51 protein complex.
Role in transcriptional regulation: SFPQ and PTK6
(protein tyrosine kinase 6, also called BRK) play a
role downstream of the EGF receptor (EGFR).
SFPQ and NONO form complexes with the
androgen receptor (AR) and modulate its
transcriptional activity (Huret, 2011).
ABL1
Location
9q34
Protein
ABL1, when localized in the nucleus, induces
apoptosis after DNA damage. Cytoplasmic ABL1
has a possible function in adhesion signalling
(Turhan, 2008).
Result of the chromosomal anomaly
Hybrid gene
Description
Break in the 3' of SFPQ exon 10 and reunion with
ABL1 intron 3; a further mRNA splicing gives rise
t(1;9)(p34;q34) Huret JL
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 982
to a chimeric SFPQ exons 1 to 9 (nucleotide 2072)
fused to ABL1 exon 4 to end.
Fusion protein
Description
1609 amino acids fusion protein of 174 kDa; retains
most of SFPQ, including the RNA recognition
motifs and the coiled-coil domain (dimerization
domain), fused to the SH2 domain of ABL1; the
fusion protein also includes the SH1 domain
(tyrosine kinase activity), the nuclear localization
domain, and the actin binding domain of ABL1.
Oncogenesis
Constitutive tyrosine kinase activation is likely,
through dimerization of the fusion protein.
References Huret JL.. SFPQ (splicing factor proline/glutamine-rich). Atlas Genet Cytogenet Oncol Haematol. January 1999. http://atlasgeneticsoncology.org/Genes/PSFID167.html
Hidalgo-Curtis C, Chase A, Drachenberg M, Roberts MW, Finkelstein JZ, Mould S, Oscier D, Cross NC, Grand FH.. The t(1;9)(p34;q34) and t(8;12)(p11;q15) fuse pre-mRNA processing proteins SFPQ (PSF) and CPSF6 to ABL and FGFR1. Genes Chromosomes Cancer. 2008 May;47(5):379-85.
Turhan AG.. ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1). Atlas Genet Cytogenet Oncol Haematol. August 2008. http://atlasgeneticsoncology.org/Genes/ABL.html
This article should be referenced as such:
Huret JL. t(1;9)(p34;q34). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):981-982.
Deep Insight Section
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 983
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Understanding the structure and function of ASH2L Paul F South, Scott D Briggs
Department of Biochemistry and Purdue University Center for Cancer Research, Purdue University,
West Lafayette, Indiana 47907, USA (PFS, SDB)
Published in Atlas Database: June 2011
Online updated version : http://AtlasGeneticsOncology.org/Deep/ASH2LFunctionID20097.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI ASH2LFunctionID20097.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Introduction ASH2L (Absent, Small, or Homeotic-Like) encodes
the protein ASH2L which was named after the
Drosophila protein Ash2 a known regulator of
HOX genes (Ikegawa et al., 1999). ASH2L is
known to be a component of histone H3 lysine 4
(H3K4) methyltransferase complexes and H3K4
methylation is commonly associated with active
gene transcription (Ikegawa et al., 1999; Hughes et
al., 2004; Dou et al., 2006; Steward et al., 2006;
Cho et al., 2007). Previous studies have shown that
disruption of ASH2L leads to a decrease in H3K4
trimethylation, which negatively affects gene
expression (Dou et al., 2006; Steward et al., 2006).
Furthermore, disruption of ASH2L or the
methyltransferases involved in H3K4 methylation
can lead to oncogenesis mostly through the
regulation of HOX gene expression (Hughes et al.,
2004; Lüscher-Firzlaff et al., 2008). Interestingly,
overexpression of ASH2L leads to tumor
proliferation and knock-down of ASH2L inhibits
tumorigenesis, which is the reason why ASH2L is
thought to be an oncoprotein (Lüscher-Firzlaff et
al., 2008). Understanding the role that ASH2L
plays in facilitating proper H3K4 methylation may
provide insight into how disruption of ASH2L can
lead to abnormal cell proliferation and oncogenesis.
ASH2L function Genetic information and sequence alignments
identified ASH2L to be homologous to the
transcriptional activator Drosophila Ash2 (Wang et
al., 2001; Ikegawa et al., 1999). Drosophila Ash2
(Absent, small, and homeotic discs) is a member of
the Trithorax family, known regulators of
developmental homeotic genes (LaJeunesse and
Shearn, 1995). Mammalian ASH2L is known to be
important for development because ASH2L-null
mice exhibit an embryonic lethal phenotype (Stoller
et al., 2010). Work has established ASH2L as a
core component of the H3K4 methyltransferase
complexes MLL1-4 and SET1A and SET1B.
Furthermore, ASH2L containing methyltransferase
complexes are shown to be important for the
maintenance of HOX gene expression by binding to
HOX gene promoters and by adding H3K4 di- and
trimethylation (Fig. 1) (Hughes et al., 2004; Tan et
al., 2008; Yates et al., 2010). HOX gene expression
is important for proper development and
differentiation, and disruption in H3K4 methylation
leads to defects in HOX gene expression and the
development of cancer (Tan et al., 2008; Hess,
2006; Rampalli et al., 2007; MacConaill et al.,
2006; Hughes et al., 2004).
Biochemical data has shown that ASH2L is found
in a methyltransferase core complex composed of
ASH2L, RBBP5, DPY30, WDR5, and the catalytic
SET domain containing protein (Fig. 1). This core
complex is highly conserved and similar to the
budding yeast Set1 complex that consists of Set1
(MLL/SET1), Bre2 (ASH2L), Swd1 (RBBP5),
Swd3 (WDR5), Swd2 (WDR82), Sdc1 (DPY-30),
Spp1 (CFP1/CGBP). ASH2L is also known to
associate with numerous additional factors listed in
Table 1. Many of these additional factors are
thought to associate with ASH2L and the H3K4
methyltransferase complexes to target the complex
to specific sites within the genome (Stoller et al.,
2010; Cho et al., 2007; Steward et al., 2006; Dou et
al., 2006; Hughes et al., 2004).
Understanding the structure and function of ASH2L South PF, Briggs SD
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 984
Figure 1. ASH2L functions in a histone methyltransferase complex. The role of ASH2L within the MLL histone H3K4 methyltransferase complex. ASH2L interacts with RBBP5 and DPY-30 increasing the activity of the MLL complex. Histone H3K4 methylation in mammals peaks at the start sight of open reading frames and is important in active transcription. Knock-down of ASH2L in mammalian cells results in a decrease in H3K4 trimethylation and changes in gene expression.
ASH2L interacting protein Function
MLL1-4/ SET1 A and B Catalytic core; Histone methyltransferase (HMT)
RBBP5 Component of HMT complex
DPY-30 Component of HMT complex
WDR5 Component of HMT complex
CXXC1 Component of HMT complex
C16orf53/PA1 Glutamate rich coactivator
C17orf49 Unknown
CHD8 Chromatin remodeling factor
E2F6 Transcription factor
HCFC1 Host cell factor
IN080C Unknown
KDM6A H3K27 demethylase
KIAA1267 Unknown
LAS1L Unknown
MAX Transcription factor
MCRS1 Transcriptional repressor
MEN1 Tumor suppressor
MYST1/MOF Histone acetyltransferase
NCOA6 Transcriptional co-activator
PAXIP1/PTIP Transcription factor
PELP1 Transcription factor
PHF20 Unknown
PRP31 Component of spliceosome
RING2 E3-ligase
SENP3 Sumo-specific protease
TAF1, 4, 6, 7, 9 TATA-box binding proteins
TEX10 Unknown
TBX1 Transcription factor
Table 1.
Understanding the structure and function of ASH2L South PF, Briggs SD
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 985
ASH2L and Bre2 subunits are important for proper
histone methylation. Studies done in yeast show
that deletion of the ASH2L homolog BRE2 leads to
a complete loss of H3K4 trimethylation and
reductions in mono- and dimethylation (Dehé et al.,
2006; South et al., 2010; Roguev et al., 2001). In
addition, knock-down of ASH2L using siRNA
globally decreases H3K4 trimethylation (Steward et
al., 2006; Dou et al., 2006). These data suggest that
ASH2L may act in a similar manner to yeast Bre2.
From these studies it is clear that ASH2L is playing
an important role in histone methyltransferase
complexes in order to maintain proper H3K4
methylation and gene expression (Patel et al., 2009;
Roguev et al., 2001).
Alternative to ASH2L's function in H3K4
methylation ASH2L may also be playing a role in
endosomal trafficking (Xu et al., 2009). ASH2L,
DPY-30 and WDR5 were originally implicated in
endosomal trafficking when siRNA knock-down of
these genes increased the amount of internalized
CD8-CIMPR and overexpression increased the
amount of cells displaying a altered CIMPR
distribution (Xu et al., 2009). This affect was
limited to components of H3K4 methyltransferases
and not to other methyl marks such as lysine 9 (Xu
et al., 2009). The mechanism in which ASH2L and
other components of H3K4 methyltransferase
complexes modulate endosomal trafficking remains
unclear. However, two possible mechanisms have
been suggested, one is that the H3K4
methyltransferase components are part of an
unknown complex that regulates trafficking, or that
changes in H3K4 methylation lead to changes in
expression of another regulating factor (Xu et al.,
2009).
ASH2L structure One way to better understand the function of
ASH2L is to determine the role of specific domains
within ASH2L in facilitating H3K4 methylation.
There are three known isoforms of ASH2L (Wang
et al., 2001). Isoform 1 is considered the canonical
sequence and consists of 628 amino acids (Wang et
al., 2001). Isoform 2 is missing amino acids 1-94
and 541-573 from isoform 1 (Wang et al., 2001).
Isoform 3 is missing the amino acids 1-94 from
isoform 1 (Fig. 2) (Wang et al., 2001). There are
four identified domains within ASH2L which
include a N-terminus containing a PHD finger and a
winged helix motif (WH) and the C-terminus
containing a SPRY domain and a newly identified
Sdc1 DPY-30 Interacting domain (SDI) (Fig. 2)
(Wang et al., 2001; Roguev et al., 2001; South et
al., 2010; Sarvan et al., 2011; Chen et al., 2011).
Interestingly, the domains with known biological
function are the C-terminal SDI domain, which is
responsible for the interaction with another histone
methyltransferase component DPY-30 and the
winged helix motif which binds to DNA (South et
al., 2010; Sarvan et al., 2011; Chen et al., 2011).
The function of the SDI domain was determined
using in vitro binding experiments. ASH2L was
shown to directly interact with DPY-30 without any
additional MLL or Set1 complex components
(South et al., 2010). The function of the SDI
domain is conserved from yeast to humans because
the yeast ASH2L homolog Bre2 was also shown to
interact with the DPY-30 homolog Sdc1 (South et
al., 2010). There are conserved hydrophobic
residues in both the SDI domain of ASH2L and the
Dpy-30 domain of DPY-30 that are important for
binding, which suggests that the interaction
between the SDI domain of ASH2L and the DPY-
30 domain of DPY-30 is through hydrophobic
interactions (South et al., 2010). In addition,
binding affinities between ASH2L and DPY-30, as
well as ASH2L and RBBP5 have been determined
by sedimentation velocity analytical
ultracentrifugation showing dissociation constants
of 0.1 μM and 0.75 μM respectively (Patel et al.,
2009). Interestingly, in yeast the ASH2L homolog
Bre2 must interact with Sdc1 through the SDI
domain to interact with the yeast Set1 histone
methyltransferase complex (South et al., 2010). In
contrast, in vitro experiments have shown ASH2L
does not require DPY-30 to interact with MLL
complex. To better understand how ASH2L
interacts with MLL, in vivo studies must be done to
determine if DPY-30 is required for ASH2L
interaction. However, it is quite possible that the
yeast and human complexes assemble differently.
Figure 2. ASH2L has three known isoforms. Schematic model of the three known isoforms of ASH2L and the amino acid
sequence changes compared to the canonical isoform 1 (aa 1-628). The positions of known domains within ASH2L are displayed. PHD finger (aa 95-161), WH motif (aa 162-273), SPRY domain (aa 360-583), and SDI domain (aa 602-628). Isoform
2 and 3 are numbered according to isoform 1.
Understanding the structure and function of ASH2L South PF, Briggs SD
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 986
The N-terminal winged helix (WH) motif was
recently discovered when the crystal structure of the
N-terminus of ASH2L was solved (Sarvan et al.,
2011; Chen et al., 2011). Using in vitro DNA
binding analyses as well as chromatin
immunoprecipitation, it was determined that
ASH2L can bind DNA at the HS2 promoter region
and the β-globin locus as well as non-specific DNA
sequence (Sarvan et al., 2011; Chen et al., 2011).
The DNA binding activity of ASH2L promotes
H3K4 methylation and gene expression at the β-
globin locus by 50% when overexpressed in a cell
line where ASH2L is knocked-down by siRNA
(Sarvan et al., 2011). In addition, chromatin
immunoprecipitation followed by a tiling array
(ChIP-chip) analysis shows that disruption of the
winged helix motif causes mis-localization of
ASH2L (Chen et al., 2011). It was also shown that
the DNA binding activity of the N-terminus of
ASH2L increases when the C-terminal SPRY and
SDI domains are present (Chen et al., 2011).
Altogether, these data suggests that multiple
domains in ASH2L may contribute to its ability to
bind chromatin. However, more work will be
needed to clearly establish the function of each
domain.
The largest of the three identified domains within
ASH2L is the SPRY domain, which is also
conserved from yeast to humans. SPRY domains
were originally named after the SPIa kinase and the
RYanodine receptor proteins in which it was first
identified (Rhodes et al., 2005). Multiple crystal
structures have been solved for proteins that contain
an SPRY domain. Crystal structures of SPRY
domain containing proteins show primarily a β-
sandwich structure with extending loops (Woo et
al., 2006b; Kuang et al., 2009; Filippakopoulos et
al., 2010; Simonet et al., 2007). The SPRY domain
is thought to be a specific protein-protein
interaction domain with specific partners, but
instead of recognizing a particular motif or
interaction domain the SPRY domain binds to
interaction partners using non-conserved binding
loops (Filippakopoulos et al., 2010; Woo et al.,
2006b; Woo et al., 2006a). SPRY domain-
containing proteins are involved in a wide array of
functions including RNA metabolism, calcium
release, and developmental processes (Woo et al.,
2006b; Kuang et al., 2009; Filippakopoulos et al.,
2010; Simonet et al., 2007; Woo et al., 2006a).
Recent work has shown that the C-terminus of
ASH2L that contains the SPRY domain and the
SDI domain are able to interact with the other MLL
complex member RBBP5 in vitro (Avdic et al.,
2011). This interaction is most likely through the
SPRY domain and not the SDI domain, though
further work would need to be done to better map
this interaction.
ASH2L also contains a putative Plant Homeo
Domain (PHD) finger in its N-terminus (Wang et
al., 2001). PHD fingers are a family of zinc finger
domains that are known to bind to both modified
and unmodified histone tails (Bienz, 2006; Mellor,
2006). The structure of PHD fingers shows that
conserved cysteine and histidine residues bind to
Zn2+
ions (Champagne et al., 2008; van Ingen et al.,
2008; Champagne and Kutateladze, 2009). PHD
fingers generally form a globular fold, consisting of
a two-stranded beta-sheet and an alpha-helix. Loop
regions of PHD fingers tend to vary giving rise to
specificity of the domain. Some PHD fingers are
considered to be readers of epigenetic marks by
binding to specific modifications or sites on
histones to stabilize or localize an interaction
(Mellor, 2006). Primarily, PHD fingers have been
shown to interact with trimethylated histone
residues such as trimethylated histone H3 lysine 4
and lysine 9 (Mellor, 2006). There is no known
function attributed to the PHD finger in ASH2L,
though in conjunction with the winged helix motif
it may be necessary for DNA binding. However, the
PHD finger may also be needed in binding to MLL,
other MLL/SET1 components, or recognizing a
specific histone modification or for binding to a
histone tail. Additional studies are needed to
determine how the PHD finger of ASH2L and the
SPRY domain may help the MLL and Set1
methyltransferase complexes interact and catalyze
H3K4 methylation.
Conclusion Currently, relatively little is known about the
contribution of ASH2L to facilitate and or regulate
the degree of methylation along the eukaryotic
genome, but disruption of ASH2L and H3K4
methylation both appear to play a key role in
oncogenesis (Lüscher-Firzlaff et al., 2008; Hess,
2006). Interestingly, recent work has suggested that
ASH2L in combination with WDR5 and RBBP5
exhibits H3K4 methyltransferase activity (Cao et
al., 2010; Patel et al., 2009; Patel et al., 2011). In
addition, this catalytic activity is not dependent on
the SET domain containing proteins such as MLL1
(Patel et al., 2009; Cao et al., 2010; Patel et al.,
2011). One report shows the catalytic activity of the
ASH2L, WDR5, RBBP5, DPY-30 complex in an in
vitro histone methyltransferase assay is observed
but only after eight hours of incubation (Patel et al.,
2009; Patel et al., 2011). In contrast, more
methyltransferase activity and much shorter
incubation times are required when these
components are incubated with the MLL1 SET
domain containing methyltransferase (Patel et al.,
2009; Patel et al., 2011). This indicates the sub-
complex has poor catalytic activity when the main
catalytic SET domain-containing subunit is not
present in the reaction. However, Cao et al. shows
that only ASH2L/RBBP5 heterodimer is needed for
weak H3K4 methyltransferase activity (Cao et al.,
2010). Because ASH2L, WDR5, RBBP5, and
Understanding the structure and function of ASH2L South PF, Briggs SD
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 987
DPY-30 complex does not contain a known
methyltransferase domain, more work needs to be
done to determine if a new class of
methyltransferase has been identified and whether
or not this methyltransferase activity is biologically
relevant.
ASH2L is found to be over abundant in many
cancer cell lines and knock-down of ASH2L by
siRNA can prevent tumorigenesis (Lüscher-Firzlaff
et al., 2008). ASH2L is important for proper H3K4
methylation but how ASH2L contributes to the
distribution and degree of methylation and its role
in gene expression remains unclear. To better
understand the role of ASH2L in methylation and
gene expression several questions need to be
addressed. What is the mechanism of interaction
that contributes to ASH2L's interaction with histone
methyltransferase complexes? What is ASH2L's
role in regulating the degree of methylation along
genes and what genes are affected by changes in
ASH2L? Additional structural studies will help
address the mechanism of how ASH2L interacts
with other methyltransferase complex members and
microarray experiments will be needed to determine
the genes that are affected by changes in ASH2L
expression levels. Addressing these questions could
provide valuable information for the development
specific inhibitors for the treatment of various
cancers.
References LaJeunesse D, Shearn A. Trans-regulation of thoracic homeotic selector genes of the Antennapedia and bithorax complexes by the trithorax group genes: absent, small, and homeotic discs 1 and 2. Mech Dev. 1995 Sep;53(1):123-39
Ikegawa S, Isomura M, Koshizuka Y, Nakamura Y. Cloning and characterization of ASH2L and Ash2l, human and mouse homologs of the Drosophila ash2 gene. Cytogenet Cell Genet. 1999;84(3-4):167-72
Roguev A, Schaft D, Shevchenko A, Pijnappel WW, Wilm M, Aasland R, Stewart AF. The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4. EMBO J. 2001 Dec 17;20(24):7137-48
Wang J, Zhou Y, Yin B, Du G, Huang X, Li G, Shen Y, Yuan J, Qiang B. ASH2L: alternative splicing and downregulation during induced megakaryocytic differentiation of multipotential leukemia cell lines. J Mol Med (Berl). 2001 Jul;79(7):399-405
Hess JL.. MLL: Deep Insight. Atlas Genet Cytogenet Oncol Haematol. August 2003 .
Hughes CM, Rozenblatt-Rosen O, Milne TA, Copeland TD, Levine SS, Lee JC, Hayes DN, Shanmugam KS, Bhattacharjee A, Biondi CA, Kay GF, Hayward NK, Hess JL, Meyerson M.. Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell. 2004 Feb 27;13(4):587-97.
Rhodes DA, de Bono B, Trowsdale J.. Relationship between SPRY and B30.2 protein domains. Evolution of a component of immune defence? Immunology. 2005 Dec;116(4):411-7. (REVIEW)
Bienz M.. The PHD finger, a nuclear protein-interaction domain. Trends Biochem Sci. 2006 Jan;31(1):35-40. Epub 2005 Nov 16. (REVIEW)
Dehe PM, Dichtl B, Schaft D, Roguev A, Pamblanco M, Lebrun R, Rodriguez-Gil A, Mkandawire M, Landsberg K, Shevchenko A, Shevchenko A, Rosaleny LE, Tordera V, Chavez S, Stewart AF, Geli V.. Protein interactions within the Set1 complex and their roles in the regulation of histone 3 lysine 4 methylation. J Biol Chem. 2006 Nov 17;281(46):35404-12. Epub 2006 Aug 18.
Dou Y, Milne TA, Ruthenburg AJ, Lee S, Lee JW, Verdine GL, Allis CD, Roeder RG.. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat Struct Mol Biol. 2006 Aug;13(8):713-9. Epub 2006 Jul 30.
MacConaill LE, Hughes CM, Rozenblatt-Rosen O, Nannepaga S, Meyerson M.. Phosphorylation of the menin tumor suppressor protein on serine 543 and serine 583. Mol Cancer Res. 2006 Oct;4(10):793-801.
Mellor J.. It takes a PHD to read the histone code. Cell. 2006 Jul 14;126(1):22-4. (REVIEW)
Steward MM, Lee JS, O'Donovan A, Wyatt M, Bernstein BE, Shilatifard A.. Molecular regulation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes. Nat Struct Mol Biol. 2006 Sep;13(9):852-4. Epub 2006 Aug 6.
Woo JS, Imm JH, Min CK, Kim KJ, Cha SS, Oh BH.. Structural and functional insights into the B30.2/SPRY domain. EMBO J. 2006a Mar 22;25(6):1353-63. Epub 2006 Feb 23.
Woo JS, Suh HY, Park SY, Oh BH.. Structural basis for protein recognition by B30.2/SPRY domains. Mol Cell. 2006b Dec 28;24(6):967-76.
Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski T, Dressler GR, Copeland TD, Kalkum M, Ge K.. PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. J Biol Chem. 2007 Jul 13;282(28):20395-406. Epub 2007 May 11.
Rampalli S, Li L, Mak E, Ge K, Brand M, Tapscott SJ, Dilworth FJ.. p38 MAPK signaling regulates recruitment of Ash2L-containing methyltransferase complexes to specific genes during differentiation. Nat Struct Mol Biol. 2007 Dec;14(12):1150-6. Epub 2007 Nov 18.
Simonet T, Dulermo R, Schott S, Palladino F.. Antagonistic functions of SET-2/SET1 and HPL/HP1 proteins in C. elegans development. Dev Biol. 2007 Dec 1;312(1):367-83. Epub 2007 Oct 29.
Champagne KS, Saksouk N, Pena PV, Johnson K, Ullah M, Yang XJ, Cote J, Kutateladze TG.. The crystal structure of the ING5 PHD finger in complex with an H3K4me3 histone peptide. Proteins. 2008 Sep;72(4):1371-6.
Luscher-Firzlaff J, Gawlista I, Vervoorts J, Kapelle K, Braunschweig T, Walsemann G, Rodgarkia-Schamberger C, Schuchlautz H, Dreschers S, Kremmer E, Lilischkis R, Cerni C, Wellmann A, Luscher B.. The human trithorax protein hASH2 functions as an oncoprotein. Cancer Res. 2008 Feb 1;68(3):749-58.
Tan CC, Sindhu KV, Li S, Nishio H, Stoller JZ, Oishi K, Puttreddy S, Lee TJ, Epstein JA, Walsh MJ, Gelb BD.. Transcription factor Ap2delta associates with Ash2l and ALR, a trithorax family histone methyltransferase, to activate Hoxc8 transcription. Proc Natl Acad Sci U S A. 2008 May 27;105(21):7472-7. Epub 2008 May 21.
van Ingen H, van Schaik FM, Wienk H, Ballering J, Rehmann H, Dechesne AC, Kruijzer JA, Liskamp RM, Timmers HT, Boelens R.. Structural insight into the
Understanding the structure and function of ASH2L South PF, Briggs SD
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 988
recognition of the H3K4me3 mark by the TFIID subunit TAF3. Structure. 2008 Aug 6;16(8):1245-56.
Champagne KS, Kutateladze TG.. Structural insight into histone recognition by the ING PHD fingers. Curr Drug Targets. 2009 May;10(5):432-41. (REVIEW)
Kuang Z, Yao S, Xu Y, Lewis RS, Low A, Masters SL, Willson TA, Kolesnik TB, Nicholson SE, Garrett TJ, Norton RS.. SPRY domain-containing SOCS box protein 2: crystal structure and residues critical for protein binding. J Mol Biol. 2009 Feb 27;386(3):662-74. Epub 2009 Jan 6.
Patel A, Dharmarajan V, Vought VE, Cosgrove MS.. On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. 2009 Sep 4;284(36):24242-56. Epub 2009 Jun 25.
Xu Z, Gong Q, Xia B, Groves B, Zimmermann M, Mugler C, Mu D, Matsumoto B, Seaman M, Ma D.. A role of histone H3 lysine 4 methyltransferase components in endosomal trafficking. J Cell Biol. 2009 Aug 10;186(3):343-53. Epub 2009 Aug 3.
Cao F, Chen Y, Cierpicki T, Liu Y, Basrur V, Lei M, Dou Y.. An Ash2L/RbBP5 heterodimer stimulates the MLL1 methyltransferase activity through coordinated substrate interactions with the MLL1 SET domain. PLoS One. 2010 Nov 23;5(11):e14102.
Filippakopoulos P, Low A, Sharpe TD, Uppenberg J, Yao S, Kuang Z, Savitsky P, Lewis RS, Nicholson SE, Norton RS, Bullock AN.. Structural basis for Par-4 recognition by the SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4. J Mol Biol. 2010 Aug 20;401(3):389-402. Epub 2010 Jun 16.
South PF, Fingerman IM, Mersman DP, Du HN, Briggs SD.. A conserved interaction between the SDI domain of Bre2 and the Dpy-30 domain of Sdc1 is required for histone methylation and gene expression. J Biol Chem. 2010 Jan 1;285(1):595-607. Epub 2009 Nov 6.
Stoller JZ, Huang L, Tan CC, Huang F, Zhou DD, Yang J, Gelb BD, Epstein JA.. Ash2l interacts with Tbx1 and is required during early embryogenesis. Exp Biol Med (Maywood). 2010 May;235(5):569-76.
Yates JA, Menon T, Thompson BA, Bochar DA.. Regulation of HOXA2 gene expression by the ATP-dependent chromatin remodeling enzyme CHD8. FEBS Lett. 2010 Feb 19;584(4):689-93. Epub 2010 Jan 17.
Avdic V, Zhang P, Lanouette S, Groulx A, Tremblay V, Brunzelle J, Couture JF.. Structural and biochemical insights into MLL1 core complex assembly. Structure. 2011 Jan 12;19(1):101-8.
Chen Y, Wan B, Wang KC, Cao F, Yang Y, Protacio A, Dou Y, Chang HY, Lei M.. Crystal structure of the N-terminal region of human Ash2L shows a winged-helix motif involved in DNA binding. EMBO Rep. 2011 Jun 10;12(8):797-803. doi: 10.1038/embor.2011.101.
Patel A, Vought VE, Dharmarajan V, Cosgrove MS.. A novel non-SET domain multi-subunit methyltransferase required for sequential nucleosomal histone H3 methylation by the mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. 2011 Feb 4;286(5):3359-69. Epub 2010 Nov 24.
Sarvan S, Avdic V, Tremblay V, Chaturvedi CP, Zhang P, Lanouette S, Blais A, Brunzelle JS, Brand M, Couture JF.. Crystal structure of the trithorax group protein ASH2L reveals a forkhead-like DNA binding domain. Nat Struct Mol Biol. 2011 Jun 5;18(7):857-9. doi: 10.1038/nsmb.2093.
This article should be referenced as such:
South PF, Briggs SD. Understanding the structure and function of ASH2L. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11):983-988.
Case Report Section Paper co-edited with the European LeukemiaNet
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(10) 989
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
A new case of t(4;12)(q12;p13) in a secondary acute myeloid leukemia with review of literature Sarah M Heaton, Frederick Koppitch, Anwar N Mohamed
Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine, Detroit
Medical Center, Detroit MI, USA (SMH, FK, ANM)
Published in Atlas Database: March 2011
Online updated version : http://AtlasGeneticsOncology.org/Reports/t0412HeatonID100051.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI t0412HeatonID100051.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics
Age and sex
57 years old male patient.
Previous history
No preleukemia. Previous malignancy Hodgkin's
Lymphoma, stage IVA at age 25 year, treated with
ABVD for 12 months. Tumor mass in the upper
cervical spine diagnosed at age 27 year, treated with
laminectomy and five doses of radiation. No inborn
condition of note.
Organomegaly
No hepatomegaly, no splenomegaly, no enlarged
lymph nodes, no central nervous system
involvement.
Blood WBC : 0.8X 10
9/l
HB : 9.7g/dl
Platelets : 21.0X 109/l
Blasts : 18%
Bone marrow : Variably cellular with 20%
myeloblasts and dysplastic changes in the erythroid
and myeloid cell lines.
Cyto-Pathology Classification
Cytology
His bone marrow showed 60% blasts, and
dysplastic changes were noted in the erythroid and
myeloid cell lines.
Immunophenotype
Flow cytometry (FCM) revealed that the blasts
were of myeloid lineage expressing CD13, CD33,
CD34, CD117, HLA-DR, and CD56.
Diagnosis
Acute myeloid leukemia (AML) with dysplastic
changes.
Survival
Date of diagnosis: 08-2007
Treatment
He was treated with Idarubicin+Ara-c (3+7)
regimen. Because of 15% residual blasts in bone
marrow, patient received additional 2+5 therapy,
and then he underwent consolidation with Ara-C.
Result of karyotype: 46,XY[20]. On April 2008, the
patient received a matched unrelated female donor
stem cell transplant (SCT). 30 days post transplant;
bone marrow revealed no morphological evidence
of leukemia and the karyotype was 46,XX[20]. On
June 2008; patient developed pancytopenia; WBC:
2.2 x 109/l; Hb: 11.6 g/dl; platelets: 18.0 x 10
3/l. His
bone marrow showed an increased dysplastic
changes and <5% blasts, suggestive of possible
early relapse. The karyotype became abnormal (see
below). On June 2010; bone marrow was
hypocellular with 20% blasts and dysplastic
changes in the erythroid and myeloid lineages.
FCM revealed myeloblasts expressing CD4, CD7,
CD33, CD34, CD56, CD117 and HLA-DR.
myeloperoxidase was negative. Non-specific
esterase was positive in occasional blasts.
Cytology: AML possibly of monocytic origin
(AML-M5).
Treatment related death : no
A new case of t(4;12)(q12;p13) in a secondary acute myeloid leukemia with review of literature
Heaton SM, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(10) 990
Figure 1. G-banded karyotype showing the balanced t(4;12)(q12;p13) translocation.
Figure 2. FISH on abnormal metaphases; (A) Metaphase hybridized with LSI 4q12 tricolor DNA probe showed a translocation of
PDGFRA (SA) to derivative chromosome 12 (arrow), with the dual fusion of spectrunOrange (SO) and spectrunGreen (SG) remained on derivative 4. (B) Metaphase hybridized with LSI ETV6/RUNX1 ES dual color probe revealed a split of ETV6 (SG)
with the smaller signal being translcated to derivative 4 (arrows). (C) Metaphase hybridized with both LSI 4q12 and ETV6/RUNX1 probes showed PDGFRA (SA) translocted to derivative 12 adjacent to ETV6 locus (arrows).
Phenotype at relapse: M5-AML
Status: Alive. Last follow up: 06-2010.
Survival: 24 months
Karyotype
Sample: Bone marrow
Culture time: 24 and 48h with 10% conditioned
medium
Banding: GTG
Results
46,XY,t(4;12)(q12;p13)[6]/46,XX[14] in June 2008
(post transplant)
Karyotype at Relapse
46,XY,t(4;12)(q12;p13)[12]/
46,idem,del(7)(q22q36)[4]/ 47,idem,+19[2]/
46,XX[2], consistent with the recurrence and clonal
evolution of the leukemic clone.
Other molecular cytogenetics technics
Fluorescence in situ hybridization (FISH) using LSI
4q12 tricolor and LSI ETV6/RUNX1 ES dual color
DNA probes were performed (Abbott Molecular.
Downers Grove, IL) on the abnormal metaphase
cells.
Other molecular cytogenetics results
Translocation of the PDGFRA gene in Toto,
spectrunAqua (SA), to derivative 12 and
colocalized with centromeric region of ETV6;
Break within ETV6 gene locus, sepctrunGreen
(SG) and the telomeric region of ETV6 translocated
to derivative 4 (Figure 2 A-C).
Comments Acute leukemia with t(4;12)(q11-q12;p13) is a rare,
nonrandom event with an estimated incidence of
0.6% among adults according to Harada et al.
(Harada et al., 1997). This translocation is seen
mostly in adult AML but less frequent in pediatric
ALL (Hamaguchi et al., 1999). A review of the
literature revealed at least twenty-two additional
cases with a t(4;12)(q11-q12;p13); eighteen adults
and four children. The male to female ratio is 1.5:1
(1.7:1 in adults and 1:1 in children). The majority
of patients are adults, aged 18 to 82 with the mean
being 58.9 years old (Harada et al., 1995; Harada et
al., 1997; Ma et al., 1997; Cools et al., 1999;
Hamaguchi et al., 1999; Chaufaille et al., 2003;
Manabe et al., 2010). Four children have been
reported, aged 3-14 years old, of which three had
ALL and the oldest had AML (Harada et al., 1997).
Among the 23 cases including our case with t(4;12)
leukemia; 19 had AML; 3 ALL, and one
unclassified leukemia. Common features to t(4;12)
AML include dysplasia of three hematopoietic
lineages (erythroid, myeloid and megakaryocytic),
low or absent myeloperoxidase activity, basophilia
and a pseudo-lymphoid morphology. The surface
markers of the blasts show positivity for CD7,
CD13, CD33, CD34 and HLA DR, suggesting that
the leukemic cells have an immature myeloid stem
A new case of t(4;12)(q12;p13) in a secondary acute myeloid leukemia with review of literature
Heaton SM, et al.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 991
cell origin (Harada et al., 1995; Ma et al., 1997;
Hamaguchi et al., 1999). Of the reported t(4;12)
AML cases; seven were characterized as AML-M0
and four AML-M1. Previous reports suggest that
less than 50% of cases achieve remission with
intensive induction chemotherapy. Of the patients
who do not achieve morphologic remission, none
survived beyond six months (Hamaguchi et al.,
1999; Chaufaille et al., 2003; Manabe et al., 2010).
The breakpoint at 12p13 in t(4;12) AML is located
within or near the ETV6 gene locus. The ETV6
gene has been implicated in both myeloid and
lymphoid malignancies (Wlodarska et al., 1998).
ETV6 belongs to the ETS family of transcription
factors and has two important domains: HLH and
an ETS DNA binding domain. Cools et al, found
the t(4;12) caused the ETV6 gene recombined to
CHIC2 (formerly BLT) (Cools et al., 1999). A
number of genes have been mapped to the band
4q12 including mac25, PDGFRA, AFP, and a beta-
sarcoglycan gene (Hamaguchi et al., 1999).
The case reported here shared some features to
those reported in the literature including positivity
for CD7, CD33, CD34, CD117 and HLA-DR, lack
of myeloperoxidase activity and dysplastic bone
marrow. Unlike other reported cases, bone marrow
basophilia and high platelets were not found.
Clearly in our case, FISH showed a break within
ETV6/12p13 gene, and colocalization of PDGFR1
gene to derivative 12 next to 5’ ETV6 region.
References Harada H, Asou H, Kyo T, Asaoku H, Iwato K, Dohy H, Oda K, Harada Y, Kita K, Kamada N. A specific chromosome abnormality of t(4;12)(q11-12;p13) in CD7+ acute leukaemia. Br J Haematol. 1995 Aug;90(4):850-4
Harada H, Harada Y, Eguchi M, Dohy H, Kamada N. Characterization of acute leukemia with t(4;12). Leuk Lymphoma. 1997 Mar;25(1-2):47-53
Ma SK, Lie AK, Au WY, Wan TS, Chan LC. CD7+ acute myeloid leukaemia with 'mature lymphoid' blast morphology, marrow basophilia and t(4;12)(q12;p13) Br J Haematol. 1997 Dec;99(4):978-80
Wlodarska I, La Starza R, Baens M, Dierlamm J, Uyttebroeck A, Selleslag D, Francine A, Mecucci C, Hagemeijer A, Van den Berghe H, Marynen P. Fluorescence in situ hybridization characterization of new translocations involving TEL (ETV6) in a wide spectrum of hematologic malignancies. Blood. 1998 Feb 15;91(4):1399-406
Cools J, Bilhou-Nabera C, Wlodarska I, Cabrol C, Talmant P, Bernard P, Hagemeijer A, Marynen P. Fusion of a novel gene, BTL, to ETV6 in acute myeloid leukemias with a t(4;12)(q11-q12;p13). Blood. 1999 Sep 1;94(5):1820-4
Hamaguchi H, Nagata K, Yamamoto K, Kobayashi M, Takashima T, Taniwaki M. A new translocation, t(2;4;12)(p21;q12;p13), in CD7-positive acute myeloid leukemia: a variant form of t(4;12). Cancer Genet Cytogenet. 1999 Oct 15;114(2):96-9
Chauffaille Mde L, Fermino FA, Pelloso LA, Silva MR, Bordin JO, Yamamoto M. t(4;12)(q11;p13): a rare chromosomal translocation in acute myeloid leukemia. Leuk Res. 2003 Apr;27(4):363-6
Manabe M, Nakamura K, Inaba A, Fujitani Y, Kosaka S, Yamamura R, Inoue A, Hino M, Senzaki H, Ohta K. A rare t(4;12)(q12;p13) in an adolescent patient with acute myeloid leukemia. Cancer Genet Cytogenet. 2010 Jul 1;200(1):70-2
This article should be referenced as such:
Heaton SM, Koppitch F, Mohamed AN. A new case of t(4;12)(q12;p13) in a secondary acute myeloid leukemia with review of literature. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(10):989-991.
Case Report Section Paper co-edited with the European LeukemiaNet
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(10) 992
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myelodysplastic syndrome: Case 0002M Kavita S Reddy
Kaiser Permanente Southern California, 4580 ElectronicPlace, Los Angeles, CA 90039, USA (KSR)
Published in Atlas Database: March 2011
Online updated version : http://AtlasGeneticsOncology.org/Reports/der918Case2ReddyID100053.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI der918Case2ReddyID100053.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics
Age and sex
85 years old male patient.
Previous history
Preleukemia. Previous malignancy Bladder cancer,
status post removal and BCG treatment. No inborn
condition of note.
Organomegaly
No hepatomegaly, no splenomegaly, no enlarged
lymph nodes, no central nervous system
involvement.
Blood WBC : 1.9X 10
9/l
HB : 10.9g/dl
Platelets : 57X 109/l
Cyto-Pathology Classification
Cytology
MDS (normocellular marrow with
dysmegakaryopoiesis and dysgranulopoiesis;
consistent with myelodysplastic syndrome)
Immunophenotype: NA
Rearranged Ig Tcr: NA
Diagnosis: MDS
Survival
Date of diagnosis: 03-2005
Treatment: not on any treatment
Complete remission : None
Treatment related death : NA
Relapse : no
Phenotype at relapse: NA
Status: Alive. Last follow up: 12-2010
Survival: 66 months.
Karyotype
Sample: 3/2005 BM, 6/2007 BM and 12/2010 BM
Culture time : 24 and 72 hours with overnight
Colcemid
Banding: GTW at 400 bands
Results
3/2005 BM 45,X,-Y[5]/46,XY,+9,
der(9;18)(p10;q10)[11]/46,XY[4];
6/2007 BM 45,X,-Y[5][4]/46,XY[16];
12/2010 BM 46,XY,+9,
der(9;18)(p10;q10)[15]/46,XY[5]
Karyotype at Relapse: NA
Other molecular cytogenetics technics: None
Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myelodysplastic syndrome. Case 0002M.
Reddy KS
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 993
Case 0002M : two partial karyotypes with a normal
chromosome 9 pair, a der(9;18)and a normal chromosome 18 and arrow)
Comments Both the cases described in this study were
followed for >5 years. Case 0001M, had
thrombocytosis and could not tolerate Interferon or
Hydrea treatment and hence was treated with
Busulfan. The patient was positive for JAK2
mutation (on chromosome 9). A recent study was to
rule out transformation of MPN as there was
myelofibrosis, splenomegaly and apparent
progression of the disease. The der(9;18) was first
identified in the stem line and a sideline had partial
deletion of chromosome 13q. Case 0002M was a
MDS case with a der(9;18) detected in the initial
study and again when the patient was suspected to
be transforming >5 years later. This patient had
very little symptoms and was not treated.
In this report for the first time a long standing MDS
case was found to have the der(9;18) at initial
diagnosis and after over 5 years . Others reported
with der(9;18)(n 7) had PV (n 3) or post PV
myelofibrosis (n 4) and one had sAML after ET.
The JAK2V617F is a gain in function mutation on
chromosome 9. Hence, the extra copy of 9p may
exacerbate the MPN as observed in 0001M case.
The patient had splenomegaly and also
myelofibrosis when the patient was found with the
der(9;18). Der(9;18) is the sole abnormality in most
reported cases, balanced translocations or complex
aberrant karyotypes were reported as additional
abnormalities. Our patient had del(13) in a sideline
and this abnormality is observed in MPN. Among
the 9 patients with der(9;18) two arose post
treatment (present case 0001M and Andrieux et al
2003). and the other were at diagnosis.
The der(9;18) supports progression of the disease in
case 0001M but in case 0002M with MDS it
reappears when there is suspicion of transformation
and its role is less uncertain.
References Chen Z, Notohamiprodjo M, Guan XY, Paietta E, Blackwell S, Stout K, Turner A, Richkind K, Trent JM, Lamb A, Sandberg AA. Gain of 9p in the pathogenesis of polycythemia vera. Genes Chromosomes Cancer. 1998 Aug;22(4):321-4
Andrieux J, Demory JL, Caulier MT, Agape P, Wetterwald M, Bauters F, Laï JL. Karyotypic abnormalities in myelofibrosis following polycythemia vera. Cancer Genet Cytogenet. 2003 Jan 15;140(2):118-23
Bacher U, Haferlach T, Schoch C. Gain of 9p due to an unbalanced rearrangement der(9;18): a recurrent clonal abnormality in chronic myeloproliferative disorders. Cancer Genet Cytogenet. 2005 Jul 15;160(2):179-83
Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005 Apr 28;352(17):1779-90
Xu X, Chen X, Rauch EA, Johnson EB, Thompson KJ, Laffin JJS, Raca G, Kurtycz DF.. Unbalanced rearrangement der(9;18)(p10;q10) in a patient with polycythemia vera. Atlas Genet Cytogenet Oncol Haematol. April 2010. URL : http://AtlasGeneticsOncology.org/Reports/der0918XuID100044.html
This article should be referenced as such:
Reddy KS. Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myelodysplastic syndrome. Case 0002M.. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(10):992-993.
Case Report Section Paper co-edited with the European LeukemiaNet
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(10) 994
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myeloproliferative neoplasm: Case 0001M Kavita S Reddy
Kaiser Permanente Southern California, 4580 ElectronicPlace, Los Angeles, CA 90039, USA (KSR)
Published in Atlas Database: March 2011
Online updated version : http://AtlasGeneticsOncology.org/Reports/der918Case1ReddyID100052.html Printable original version : http://documents.irevues.inist.fr/bitstream/DOI der918Case1ReddyID100052.txt This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics
Age and sex
71 years old male patient.
Previous history
Preleukemia. No previous malignancy. No inborn
condition of note.
Organomegaly
No hepatomegaly, splenomegaly (Spleen appears
enlarged measures 15.8 cm in length), no enlarged
lymph nodes, no central nervous system
involvement.
Blood WBC : 112.7X 10
9/l
HB : 13.3g/dl
Platelets : 42X 109/l
Cyto-Pathology Classification
Cytology
MPN (near 100% cellular marrow with
granulocytic and megakaryocytic hyperplasia
consistent with chronic myeloproliferative
neoplasm).
Immunophenotype: NA
Rearranged Ig Tcr: NA
Diagnosis: CMPN
Survival
Date of diagnosis: 10-2004
Treatment: Could tolerate Interferon or Hydrea
and is on regulated dose of Busulfan.
Complete remission : None
Treatment related death : NA
Relapse : no
Phenotype at relapse: NA
Status: Alive. Last follow up: 12-2010.
Survival: 74 months
Karyotype
Sample: 10/2004 BM, 6/2007 PB and 12/2010 BM
Culture time: 24 and 72 hours with overnight
Colcemid
Banding: GTW at 400 bands
Results
10/2004 BM 46,XY[20];
6/2007 PB 46,XY[10];
12/2010 BM 46,XY,+9,der(9;18)(p10;q10)
[8]/46,sl,del(13)(q12q14)[cp6]/46,XY[6]
Karyotype at Relapse: NA
Other molecular cytogenetics technics: None
Other Molecular Studies
Technics: PCR
Results: JAK2V617F mutation
Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myeloproliferative neoplasm. Case 0001M.
Reddy KS
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(11) 995
Case 0001M : two partial karyotypes of the stemline (row1-
2) with 2 normal chromosomes 9 a der(9;18), 13 pairs, a one normal chromosome 18 and arrow). Two partial
karyotpes of the sideline (row 3-4) with a normal chromosome 9 pair, a der(9;18), a normal chromosome 13
and a deleted 13 (arrow) and a normal 18 (arrow).
Comments
Both the cases described in this study were
followed for > 5 years. Case 0001M, had
thrombocytosis and could not tolerate Interferon or
Hydrea treatment and hence was treated with
Busulfan. The patient was positive for JAK2
mutation (on chromosome 9). A recent study was to
rule out transformation of MPN as there was
myelofibrosis, splenomegaly and apparent
progression of the disease. The der(9;18) was first
identified in the stem line and a sideline had partial
deletion of chromosome 13q. Case 0002M was a
MDS case with a der(9;18) detected in the initial
study and again when the patient was suspected to
be transforming > 5 years later. This patient had
very little symptoms and was not treated.
In this report for the first time a long standing MDS
case was found to have the der(9;18) at initial
diagnosis and after over 5 years . Others reported
with der(9;18)(n 7) had PV (n 3) or post PV
myelofibrosis (n 4) and one had sAML after ET.
The JAK2V617F is a gain in function mutation on
chromosome 9. Hence, the extra copy of 9p may
exacerbate the MPN as observed in 0001M case.
The patient had splenomegaly and also
myelofibrosis when the patient was found with the
der(9;18). Der(9;18) is the sole abnormality in most
reported cases, balanced translocations or complex
aberrant karyotypes were reported as additional
abnormalities. Our patient had del(13) in a sideline
and this abnormality is observed in MPN. Among
the 9 patients with der(9;18) two arose post
treatment (present case 0001M and Andrieux et al
2003). and the other were at diagnosis.
The der(9;18) supports progression of the disease in
case 0001M but in case 0002M with MDS it
reappears when there is suspicion of transformation
and its role is less uncertain.
References Chen Z, Notohamiprodjo M, Guan XY, Paietta E, Blackwell S, Stout K, Turner A, Richkind K, Trent JM, Lamb A, Sandberg AA. Gain of 9p in the pathogenesis of polycythemia vera. Genes Chromosomes Cancer. 1998 Aug;22(4):321-4
Andrieux J, Demory JL, Caulier MT, Agape P, Wetterwald M, Bauters F, Laï JL. Karyotypic abnormalities in myelofibrosis following polycythemia vera. Cancer Genet Cytogenet. 2003 Jan 15;140(2):118-23
Bacher U, Haferlach T, Schoch C. Gain of 9p due to an unbalanced rearrangement der(9;18): a recurrent clonal abnormality in chronic myeloproliferative disorders. Cancer Genet Cytogenet. 2005 Jul 15;160(2):179-83
Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005 Apr 28;352(17):1779-90
Xu X, Chen X, Rauch EA, Johnson EB, Thompson KJ, Laffin JJS, Raca G, Kurtycz DF.. Unbalanced rearrangement der(9;18)(p10;q10) in a patient with polycythemia vera. Atlas Genet Cytogenet Oncol Haematol. April 2010. URL : http://AtlasGeneticsOncology.org/Reports/der0918XuID100044.html
This article should be referenced as such:
Reddy KS. Unbalanced rearrangement, der(9;18)(p10;q10) in a patient with myeloproliferative neoplasm. Case 0001M.. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(10):994-995.
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