vol 16 5 2012 - Revues et...

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 lInformation 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

Volume 16 - Number 5 May 2012

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 lInformation 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.



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, Mlanie Arsaban, Marie-Christine Jacquemot-Perbal, 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. 2012; 16(5)







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 Bove (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 Franois 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 Vigui (Paris, France) Leukaemia Section Jos Luis Vizmanos (Pamplona, Spain) Leukaemia Section Thomas Wan (Hong Kong, China) Genes / Leukaemia Sections




Volume 16, Number 5, May 2012

Table of contents

Gene Section

AMBN (ameloblastin (enamel matrix protein)) 326 Marina Gonalves Diniz, Ricardo Santiago Gomez, Carolina Cavalieri Gomes, Andr Luiz Sena Guimares

BCAR1 (breast cancer anti-estrogen resistance 1) 329 Allison Berrier

CEP57 (centrosomal protein 57kDa) 336 Sandra Hanks, Katie Snape, Nazneen Rahman

CLDN10 (claudin 10) 339 Madhu Lal-Nag

GATA3 (GATA binding protein 3) 342 Mathieu Tremblay, Maxime Bouchard

HTRA2 (HtrA serine peptidase 2) 347 Miroslaw Jarzab, Dorota Zurawa-Janicka, Barbara Lipinska

MIR196B (microRNA 196b) 357 Deepak Kaul, Deepti Malik

PRLR (prolactin receptor) 361 Chon-Hwa Tsai-Morris, Maria L Dufau

Leukaemia Section

t(3;11)(p25;p15) 366 Jean-Loup Huret

Solid Tumour Section

Bone: Aneurysmal bone cysts 368 Jean-Loup Huret

Bone: t(16;17)(q22;p13) in aneurysmal bone cyst 372 Jean-Loup Huret

Bone: t(17;17)(p13;q21) in aneurysmal bone cyst 374 Jean-Loup Huret

Cancer Prone Disease Section

Mosaic variegated aneuploidy syndrome 376 Sandra Hanks, Katie Snape, Nazneen Rahman

t(11;14)(q13;q32) in multiple myeloma Huret JL, La JL




Deep Insight Section

Chromothripsis: a new molecular mechanism in cancer development 381 Jian-Min Chen, Claude Frec, David N Cooper

Gene Section Short Communication

Atlas Genet Cytogenet Oncol Haematol. 2012; 16(5) 326



AMBN (ameloblastin (enamel matrix protein)) Marina Gonalves Diniz, Ricardo Santiago Gomez, Carolina Cavalieri Gomes, Andr Luiz Sena Guimares

Department of Oral Surgery and Pathology, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Belo Horizonte-MG CEP 31270, Brazil (MGD, RSG), Department of Pathology, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Belo Horizonte-MG CEP 31270, Brazil (CCG), Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Brazil (ALSG)

Published in Atlas Database: December 2011

Online updated version : http://AtlasGeneticsOncology.org/Genes/AMBNID51161ch4q13.html DOI: 10.4267/2042/47320

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity HGNC (Hugo): AMBN

Location: 4q13.3

Local order: AMBN is between the sequence tagged site markers D4S409 and D4S1558 (Karrman et al., 1997).

DNA/RNA Note The putative start codon location and exon-intron sizes differs among reports in literature.

Description 13 exons and 12 introns (Toyosawa et al., 2000; Macdougall et al., 2000) encompassing approximately 15005 bp. Until 2011, 44 SNP were described (NCBI dbSNP).

Transcription Alternatively spliced. Exon 6 can be excluded by the use of an alternative splice site (Macdougall et al., 2000). There are 2 validated alternative polyadenylation sites.

Protein Description The predicted protein has 447 aa (48,3 kDa). There are 3 protein isoforms. The human precursor protein contains a phosphorylation site for tyrosine kinase, a SH3 binding region, an O-linked glycosylation, and a heparin binding domain (Kobayashi et al., 2007; Krebsbach et al., 1996; Yamakoshi et al., 2001; Sonoda et al., 2009). Ameloblastin is cleaved after secretion into several lower-molecular-mass proteins that are developmentally expressed (Ravindranath et al., 2007).

The genomic organization of the human ameloblastin gene according to Mardh et al., 2001. The map is drawn to scale. Filled boxes represent exons and the thin lines indicate introns. Sequencing of AMBN intron 11 revealed an interrupted dinucleotide repeat (CA)n.

AMBN (ameloblastin (enamel matrix protein)) Diniz MG, et al.


Expression Tomes processes of secretory ameloblasts (Krebsbach et al., 1996; Cerny et al., 1996; Fong et al., 1996), odontoblasts and pre-odontoblasts (Fong et al., 1996; Nagano et al., 2003). Outer enamel, and sheath space between rod and interrod enamel (Uchida et al., 1995; Macdougall et al., 2000). Early bone and cartilage extracellular matrices during embryogenesis (Spahr et al., 2006).

Localisation Extracellular matrix.

Function Tooth enamel biomineralization (Uchida et al., 1997). Interactions between the ameloblasts and the enamel extracellular matrix (Fukumoto et al., 2004). Dental epithelium cell adhesion (Sonoda et al., 2009). Early bone formation and repair (Iizuza et al., 2011; Tamburstuen et al., 2011).

Homology Pig (sheathlin), cattle, rat, and mouse AMBN sequences showed a high amino acid sequence similarity.

Mutations Somatic AMBN gene mutations have been observed in several epithelial odontogenic tumor entities: unicystic ameloblastoma, solid ameloblastoma, adenomatoid odontogenic tumor, squamous odontogenic tumor, and calcifying epithelial odontogenic tumor (Toyosawa et al., 2000; Perdigo et al., 2004; Perdigo et al., 2009).

Implicated in Odontogenic tumors Disease Odontogenic tumours arise from the residues of odontogenic epithelium and/or ectomesenchyme, as a result of disturbances in the development of teeth and associated structures.

Oncogenesis AMBN gene is mutated in ameloblastomas and others odontogenic tumors (Toyosawa et al., 2000; Perdigo et al., 2004; Perdigo et al., 2009). Ambn-null mice develop odontogenic tumors of dental epithelium origin (Fukumoto et al., 2004). AMBN expression prevents odontogenic tumor development by suppressing cell proliferation and maintaining differentiation phenotype through Msx2, p21, and p27 (Sonoda et al., 2009). The absence of ameloblastin in epithelial odontogenic tumors has been considered a useful marker for the functional differentiation of secretory ameloblast (Takata et al., 2000).

Amelogenesis imperfecta Disease Amelogenesis imperfect is a common group of inherited defects such as hypoplastic or hypomineralized enamel. Autosomal dominant, autosomal recessive, and X-linked forms of amelogenesis imperfect are recognized.

Oncogenesis Amelogenin and ameloblastin have an impaired secretion in ameloblasts of phenocopies human X-linked amelogenesis imperfect mice, which results in severe enamel bio-mineralization defects, loss of ameloblast phenotype, increased ameloblast apoptosis, and formation of multi-cellular masses (Barron et al., 2010). AMBN mutations in the coding region or splice sites were discarted to be responsible for autosomal dominant amelogenesis imperfecta (Mardh et al., 2001).

References Uchida T, Fukae M, Tanabe T, Yamakoshi Y, Satoda T, Murakami C, et al.. Immunochemical and immunocytochemical study of a 15 kDa non-amelogenin and related proteins in the porcine immature enamel: proposal of a new group of enamel proteins sheath proteins. Biomed Res. 1995; 16:131-140.

Cerny R, Slaby I, Hammarstrom L, Wurtz T.. A novel gene expressed in rat ameloblasts codes for proteins with cell binding domains. J Bone Miner Res. 1996 Jul;11(7):883-91.

Fong CD, Slaby I, Hammarstrom L.. Amelin: an enamel-related protein, transcribed in the cells of epithelial root sheath. J Bone Miner Res. 1996 Jul;11(7):892-8.

Krebsbach PH, Lee SK, Matsuki Y, Kozak CA, Yamada KM, Yamada Y.. Full-length sequence, localization, and chromosomal mapping of ameloblastin. A novel tooth-specific gene. J Biol Chem. 1996 Feb 23;271(8):4431-5.

Uchida T, Murakami C, Dohi N, Wakida K, Satoda T, Takahashi O.. Synthesis, secretion, degradation, and fate of ameloblastin during the matrix formation stage of the rat incisor as shown by immunocytochemistry and immunochemistry using region-specific antibodies. J Histochem Cytochem. 1997 Oct;45(10):1329-40.

MacDougall M, Simmons D, Gu TT, Forsman-Semb K, Mardh CK, Mesbah M, Forest N, Krebsbach PH, Yamada Y, Berdal A.. Cloning, characterization and immunolocalization of human ameloblastin. Eur J Oral Sci. 2000 Aug;108(4):303-10.

Takata T, Zhao M, Uchida T, Kudo Y, Sato S, Nikai H.. Immunohistochemical demonstration of an enamel sheath protein, sheathlin, in odontogenic tumors. Virchows Arch. 2000 Apr;436(4):324-9.

Toyosawa S, Fujiwara T, Ooshima T, Shintani S, Sato A, Ogawa Y, Sobue S, Ijuhin N.. Cloning and characterization of the human ameloblastin gene. Gene. 2000 Oct 3;256(1-2):1-11.

Mardh CK, Backman B, Simmons D, Golovleva I, Gu TT, Holmgren G, MacDougall M, Forsman-Semb K.. Human ameloblastin gene: genomic organization and mutation analysis in amelogenesis imperfecta patients. Eur J Oral Sci. 2001 Feb;109(1):8-13.

AMBN (ameloblastin (enamel matrix protein)) Diniz MG, et al.


Yamakoshi Y, Tanabe T, Oida S, Hu CC, Simmer JP, Fukae M.. Calcium binding of enamel proteins and their derivatives with emphasis on the calcium-binding domain of porcine sheathlin. Arch Oral Biol. 2001 Nov;46(11):1005-14.

Nagano T, Oida S, Ando H, Gomi K, Arai T, Fukae M.. Relative levels of mRNA encoding enamel proteins in enamel organ epithelia and odontoblasts. J Dent Res. 2003 Dec;82(12):982-6.

Fukumoto S, Kiba T, Hall B, Iehara N, Nakamura T, Longenecker G, Krebsbach PH, Nanci A, Kulkarni AB, Yamada Y.. Ameloblastin is a cell adhesion molecule required for maintaining the differentiation state of ameloblasts. J Cell Biol. 2004 Dec 6;167(5):973-83.

Perdigao PF, Gomez RS, Pimenta FJ, De Marco L.. Ameloblastin gene (AMBN) mutations associated with epithelial odontogenic tumors. Oral Oncol. 2004 Sep;40(8):841-6.

Spahr A, Lyngstadaas SP, Slaby I, Pezeshki G.. Ameloblastin expression during craniofacial bone formation in rats. Eur J Oral Sci. 2006 Dec;114(6):504-11.

Kobayashi K, Yamakoshi Y, Hu JC, Gomi K, Arai T, Fukae M, Krebsbach PH, Simmer JP.. Splicing determines the glycosylation state of ameloblastin. J Dent Res. 2007 Oct;86(10):962-7.

Ravindranath RM, Devarajan A, Uchida T.. Spatiotemporal expression of ameloblastin isoforms during murine tooth development. J Biol Chem. 2007 Dec 14;282(50):36370-6. Epub 2007 Oct 5.

Perdigao PF, Carvalho VM, DE Marco L, Gomez RS.. Mutation of ameloblastin gene in calcifying epithelial odontogenic tumor. Anticancer Res. 2009 Aug;29(8):3065-7.

Sonoda A, Iwamoto T, Nakamura T, Fukumoto E, Yoshizaki K, Yamada A, Arakaki M, Harada H, Nonaka K, Nakamura S, Yamada Y, Fukumoto S.. Critical role of heparin binding domains of ameloblastin for dental epithelium cell adhesion and ameloblastoma proliferation. J Biol Chem. 2009 Oct 2;284(40):27176-84. Epub 2009 Jul 31.

Barron MJ, Brookes SJ, Kirkham J, Shore RC, Hunt C, Mironov A, Kingswell NJ, Maycock J, Shuttleworth CA, Dixon MJ.. A mutation in the mouse Amelx tri-tyrosyl domain results in impaired secretion of amelogenin and phenocopies human X-linked amelogenesis imperfecta. Hum Mol Genet. 2010 Apr 1;19(7):1230-47. Epub 2010 Jan 12.

Iizuka S, Kudo Y, Yoshida M, Tsunematsu T, Yoshiko Y, Uchida T, Ogawa I, Miyauchi M, Takata T.. Ameloblastin regulates osteogenic differentiation by inhibiting Src kinase via cross talk between integrin beta1 and CD63. Mol Cell Biol. 2011 Feb;31(4):783-92. Epub 2010 Dec 13.

Tamburstuen MV, Reseland JE, Spahr A, Brookes SJ, Kvalheim G, Slaby I, Snead ML, Lyngstadaas SP.. Ameloblastin expression and putative autoregulation in mesenchymal cells suggest a role in early bone formation and repair. Bone. 2011 Feb;48(2):406-13. Epub 2010 Sep 18.

This article should be referenced as such:

Diniz MG, Gomez RS, Gomes CC, Guimares ALS. AMBN (ameloblastin (enamel matrix protein)). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(5):326-328.

Gene Section Review




BCAR1 (breast cancer anti-estrogen resistance 1) Allison Berrier

Department of Oral and Craniofacial Biology, LSUHSC-NO School of Dentistry, 1100 Florida Avenue, Clinical Bldg, Room 8301, New Orleans, LA 70119, USA (AB)


Online updated version : http://AtlasGeneticsOncology.org/Genes/BCAR1ID761ch16q23.html DOI: 10.4267/2042/47321


Identity Other names: CAS, CAS1, CASS1, CRKAS, FLJ12176, FLJ45059, P130Cas

HGNC (Hugo): BCAR1

Location: 16q23.1

DNA/RNA See figure 1 below.

Figure 1.

BCAR1 (breast cancer anti-estrogen resistance 1) Berrier A


Protein Note BCAR1 isoforms Isoform 1: 916 aa, calc MW= 97,7 kDa. Isoform 2: 888 aa, (alternate 5' sequence compared to variant 1) calc MW= 95,1 kDa. Isoform 3: 888 aa, (alternate 5' sequence compared to variant 1) calc MW= 95,3 kDa. Isoform 4: 888 aa, (alternate 5' sequence and alternate splice site in the substrate domain compared to variant 1 resulting in a different N-terminus and additional segment in the middle region compared to isoform 1) calc MW= 95,3 kDa. Isoform 5: 870 aa, (lacks an exon in the 5' region, alternate AUG start codon, has a different N-terminus compared to isoform 1) calc MW= 93,16 kDa. Isoform 6: 870 aa, (different N-terminus compared to isoform 1) calc MW= 93,2 kDa. Isoform 7, 868 aa (shorter, alternate 5' sequence, different N-terminus compared to isoform 1) calc MW= 93 kDa. Isoform 8, 722 aa, (alternate internal sequence compared to isoform 1, different N-terminus compared to isoform 1) calc MW= 77,6 kDa. Isoform 9: 660 aa, (shorter alternate 5' sequence, different N-terminus compared to isoform 1) calc MW= 70,7 kDa. BCAR proteins migrate during SDS-PAGE electrophoresis at a significantly higher molecular weight than predicted from sequence analysis perhaps due to the extensive phosphorylation of BCAR proteins. Calculated MW 93,2 kDa, SDS-PAGE observed MW 130 kDa. Potential sites of human BCAR1 phosphorylation (PhosphoSitePlus): tyrosine residues aa 12, 128, 165, 192, 222, 224, 234, 249, 267, 287, 306, 327, 362, 372, 387, 410, 653, 664, 666; serine residues aa 134, 139, 292, 437, 639; and threonine residues aa 269, 326, 385. Inducers of BCAR1 phosphorylation include cell matrix adhesion, extracellular matrix rigidity, growth factors, hormones and progression through the cell cycle. Phosphorylation of BCAR1 regulates BCAR1 dependent activities through altering protein interactions, protein localization and signaling cascades (Tikhmyanova et al., 2010).

Description BCAR1 domains as described in Tikhmyanova et al., 2010 are shown in the schematic diagram in figure 2. The amino terminal 1-65 aa contain the Src homology

3 domain (SH3) domain that binds proline-rich PxxP ligands. The adjacent region 66-447 aa contains the substrate domain (SD) comprised of 15 YxxP motifs that when phosphorylated by tyrosine kinases provides canonical binding sites for proteins containing SH2 domains such as Crk, mechanical forces and stretching of SD may induce conformational changes that allows phosphorylation by kinases and this stretching may promote protein-protein interactions in this domain (Sawada et al., 2006). The serine rich domain within 448-610 aa (serine rich protein interaction domain) contains a four-helix bundle that functions as a scaffold for BCAR1 binding proteins such as Grb2 and 14-3-3 (Nasertorabi et al., 2004; Briknarov et al., 2005). The C-terminal domain of 746-870 aa has a potential FAT (focal adhesion targeting) domain and a helix-loop-helix domain with homology to the transcription factor Id. This region contains the YDYVHL motif that is phosphorylated during cell adhesion. BCAR1 interacting proteins (BioGRID) CRKII, p60-Src, PTPN12, PTK2 (FAK), RapGEF1 (C3G), NPHP1, PTPN1 (PTP1B), FES, SHIP2 (INPPL1), ARHGAP32 (p250GAP), Pyk2 (PTK2B), Fyn, CRKL, YWHAZ, SrcIN1 (SNIP), p85-alpha (PI3KR1), c-ABL (bcr/abl), Lyn, Grb2, Dock1, paxillin, TRIP6, SH-PTP2, ID2A, UHRF2, NEDD9, NCK1, VCL, SAP1, Zyxin, BCAR3 (AND-34), CD2AP, LCK, SFN, SH2D3C, JNK/SAPK1, SH3KBP1, tensin 1 (TNS1), HCK, EFS, E2F2, VPS11, HspA5, TUBA1A, GADD34, p140Cap, BCAR1 (p130CAS), PTP-PEST, CIZ, Aurora-A, 14-3-3, CHAT-H, AIP4, APC/C and CDH1.

Expression BCAR1 is ubiquitously expressed and is reportedly detectable in all phases of the cell cycle. In lymphoid development, BCAR is expressed at higher levels in differentiated cells compared to precursors. Barrett's esophagus cancer cell line compared to normal tissue 2,51 increase in BCAR1 expression (Oncomine). Colorectal cancer Ramaswamy multi-cancer there is a 4,2 fold increase in BCAR1 expression compared to other cancers (Oncomine). Gastric cancer cell line Gyorffy cell line 2 there is a 5,0 fold reduction in BCAR 1 expression (Oncomine). In lymphomas, BCAR1 expression is reduced 2,5 fold (Oncomine).

Figure 2. Schematic diagram containing BCAR1 protein domains.



Localisation Cytoplasm, ruffles, cell junctions (Donaldson et al., 2000), nucleus (Kim et al., 2004) and focal adhesions (Nakamoto et al., 1997; Volberg et al., 1995; Winograd-Katz et al., 2009).

Function BCAR1 regulates numerous cellular processes such as invasion, migration, transformation, survival and drug resistance (Di Stefano et al., 2011; Brbek et al., 2004; Brbek et al., 2005) (summarized in figure 3). BCAR1 lacks intrinsic enzymatic activity, yet it is a substrate for several kinases including the Src tyrosine kinase. The original name for BCAR1 was p130CAS abbreviated from Crk-associated substrate because it was first identified as a tyrosine phosphorylated protein in cells transformed by v-src and v-crk oncogenes. BCAR1 regulates cellular behavior by controlling signaling cascades and the dynamic localization of multi-protein complexes. The BCAR1 phosphorylation state is regulated during the cell cycle. During the exit of G2, BCAR1 serine and threonine phosphorylation levels increase and these events disrupt the interactions of BCAR1 with Src and FAK and thus dissociates this complex and contributes to the disassembly of focal adhesions allowing cells to loosen matrix adhesions and thus permitting cell rounding in mitosis. The subsequent reformation of matrix adhesions promotes progression through the cell cycle from mitosis to G1 (Pugacheva et al., 2006).

Homology There is a family containing four proteins related to BCAR1 (breast cancer resistance) that possess names related to the prior nomenclature for BCAR1 homologs in the rat and mouse. The non-human homologs of BCAR1 were named CAS for Crk-associated substrate. This family of proteins includes the protein EFS (embryonal Fyn-associated substrate) (CAS3, CASS3, EFS1, EFS2, HEFS, SIN) identified because of interactions with the Src-family kinases Fyn and Yes and maps to chromosome 14q11.2-q12. A third family member is HEF1 (human enhancer of filamentation 1 known as CASL, CAS-L, NEDD9, CAS2 and CASS2) that maps to chromosome 6p25-p24 and was isolated as a human gene that promotes filamentous growth in yeast. This screen was performed to identify regulators of the cell cycle and polarity.

It was also identified as a protein that is tyrosine phosphorylated after clustering integrin 1 in T-lymphocytes. NEDD9 (neural precursor cell expressed, developmentally down-regulated 9) is a gene restricted in expression to early embryonic, but not adult mouse brain. The fourth family member is CASS4 ((HEF-EFS-P130CAS-like)/CAS4) that maps to chromosome 20q13.2-q13.31 and is the newest member of the family that was identified by genomic and transcript homology and demonstrated to function similarly to other BCAR family members. These 4 proteins are conserved from jawed vertebrates through mammals. One BCAR member is found in lower vertebrates and insects. However, no BCAR family member is detectable in C. elegans, S. cerevisiae and other lower eukaryotes.

Mutations Somatic Catalogue of somatic mutations in cancer: there are currently 10 known somatic mutations in BCAR1. Proceeding from the N-terminus to the C-Terminus of BCAR1, aa 118 proline (identified in the central nervous system), 185 alanine (identified in the central nervous system), 407 threonine (identified in breast tissue), 430 serine (upper aerodigestive tract), 583 serine (identified in prostate tissue), 592 histidine (identified in liver), 708 lysine (identified in the central nervous system), 759 threonine (identified in central nervous system), 780 valine (identified in central nervous system), 795 isoleucine (identified in upper aerodigestive tract). Mutations at aa 118 and 185 are in the substrate domain, 407 and 430 are amino-terminal to the 4 helical bundle, 583 and 592 are in the 4-helix bundle, whereas 759, 780 and 795 localize to the C-terminal domain.

Implicated in Various cancers Note Overexpression of BCAR1 is linked to poor prognosis and increased cancer metastasis in many cancers. BCAR1 can be upregulated by gene amplification, transcriptional upregulation and changes in protein stability. Hyperphosphorylation of BCAR1 drives cell migration, invasion, cell survival and drug resistance.



Figure 3. Extracellular cues that control CAR1 phosphorylation and cellular processes that are regulated by BCAR1.

Breast cancer Prognosis In breast cancers that express high levels of BCAR1, the cancer is more likely to relapse and the tumors frequently have an intrinsic reduced response to tamoxifen (van der Flier et al., 2000; Dorssers et al., 2004).

Oncogenesis Elevated BCAR levels in breast cancers correlates with increased expression of HER2/neu and enhanced cell proliferation (Cabodi et al., 2006; Cabodi et al., 2010). BCAR1 overexpression in breast cancer cells is linked to resistance to the cytotoxic agent Adriamycin (Ta et al., 2008). BCAR1 overexpression is sufficient to induce hyperplasia in the mammary pad during development and pregnancy.

Prostate cancer Oncogenesis In prostate cancer, BCAR1 expression is higher compared to control tissue and expression of BCAR1 in prostate cancer correlates with elevated EGFR expression levels (Fromont et al., 2007; Fromont et al., 2011; Cabodi et al., 2010).

Hepatocellular carcinoma Prognosis In hepatocellular carcinoma, tumor invasion and

poor prognosis correlate with overexpression of BCAR1 and reductions in E-cadherin and -catenin levels (Guo et al., 2008).

Nasal polyps Oncogenesis Nasal polyps can express high levels of BCAR1 (Zhang et al., 2003).

Colorectal cancer Oncogenesis Celecoxib cytotoxicity in colorectal cancer is linked to cleavage of BCAR1 and apoptosis. Overexpression of BCAR1 in colorectal cancer cell lines is linked to resistance to celecoxib (Casanova et al., 2006; Weyant et al., 2000).

Non-small-cell lung cancer (NSCLC) Oncogenesis BCAR1 is not detected in normal lung tissue, however in non-small-cell lung cancer and tuberculosis and other pulmonary disorders elevated levels of BCAR1 are observed in both the diseased tissue and elevated levels are noted in serum (Deng et al., 2011). In patients with NSCLC the serum levels of BCAR1 proportionally increase with the progression of tumor stage. Interestingly, in patients with elevated serum BCAR1 levels, the serum levels of BCAR1 diminish after removal of the pulmonary lesion or tumor.



Ovarian cancer Prognosis In ovarian cancer, an increase in BCAR1 expression correlates with poor 5 year survival rates and reductions in BCAR1 expression result in reduced tumor growth following docetaxel chemotherapy (Nick et al., 2011).

Oral cancer Oncogenesis In oral cancers elevated levels of UPAR are indicative of more invasive tumors and enhanced lymph node metastasis. The levels of UPAR in oral cancer correlate with the levels of BCAR1 (Shi et al., 2011).

Anaplastic large-cell lymphomas Oncogenesis In anaplastic large-cell lymphomas, the anaplastic lymphoma kinase (ALK) is frequently translocated and a fusion protein with nucleophosmin (NPM)-ALK is generated that contains kinase activity. NPM-ALK transforms fibroblasts, however in BCAR1-/- fibroblasts NPM-ALK fails to induce transformation. Hence, BCAR1 is critical for ALK transformation activity (Ambrogio et al., 2005).

Chemotherapeutic resistance Note Overexpression of BCAR1 is linked to drug resistance in multiple tumor types such as breast cancer, lung cancers, glioblastoma and melanoma (Ta et al., 2008). BCAR1 and NEDD9 interact with BCAR3 to mediate anti-estrogen resistance and to control Rap1 GTPase activation (Cai et al., 2003). In a screen of an estrogen dependent cell line, BCAR1 was identified as a gene required for tamoxifen resistance (Brinkman et al., 2000; van der Flier et al., 2000).

Role of BCAR1 in other pathological conditions or diseases Note BCAR1 dysfunction is linked to inflammatory disorders, ischemic stroke (Ziemka-Nalecz et al., 2007; Zalewska et al., 2005) and developmental defects. Knockout of BCAR1 is lethal at embryonic stages days 11,5 to 12,5 as a result of cardiovascular dysfunction (Honda et al., 1998). BCAR1 is critical for the pathology of many infectious diseases. The bacterial species Yersinia encodes and secretes a phosphatase YOP that inactivates/dephosphorylates BCAR1 and YOP activity minimizes phagocytosis by macrophages and neutrophils facilitating Yersinia evasion of components of the cellular immune response which disrupts clearance of the bacteria by the host (Deleuil et al., 2003; Hamid et al., 1999). In contrast, in epithelial cells, Yersinia uptake is associated with phosphorylation of BCAR1, thus the bacterium triggers

BCAR1 phosphorylation to promote the uptake of the organism in non-phagocytic cells (Weidow et al., 2000). S. typhimurium is an obligate intracellular bacterial pathogen that requires eukaryotic cellular uptake for infection. These bacteria utilize host eukaryotic BCAR1 for efficient bacterial uptake and their infectious cycle (Shi et al., 2006). In addition to bacteria, many viruses also utilize the host protein machinery and BCAR1 for their viral propagation. For instance, internalization of adenovirus is initiated by virus binding to host integrin receptors and virus internalization requires BCAR1 phosphorylation (Li et al., 1998; Li et al., 2000).

References Sakai R, Iwamatsu A, Hirano N, Ogawa S, Tanaka T, Mano H, Yazaki Y, Hirai H. A novel signaling molecule, p130, forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner. EMBO J. 1994 Aug 15;13(16):3748-56

Volberg T, Geiger B, Kam Z, Pankov R, Simcha I, Sabanay H, Coll JL, Adamson E, Ben-Ze'ev A. Focal adhesion formation by F9 embryonal carcinoma cells after vinculin gene disruption. J Cell Sci. 1995 Jun;108 ( Pt 6):2253-60

Vuori K, Ruoslahti E. Tyrosine phosphorylation of p130Cas and cortactin accompanies integrin-mediated cell adhesion to extracellular matrix. J Biol Chem. 1995 Sep 22;270(38):22259-62

Burnham MR, Harte MT, Richardson A, Parsons JT, Bouton AH. The identification of p130cas-binding proteins and their role in cellular transformation. Oncogene. 1996 Jun 6;12(11):2467-72

Harte MT, Hildebrand JD, Burnham MR, Bouton AH, Parsons JT. p130Cas, a substrate associated with v-Src and v-Crk, localizes to focal adhesions and binds to focal adhesion kinase. J Biol Chem. 1996 Jun 7;271(23):13649-55

Khwaja A, Hallberg B, Warne PH, Downward J. Networks of interaction of p120cbl and p130cas with Crk and Grb2 adaptor proteins. Oncogene. 1996 Jun 20;12(12):2491-8

Vuori K, Hirai H, Aizawa S, Ruoslahti E. Introduction of p130cas signaling complex formation upon integrin-mediated cell adhesion: a role for Src family kinases. Mol Cell Biol. 1996 Jun;16(6):2606-13

Astier A, Avraham H, Manie SN, Groopman J, Canty T, Avraham S, Freedman AS. The related adhesion focal tyrosine kinase is tyrosine-phosphorylated after beta1-integrin stimulation in B cells and binds to p130cas. J Biol Chem. 1997 Jan 3;272(1):228-32

Nakamoto T, Sakai R, Honda H, Ogawa S, Ueno H, Suzuki T, Aizawa S, Yazaki Y, Hirai H. Requirements for localization of p130cas to focal adhesions. Mol Cell Biol. 1997 Jul;17(7):3884-97

Honda H, Oda H, Nakamoto T, Honda Z, Sakai R, Suzuki T, Saito T, Nakamura K, Nakao K, Ishikawa T, Katsuki M, Yazaki Y, Hirai H. Cardiovascular anomaly, impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas. Nat Genet. 1998 Aug;19(4):361-5

Klemke RL, Leng J, Molander R, Brooks PC, Vuori K, Cheresh DA. CAS/Crk coupling serves as a "molecular switch" for induction of cell migration. J Cell Biol. 1998 Feb 23;140(4):961-72



Li E, Stupack D, Klemke R, Cheresh DA, Nemerow GR. Adenovirus endocytosis via alpha(v) integrins requires phosphoinositide-3-OH kinase. J Virol. 1998 Mar;72(3):2055-61

Hamid N, Gustavsson A, Andersson K, McGee K, Persson C, Rudd CE, Fllman M. YopH dephosphorylates Cas and Fyn-binding protein in macrophages. Microb Pathog. 1999 Oct;27(4):231-42

Brinkman A, van der Flier S, Kok EM, Dorssers LC. BCAR1, a human homologue of the adapter protein p130Cas, and antiestrogen resistance in breast cancer cells. J Natl Cancer Inst. 2000 Jan 19;92(2):112-20

Donaldson JC, Dempsey PJ, Reddy S, Bouton AH, Coffey RJ, Hanks SK. Crk-associated substrate p130(Cas) interacts with nephrocystin and both proteins localize to cell-cell contacts of polarized epithelial cells. Exp Cell Res. 2000 Apr 10;256(1):168-78

Gotoh T, Cai D, Tian X, Feig LA, Lerner A. p130Cas regulates the activity of AND-34, a novel Ral, Rap1, and R-Ras guanine nucleotide exchange factor. J Biol Chem. 2000 Sep 29;275(39):30118-23

Li E, Stupack DG, Brown SL, Klemke R, Schlaepfer DD, Nemerow GR. Association of p130CAS with phosphatidylinositol-3-OH kinase mediates adenovirus cell entry. J Biol Chem. 2000 May 12;275(19):14729-35

Nakamoto T, Yamagata T, Sakai R, Ogawa S, Honda H, Ueno H, Hirano N, Yazaki Y, Hirai H. CIZ, a zinc finger protein that interacts with p130(cas) and activates the expression of matrix metalloproteinases. Mol Cell Biol. 2000 Mar;20(5):1649-58

van der Flier S, Brinkman A, Look MP, Kok EM, Meijer-van Gelder ME, Klijn JG, Dorssers LC, Foekens JA. Bcar1/p130Cas protein and primary breast cancer: prognosis and response to tamoxifen treatment. J Natl Cancer Inst. 2000 Jan 19;92(2):120-7

Weidow CL, Black DS, Bliska JB, Bouton AH. CAS/Crk signalling mediates uptake of Yersinia into human epithelial cells. Cell Microbiol. 2000 Dec;2(6):549-60

Weyant MJ, Carothers AM, Bertagnolli ME, Bertagnolli MM. Colon cancer chemopreventive drugs modulate integrin-mediated signaling pathways. Clin Cancer Res. 2000 Mar;6(3):949-56

Yi J, Kloeker S, Jensen CC, Bockholt S, Honda H, Hirai H, Beckerle MC. Members of the Zyxin family of LIM proteins interact with members of the p130Cas family of signal transducers. J Biol Chem. 2002 Mar 15;277(11):9580-9

Cai D, Iyer A, Felekkis KN, Near RI, Luo Z, Chernoff J, Albanese C, Pestell RG, Lerner A. AND-34/BCAR3, a GDP exchange factor whose overexpression confers antiestrogen resistance, activates Rac, PAK1, and the cyclin D1 promoter. Cancer Res. 2003 Oct 15;63(20):6802-8

Deleuil F, Mogemark L, Francis MS, Wolf-Watz H, Fllman M. Interaction between the Yersinia protein tyrosine phosphatase YopH and eukaryotic Cas/Fyb is an important virulence mechanism. Cell Microbiol. 2003 Jan;5(1):53-64

Zhang PJ, Weber R, Liang HH, Pasha TL, LiVolsi VA. Growth factors and receptors in juvenile nasopharyngeal angiofibroma and nasal polyps: an immunohistochemical study. Arch Pathol Lab Med. 2003 Nov;127(11):1480-4

Brbek J, Constancio SS, Shin NY, Pozzi A, Weaver AM, Hanks SK. CAS promotes invasiveness of Src-transformed cells. Oncogene. 2004 Sep 23;23(44):7406-15

Dorssers LC, Grebenchtchikov N, Brinkman A, Look MP, van Broekhoven SP, de Jong D, Peters HA, Portengen H, Meijer-van Gelder ME, Klijn JG, van Tienoven DT, Geurts-Moespot A,

Span PN, Foekens JA, Sweep FC. The prognostic value of BCAR1 in patients with primary breast cancer. Clin Cancer Res. 2004 Sep 15;10(18 Pt 1):6194-202

Kim W, Kook S, Kim DJ, Teodorof C, Song WK. The 31-kDa caspase-generated cleavage product of p130cas functions as a transcriptional repressor of E2A in apoptotic cells. J Biol Chem. 2004 Feb 27;279(9):8333-42

Nasertorabi F, Garcia-Guzman M, Briknarov K, Larsen E, Havert ML, Vuori K, Ely KR. Organization of functional domains in the docking protein p130Cas. Biochem Biophys Res Commun. 2004 Nov 19;324(3):993-8

Ambrogio C, Voena C, Manazza AD, Piva R, Riera L, Barberis L, Costa C, Tarone G, Defilippi P, Hirsch E, Boeri Erba E, Mohammed S, Jensen ON, Palestro G, Inghirami G, Chiarle R. p130Cas mediates the transforming properties of the anaplastic lymphoma kinase. Blood. 2005 Dec 1;106(12):3907-16

Brbek J, Constancio SS, Siesser PF, Shin NY, Pozzi A, Hanks SK. Crk-associated substrate tyrosine phosphorylation sites are critical for invasion and metastasis of SRC-transformed cells. Mol Cancer Res. 2005 Jun;3(6):307-15

Briknarov K, Nasertorabi F, Havert ML, Eggleston E, Hoyt DW, Li C, Olson AJ, Vuori K, Ely KR. The serine-rich domain from Crk-associated substrate (p130cas) is a four-helix bundle. J Biol Chem. 2005 Jun 10;280(23):21908-14

Hanks SK, Brabek J.. p130Cas. UCSD Nature Molecule Pages. 2005 Oct 10; Protein A001708.

Zalewska T, Makarewicz D, Janik B, Ziemka-Nalecz M.. Neonatal cerebral hypoxia-ischemia: involvement of FAK-dependent pathway. Int J Dev Neurosci. 2005 Nov;23(7):657-62. Epub 2005 Aug 10.

Cabodi S, Tinnirello A, Di Stefano P, Bisaro B, Ambrosino E, Castellano I, Sapino A, Arisio R, Cavallo F, Forni G, Glukhova M, Silengo L, Altruda F, Turco E, Tarone G, Defilippi P.. p130Cas as a new regulator of mammary epithelial cell proliferation, survival, and HER2-neu oncogene-dependent breast tumorigenesis. Cancer Res. 2006 May 1;66(9):4672-80.

Casanova I, Parreno M, Farre L, Guerrero S, Cespedes MV, Pavon MA, Sancho FJ, Marcuello E, Trias M, Mangues R.. Celecoxib induces anoikis in human colon carcinoma cells associated with the deregulation of focal adhesions and nuclear translocation of p130Cas. Int J Cancer. 2006 May 15;118(10):2381-9.

Pugacheva EN, Roegiers F, Golemis EA.. Interdependence of cell attachment and cell cycle signaling. Curr Opin Cell Biol. 2006 Oct;18(5):507-15. Epub 2006 Aug 17. (REVIEW)

Sawada Y, Tamada M, Dubin-Thaler BJ, Cherniavskaya O, Sakai R, Tanaka S, Sheetz MP.. Force sensing by mechanical extension of the Src family kinase substrate p130Cas. Cell. 2006 Dec 1;127(5):1015-26.

Shi J, Casanova JE.. Invasion of host cells by Salmonella typhimurium requires focal adhesion kinase and p130Cas. Mol Biol Cell. 2006 Nov;17(11):4698-708. Epub 2006 Aug 16.

Fromont G, Vallancien G, Validire P, Levillain P, Cussenot O.. BCAR1 expression in prostate cancer: association with 16q23 LOH status, tumor progression and EGFR/KAI1 staining. Prostate. 2007 Feb 15;67(3):268-73.

Van Slambrouck S, Grijelmo C, De Wever O, Bruyneel E, Emami S, Gespach C, Steelant WF.. Activation of the FAK-src molecular scaffolds and p130Cas-JNK signaling cascades by alpha1-integrins during colon cancer cell invasion. Int J Oncol. 2007 Dec;31(6):1501-8.

Ziemka-Nalecz M, Zalewska T.. Transient forebrain ischemia effects FAK-coupled signaling in gerbil hippocampus.



Neurochem Int. 2007 Nov-Dec;51(6-7):405-11. Epub 2007 Apr 22.

Berrier AL, Jones CW, LaFlamme SE.. Tac-beta1 inhibits FAK activation and Src signaling. Biochem Biophys Res Commun. 2008 Mar 28;368(1):62-7. Epub 2008 Jan 14.

Guo C, Liu QG, Yang W, Zhang ZL, Yao YM.. Relation among p130Cas, E-cadherin and beta-catenin expression, clinicopathologic significance and prognosis in human hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2008 Oct;7(5):490-6.

Ta HQ, Thomas KS, Schrecengost RS, Bouton AH.. A novel association between p130Cas and resistance to the chemotherapeutic drug adriamycin in human breast cancer cells. Cancer Res. 2008 Nov 1;68(21):8796-804.

Winograd-Katz SE, Itzkovitz S, Kam Z, Geiger B.. Multiparametric analysis of focal adhesion formation by RNAi-mediated gene knockdown. J Cell Biol. 2009 Aug 10;186(3):423-36.

Cabodi S, del Pilar Camacho-Leal M, Di Stefano P, Defilippi P.. Integrin signalling adaptors: not only figurants in the cancer story. Nat Rev Cancer. 2010 Dec;10(12):858-70. Epub 2010 Nov 24. (REVIEW)

Cabodi S, Tinnirello A, Bisaro B, Tornillo G, del Pilar Camacho-Leal M, Forni G, Cojoca R, Iezzi M, Amici A, Montani M, Eva A, Di Stefano P, Muthuswamy SK, Tarone G, Turco E, Defilippi P.. p130Cas is an essential transducer element in ErbB2 transformation. FASEB J. 2010 Oct;24(10):3796-808. Epub 2010 May 26.

Tikhmyanova N, Little JL, Golemis EA.. CAS proteins in normal and pathological cell growth control. Cell Mol Life Sci. 2010 Apr;67(7):1025-48. Epub 2009 Nov 25. (REVIEW)

Deng B, Huang W, Tan QY, Fan XQ, Jiang YG, Liu L, Zhong YY, Liang YG, Wang RW.. Breast cancer anti-estrogen resistance protein 1 (BCAR1/p130cas) in pulmonary disease tissue and serum. Mol Diagn Ther. 2011 Feb 1;15(1):31-40. doi: 10.2165/11588850-000000000-00000.

Di Stefano P, Leal MP, Tornillo G, Bisaro B, Repetto D, Pincini A, Santopietro E, Sharma N, Turco E, Cabodi S, Defilippi P..

The adaptor proteins p140CAP and p130CAS as molecular hubs in cell migration and invasion of cancer cells. Am J Cancer Res. 2011;1(5):663-73. Epub 2011 May 2.

Fromont G, Cussenot O.. The integrin signalling adaptor p130CAS is also a key player in prostate cancer. Nat Rev Cancer. 2011 Mar;11(3):227.

Nick AM, Stone RL, Armaiz-Pena G, Ozpolat B, Tekedereli I, Graybill WS, Landen CN, Villares G, Vivas-Mejia P, Bottsford-Miller J, Kim HS, Lee JS, Kim SM, Baggerly KA, Ram PT, Deavers MT, Coleman RL, Lopez-Berestein G, Sood AK.. Silencing of p130cas in ovarian carcinoma: a novel mechanism for tumor cell death. J Natl Cancer Inst. 2011 Nov 2;103(21):1596-612. Epub 2011 Sep 28.

Eberle KE, Sansing HA, Szaniszlo P, Resto VA, Berrier AL.. Carcinoma matrix controls resistance to cisplatin through talin regulation of NF-kB. PLoS One. 2011;6(6):e21496. Epub 2011 Jun 24.

Shi Z, Liu Y, Johnson JJ, Stack MS.. Urinary-type plasminogen activator receptor (uPAR) modulates oral cancer cell behavior with alteration in p130cas. Mol Cell Biochem. 2011 Nov;357(1-2):151-61. Epub 2011 Jun 1.

Sansing HA, Sarkeshik A, Yates JR, Patel V, Gutkind JS, Yamada KM, Berrier AL.. Integrin alphabeta1, alphavbeta, alpha6beta effectors p130Cas, Src and talin regulate carcinoma invasion and chemoresistance. Biochem Biophys Res Commun. 2011 Mar 11;406(2):171-6. Epub 2011 Feb 1.

Tikhmyanova N, Golemis EA.. NEDD9 and BCAR1 negatively regulate E-cadherin membrane localization, and promote E-cadherin degradation. PLoS One. 2011;6(7):e22102. Epub 2011 Jul 12.

Zhao M, Vuori K.. The docking protein p130Cas regulates cell sensitivity to proteasome inhibition. BMC Biol. 2011 Oct 28;9:73.


Berrier A. BCAR1 (breast cancer anti-estrogen resistance 1). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(5):329-335.





CEP57 (centrosomal protein 57kDa) Sandra Hanks, Katie Snape, Nazneen Rahman

Institute of Cancer Research, Division of Genetics and Epidemiology, Brookes Lawley Building, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK (SH, KS, NR)


Online updated version : http://AtlasGeneticsOncology.org/Genes/CEP57ID43008ch11q21.html DOI: 10.4267/2042/47322


Identity Other names: PIG8, TSP57, Translokin, KIAA0092

HGNC (Hugo): CEP57

Location: 11q21

DNA/RNA Description CEP57 spans over 42 kb and is composed of 11 exons.

Protein Description 500 amino acids, 57 kDa.

Expression Ubiquituously expressed.

Localisation Nucleus, cytoplasm, cytoskeleton, centrosome.

Function Centrosomal protein required for microtubule attachment to centrosomes. Also involved in intracellular bidirectional trafficking of factors such as FGF2 along microtubules.

Homology The CEP57 gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, and zebrafish.

Figure 1. Schematic representation of CEP57 demonstrating the relative exon sizes.

CEP57 (centrosomal protein 57kDa) Hanks S, et al.


Figure 2. Schematic representation of CEP57 demonstrating significant functional or structural domains.

Figure 3. Schematic representation of CEP57 demonstrating the relative exon sizes and positions of known mutations. Biallelic mutations are represented by coloured lines, with mutations in the same individual in matching colours.

Mutations Germinal Biallelic, loss-of-function mutations in CEP57 have been found in three MVA pedigrees (figure 3).

Implicated in Mosaic variegated aneuploidy syndrome (MVA) Note MVA is a rare recessive condition characterised by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple different chromosomes and tissues. Affected individuals typically present with severe intrauterine growth retardation and microcephaly. Eye anomalies, mild dysmorphism, variable developmental delay and a broad spectrum of additional congenital abnormalities and medical conditions may also occur.

Prognosis The prognosis for an individual with MVA syndrome is based on the malformations present in the individual. There is early mortality in a significant proportion of cases due to failure to thrive and/or complications of

congenital abnormalities, epilepsy, infections or malignancy.

Cytogenetics MVA is characterised by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple different chromosomes and tissues. The proportion of aneuploid cells varies but is usually >10% and is substantially greater than in normal individuals. Some patients with MVA also demonstrate premature chromatid separation in colchicine-treated blood lymphocyte and fibroblast cultures.

Oncogenesis The risk of malignancy in MVA is high with Wilms tumour, rhabdomyosarcoma, leukaemia and granulosa cell tumour of the ovary reported in several cases. Myelodysplastic syndrome has also been observed.

To be noted Note Biallelic mutations in BUB1B have also been identified in individuals with MVA syndrome.

References Lane AH, Aijaz N, Galvin-Parton P, Lanman J, Mangano R, Wilson TA.. Mosaic variegated aneuploidy with growth

CEP57 (centrosomal protein 57kDa) Hanks S, et al.


hormone deficiency and congenital heart defects. Am J Med Genet. 2002 Jul 1;110(3):273-7.

Hanks S, Coleman K, Reid S, Plaja A, Firth H, Fitzpatrick D, Kidd A, Mehes K, Nash R, Robin N, Shannon N,

Tolmie J, Swansbury J, Irrthum A, Douglas J, Rahman N.. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat Genet. 2004 Nov;36(11):1159-61. Epub 2004 Oct 10.

Matsuura S, Matsumoto Y, Morishima K, Izumi H, Matsumoto H, Ito E, Tsutsui K, Kobayashi J, Tauchi H, Kajiwara Y, Hama S, Kurisu K, Tahara H, Oshimura M, Komatsu K, Ikeuchi T, Kajii T.. Monoallelic BUB1B mutations and defective mitotic-spindle checkpoint in seven families with premature chromatid separation (PCS) syndrome. Am J Med Genet A. 2006 Feb 15;140(4):358-67.

Garcia-Castillo H, Vasquez-Velasquez AI, Rivera H, Barros-Nunez P.. Clinical and genetic heterogeneity in patients with mosaic variegated aneuploidy: delineation of clinical subtypes. Am J Med Genet A. 2008 Jul 1;146A(13):1687-95. (REVIEW)

Momotani K, Khromov AS, Miyake T, Stukenberg PT, Somlyo AV.. Cep57, a multidomain protein with unique microtubule and centrosomal localization domains. Biochem J. 2008 Jun 1;412(2):265-73.

Meunier S, Navarro MG, Bossard C, Laurell H, Touriol C, Lacazette E, Prats H.. Pivotal role of translokin/CEP57 in the unconventional secretion versus nuclear translocation of FGF2. Traffic. 2009 Dec;10(12):1765-72. Epub 2009 Sep 14.

Snape K, Hanks S, Ruark E, Barros-Nunez P, Elliott A, Murray A, Lane AH, Shannon N, Callier P, Chitayat D, Clayton-Smith J, Fitzpatrick DR, Gisselsson D, Jacquemont S, Asakura-Hay K, Micale MA, Tolmie J, Turnpenny PD, Wright M, Douglas J, Rahman N.. Mutations in CEP57 cause mosaic variegated aneuploidy syndrome. Nat Genet. 2011 Jun;43(6):527-9. Epub 2011 May 8.


Hanks S, Snape K, Rahman N. CEP57 (centrosomal protein 57kDa). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(5):336-338.





CLDN10 (claudin 10) Madhu Lal-Nag

Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health Biomedical Research Center, Baltimore, MD 21224, USA (MLN)


Online updated version : http://AtlasGeneticsOncology.org/Genes/CLDN10ID45827ch13q32.html DOI: 10.4267/2042/47323


Identity Other names: CPETRL3, OSP-L

HGNC (Hugo): CLDN10

Location: 13q32.1

DNA/RNA Transcription Claudin 10 has 3 different transcripts. NP_878268.1 [NCBI Entrez] claudin-10 isoform a: This variant (a) is the longest transcript and encodes claudin-10 isoform a. Its composition is as follows: exons: 5; transcript length: 2549 bps; translation length: 226 residues. NP_008915.1 [NCBI Entrez] claudin-10 isoform b precursor: This variant (b) is different from the isoform (a) above in the 5' UTR and 5' coding region. It uses an alternate promoter, compared to variant a. The resulting isoform (b) has a longer and more distinct N-terminus. Its composition is as follows: exons: 5; transcript length: 949 bps; translation length: 228 residues. NP_001153572.1 [NCBI Entrez] claudin-10 isoform a_i1: This variant (a_v1) uses an alternate

in-frame splice site in the 5' coding region, compared to claudin 10 isoform a. The resulting isoform (a_i1) lacks an internal segment near the N-terminus, compared to isoform a. Its composition is as follows: exons: 2; transcript length: 701 bps; translation length: 73 residues AK055855, BG697724, DA636757, DB544708 (source sequences NCBI).

Protein Note Claudin 10 plays a major role as a component of tight junctions. CLDN10 encodes a member of the claudin family. Claudins are integral membrane proteins and components of tight junction strands. Tight junction strands function as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets. They are also critical in maintaining cell polarity and mediating signals. The expression level of this gene is associated with recurrence of primary hepatocellular carcinoma. Six alternatively spliced transcripts encoding different isoforms of CLDN10 have been reported, but not all of them have been recorded.

The three different isoforms of claudin 10; claudin 10 (a), claudin 10 (b) and claudin 10 (a_i1).

CLDN10 (claudin 10) Lal-Nag M


The four transmembrane, two extracellular, 3 helical and two cytoplasmic domains of claudin protein.

Description 228 amino acids. Modified amino acid residue at position 94 is a phosphoserine. Human and mouse isoforms of CLDN10 have been cloned. Claudin-10 shares between 20 and 45% sequence similarity between other claudin family members at the amino acid level, displaying highest sequence similarity to claudin-15. CLAUDIN10 is a 4-element fingerprint that provides a signature for claudin-10 proteins. The fingerprint was derived from an initial alignment of 2 sequences: the motifs were drawn from conserved regions spanning virtually the full alignment length, focusing on those sections thatcharacterize claudin-10 and distinguish it from other family members - motif 1 lies in the first TM domain; motif 2 resides within in the second TM domain; motifs 3 spans part of the fourth TM domain and part of the C-terminal region; and motif 4 resides within the cytoplasmic C-terminus.

Expression At the cell membrane in 85 organs and 13 developmental stages (Bgee)[P78369].

Localisation Cell membrane.

Function From the KEGG pathway. Claudin 10 as an integral part of tight junction composition plays an important role in Leukocyte migration. They are also important components of cell adhesion molecules and serve as a receptor for the HCV virus via their extracellular loop. hsa04514: Cell adhesion molecules (CAMs) hsa04530: Tight junction hsa04670: Leukocyte transendothelial migration hsa05160: Hepatitis C

Homology The CLDN10 gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, and zebrafish.

Mutations Note Total disease mutations: 0; total SNPs: 5.

CLDN10 (claudin 10) Lal-Nag M


Sequence similarity between the various claudins showing that claudin 10 has the highest sequence similarity to claudin 15.

Implicated in Hepatocellular carcinoma (HCC) Prognosis Claudin 10 is highly expressed in patients suffering from HCC and is an independent prognostic survival factor after surgery. It is closely related to microvessel density and angiogenesis.

Ovarian cancer Disease Ovarian cancer in a chicken model to be used as a basis to study the relevance of CLDN10 expression in ovarian cancer in humans.

Prognosis Claudin 10 mRNA expression was significantly upregulated in cancerous chicken ovaries with respect to normal ovaries implicating it in the etiology of this disease.

References Cheung ST, Leung KL, Ip YC, Chen X, Fong DY, Ng IO, Fan ST, So S.. Claudin-10 expression level is associated with recurrence of primary hepatocellular carcinoma. Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):551-6.

Gunzel D, Stuiver M, Kausalya PJ, Haisch L, Krug SM, Rosenthal R, Meij IC, Hunziker W, Fromm M, Muller D.. Claudin-10 exists in six alternatively spliced isoforms that exhibit distinct localization and function. J Cell Sci. 2009 May 15;122(Pt 10):1507-17. Epub 2009 Apr 21.

Lal-Nag M, Morin PJ.. The claudins. Genome Biol. 2009;10(8):235. Epub 2009 Aug 26. (REVIEW)

Seo HW, Rengaraj D, Choi JW, Ahn SE, Song YS, Song G, Han JY.. Claudin 10 is a glandular epithelial marker in the chicken model as human epithelial ovarian cancer. Int J Gynecol Cancer. 2010 Dec;20(9):1465-73.

Huang GW, Ding X, Chen SL, Zeng L.. Expression of claudin 10 protein in hepatocellular carcinoma: impact on survival. J Cancer Res Clin Oncol. 2011 Aug;137(8):1213-8. Epub 2011 Jun 7.


Lal-Nag M. CLDN10 (claudin 10). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(5):339-341.

Gene Section Review




GATA3 (GATA binding protein 3) Mathieu Tremblay, Maxime Bouchard

Goodman Cancer Research Centre, Department of Biochemistry, McGill University, Montreal, Canada (MT, MB)


Online updated version : http://AtlasGeneticsOncology.org/Genes/GATA3ID107ch10p14.html DOI: 10.4267/2042/47324


Identity Other names: HDR, HDRS, MGC2346, MGC5199, MGC5445

HGNC (Hugo): GATA3

Location: 10p14

DNA/RNA Description The GATA3 locus spans 20,51 kb and contains 6 exons.

Transcription Two alternative exons 1 (1a and 1b) of the Gata3 locus are spliced to a common second exon, which contains the translation start site. All transcripts share exons 2 to 5 but transcript 1a and 1b splice to two variant exons 6

(6a and 6b respectively) giving rise to isoform a (1a-2-5-6a) and isoform b (1b-2-5-6b) (see figure 1) (Asnagli et al., 2002). The functional significance of these isoforms is unclear.

Protein Description The full length GATA3 protein contain either 443 AA (isoform a) or 444 AA (isoform b), corresponding to molecular weights of 47,9 kDa and 48,0 kDa respectively. The GATA3 protein contains two zinc finger motifs of a distinctive form CXNCX (17) and CNXC as well as two transactivation domains (TA1 and TA2). The N-terminal Zn finger (Zn1) is known to stabilize DNA binding and interact with other zinc finger proteins, whereas the C-terminal Zn finger (Zn2) binds DNA.

Figure 1. White boxes indicate a non-coding exonic sequence, and black boxes indicate coding sequences. Gata3 encodes a protein containing 2 transactivation domains (TA1 and TA2) and 2 Zn Finger domains (Zn1 and Zn2).

GATA3 (GATA binding protein 3) Tremblay M, Bouchard M


Expression Hematopoietic system (blood, bone marrow, thymus, B, T, erythroid and myeloid lineages), blood vessels (endothelial cells), adipocytes, adrenal gland, ear, eye, bladder, mammary gland, prostate, seminal vesicle, kidney, CNS, hair follicle.

Localisation Mostly nuclear.

Function GATA3 acts as a transcription factor which binds to the consensus DNA sequence 5'-(A/T)GATA(A/G)-3'. Gata3 gene inactivation in the mouse is embryonic lethal at mid-gestation (between embryonic days E11 and E12) (Tsai et al., 1994; Pandolfi et al., 1995). These mice display massive internal bleeding, marked growth retardation, severe deformities of the brain and spinal cord, and gross aberrations in fetal liver hematopoiesis. Lethality of Gata3 mutant embryos can be rescued by administration of catechol intermediates during pregnancy as it corrects the reduction in noradrenalin synthesis in the sympathetic nervous system (SNS) caused by reduced expression of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH). Pharmacologically rescued mutant embryos present developmental defects in structures derived from cephalic neural crest cells (Lim et al., 2000). In the kidney, Gata3 is important for nephric (Wolffian) duct elongation and metanephric kidney induction (Grote et al., 2006; Grote et al., 2008). Conditional inactivation of Gata3 in the nephric duct leads to hydronephrosis and defective ureter maturation, partly due to the downregulation of the receptor tyrosine kinase gene Ret (Song et al., 2009; Chia et al., 2011). Gata3 plays an important role in mammary gland maturation and cancer. The conditional deletion of Gata3 in the mouse mammary epithelium is associated with a failure in terminal end bud formation at puberty causing severe defects in mammary development. Moreover, Gata3 loss in adult mice leads to an expansion of undifferentiated luminal cells and basement-membrane detachment, which promotes tumor dissemination (Kouros-Mehr et al., 2006; Asselin-Labat et al., 2007; Kouros-Mehr et al., 2008; Kouros-Mehr et al., 2008; Dydensborg et al., 2009). Reexpression of Gata3 drives invasive breast cancer cells to undergo the reversal of epithelial-mesenchymal transition, reducing both the tumorigenicity and metastatic potential through reduction of lysyl oxidase (LOX) expression, a metastasis-promoting, matrix-remodeling protein (Chu et al., 2011; Yan et al., 2010). Moreover, Gata3 interact with BRCA1 to repress the expression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including Foxc1, Foxc2, Cxcl1 and P-cadherin. Loss of GATA3 expression also contributes to drug resistance and

epithelial-to-mesenchymal transition-like phenotypes associated with aggressive BLBCs (Tkocz et al., 2011). In T cells, Gata3 acts at multiple stages of thymocyte differentiation. It is indispensable for early thymic progenitor differentiation (Hosoya et al., 2009) and for thymocytes to pass through beta selection and T cell commitment. Gata3 is also necessary for single-positive CD4 thymocyte development as well as for Th1-Th2 lineage commitment (Ting et al., 1996; Zhang et al., 1997; Zheng and Flavell, 1997; Zhang et al., 1998; Pai et al., 2003). As master regulator of Th2 lineage commitment, GATA3 acts either as a transcriptional activator or repressor through direct action at many critical loci encoding cytokines, cytokine receptors, signaling molecules as well as transcription factors that are involved in the regulation of T(h)1 and T(h)2 differentiation (Jenner et al., 2009). For example, it regulates the expression of Th2 lineage specific cytokine gene such as IL5 and repress the Th1 lineage specific genes IL-12 receptor 2 and STAT4 as well as neutralizing RUNX3 function through protein-protein interaction. Mice lacking Gata3 produce IFN-gamma rather than Th2 cytokines (IL5 and IL13) in response to infection (Zhu et al., 2004). It acts in mutual opposition to the transcription factor T-bet, as T-bet promotes whereas GATA3 represses Fut7 transcription (Hwang et al., 2005). It also acts with Tbx21 to regulate cell lineage-specific expression of lymphocyte homing receptors and cytokine in both Th1 and Th2 lymphocyte subsets (Chen et al., 2006). Enforced expression of Gata3 during T cell development induced CD4(+)CD8(+) double-positive (DP) T cell lymphoma (Nawijn et al., 2001a; Nawijn et al., 2001b). Gata3 is essential for the expression of the cytokines IL-4, IL-5 and IL-13 that mediate allergic inflammation. Gata3 overexpression causes enhanced allergen-induced airway inflammation and airway remodeling, including subepithelial fibrosis, and smooth muscle cell hyperplasia (Kiwamoto et al., 2006). It additionally has a critical function in regulatory T cells and immune tolerance since deletion of Gata3 specifically in regulatory T cells led to a spontaneous inflammatory disorder in mice (Wang et al., 2011). Gata3 is critical for the differentiation and survival of parathyroid progenitor cells through regulation of GCM2/B (Grigorieva et al., 2010). Gata3 is essential for the survival but not the differentiation of sympathetic neurons and adrenal chromaffin cells (Tsarovina et al., 2010) and acts with Hand2 to induce noradrenergic genes during development (Pellegrino et al., 2011). Gata3 drives trophoblast differentiation and has been shown to induce a trophoblast cell fate in embryonic stem cells (Ralston et al., 2010). Gata3 and its close



paralog Gata2 are important for trophectoderm lineage specification (Ray et al., 2009). During adipogenesis, Gata3 is a negative regulator of differentiation which needs to be downregulated to permit expression of the peroxisome proliferator-activated receptor-gamma and preadipocyte to adipocyte transition (Tong et al., 2000). In keratinocytes, Gata3 is a key regulator of KLK1 expression and is involved in growth control and the maintenance of a differentiated state in epithelial cells (Son do et al., 2009). In hair follicle morphogenesis Gata3 controls cell fate decision between the inner root sheath and hair shaft cell (Kaufman et al., 2003; Kurek et al., 2007). Gata3 is essential for lens cells differentiation and proper cell cycle control (Maeda et al., 2009) as well as in the morphogenesis of the mouse inner ear (Karis et al., 2001; Lillevli et al., 2004). It plays an essential role during angiogenesis through ANGPT1-TEK and Ang-1-Tie2-mediated signaling in large vessel endothelial cells. A role for Gata3 in the developing heart was revealed by pharmacological rescue of Gata3-null embryos, which survive until birth and harbor ventricular septal defect (VSD), double-outlet of right ventricle (DORV), anomalies of the aortic arch (AAA) and persistent truncus arteriosus (PTA) (Raid et al., 2009).

Homology GATA3 is a member of the GATA family of proteins comprising 6 paralogs. GATA1, GATA2 and GATA3 are mainly expressed in hematopoiesis, whereas GATA4, GATA5 and GATA6 are expressed in mesoderm and endoderm-derived tissue. All six GATA family members share a highly conserved double zinc-finger DNA-binding domain. GATA3 Zn fingers are most closely conserved with those of GATA1.

Mutations Germinal Deletion of chromosome 10 (del10p) and GATA3 gene mutations leading to haploinsufficiency associated with

HDR syndrome (Van Esch et al., 2000; Nesbit et al., 2004; Ali et al., 2007; Lindstrand et al., 2010).

Somatic Heterozygous frameshift mutations close to the second Zn finger domain of GATA3 are associated with familial and sporadic breast tumors (Ciocca et al., 2009; Arnold et al., 2010).

Implicated in Sporadic breast cancer and familial breast cancer Cytogenetics Somatic mutations in GATA3: familial breast tumors harbored heterozygous frameshift somatic mutations close to the second Zn finger domain.

Oncogenesis GATA3 is mutated in ~5% of sporadic and ~13% of familial breast tumors (Usary et al., 2004; Mehra et al., 2005; Arnold et al., 2010). GATA3 is an important predictor of disease outcome in breast cancer patients whereby low GATA3 expression was a significant predictor of disease-related death (Yoon et al., 2010).

HDR (Barakat) syndrome Disease Familial hypoparathyroidism - deafness - renal defects syndrome. - Hypoparathyroidism. - Sensorineural deafness, bilateral, symmetric, deficit affecting all frequencies but slightly more marked at the higher end of the frequency range. - Renal defects such as aplasia, dysplasia and vesicoureteral reflux, associated or not to genital tract malformation.

Prognosis Depends on the penetrance of renal defects.

Cytogenetics - Deletion of chromosome 10 (del10p). - GATA3 gene mutations leading to functional haploinsufficiency.

Figure 2. Both chromosome deletion and point mutations of the GATA3 locus have been associated with HDR syndrome.



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Tremblay M, Bouchard M. GATA3 (GATA binding protein 3). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(5):342-346.

Gene Section Review




HTRA2 (HtrA serine peptidase 2) Miroslaw Jarzab, Dorota Zurawa-Janicka, Barbara Lipinska

Department of Biochemistry, University of Gdansk, Kladki 24, 80-822 Gdansk, Poland (MJ, DZJ, BL)


Online updated version : http://AtlasGeneticsOncology.org/Genes/HTRA2ID41879ch2p13.html DOI: 10.4267/2042/47325


Identity Other names: OMI, PARK13, PRSS25

HGNC (Hugo): HTRA2

Location: 2p13.1

Local order: Genes flanking HTRA2 in telomere to centromere direction: - DQX1: DEAQ box RNA-dependent ATPase 1 - AUP1: ancient ubiquitous protein 1 - HTRA2 - LOXL3: lysyl oxidase-like 3 - DOK1: docking protein 1

Note Amplification of 2p13-16 has frequently been found in non-Hodgkin's lymphoma, mediastinal thymic B-cell

lymphoma and in some cases of neuroblastoma, ovarian cancer, squamous cell carcinoma of the head and neck, non-small cell lung cancer and synovial sarcoma (Knuutila et al., 1998). Translocations and deletions of region 2p12 were found in acute and chronic lymphocytic leukaemias as well as nonlymphocytic leukaemia and Hodgkin disease (Shapiro et al., 1994). Genetic variations on chromosome 2p12-p13 have been associated with the development of Parkinson's disease (Gasser et al., 1998), Miyoshi myopathy, limb-girdle muscular dystrophy (Liu et al., 1998), Welander myopathy (Ahlberg et al., 1999), acute lymphoblastic childhood leukaemia (Inaba et al., 1991), chronic lymphocytic leukaemia (Richardson et al., 1992) and Burkitt's lymphomas (Lenoir et al., 1982).

Figure 1. Localization and schematic organization of the HTRA2 gene on chromosome 2. The numbers indicate the length in kilo bases. Green boxes represent exons. Exons present in the full-length HTRA2 mRNA (A) and in the short form HTRA2 mRNA (B) are shown. Black boxes indicate untranslated regions.

HTRA2 (HtrA serine peptidase 2) Jarzab M, et al.


DNA/RNA Description The HTRA2 gene encompasses 4152 bases of DNA. HTRA2 has a promoter region of about 300 bp which includes putative binding sites for Sp1, AP-2, Elk-1 and Nrf-2. The coding part is composed of eight exons (Figure 1). The 3' end of HTRA2 cDNA contains a 35 bp noncoding sequence (Faccio et al., 2000b).

Transcription Two alternatively spliced variants of HTRA2 mRNA have been sequenced, a full-length variant, length of 2550 bases, and a short form mRNA, length of 2259 bases (Figure 1). Additional transcript variants have also been described but their sequences have not been determined. The full-length HTRA2 mRNA has an open frame of 1377 bases and is expressed ubiquitously. The gene encodes a 50 kDa protein of 458 amino acids residues (Faccio et al., 2000a). The short form HTRA2 mRNA, lacking two exons: III and VII, is expressed predominantly in the kidney, colon and thyroid (Faccio et al., 2000b). A single-nucleotide polymorphism (SNP) rs1183739 located in the HTRA2 5'UTR has been found in patients with Parkinson's disease (PD). The sequence change is located 586 base pairs upstream of the transcriptional start site of the HTRA2 gene (-586G>C). In vitro transcriptional study revealed that the SNP is associated with an increased expression of the HTRA2 gene in SH-SY5Y and HEK293 cells (Bogaerts et al., 2008a). Other SNPs, the -442C>T mutation identified in the HTRA2 5'UTR and the g.53572436C>G mutation identified in the regulatory region of the gene were found to decrease the HTRA2 expression (Bogaerts et al., 2008a). The HTRA2 gene expression increases in response to cellular stresses causing aberrations in protein structure such as the heat or oxidative shocks, tunicamycin or cisplatin treatment (Gray et al., 2000; Faccio et al., 2000a; Cilenti et al., 2005; Han et al., 2008; Zurawa-Janicka et al., 2008). Upon accumulation of misfolded proteins in the mitochondrial intermembrane space an enhanced expression of HTRA2 as a consequence of ligand-independent activation of estrogen receptor alpha activity has been demonstrated (Papa and Germain, 2011). It was also shown that transcription of the HTRA2 gene is controlled by p53 protein. Enhanced expression of the gene has been observed

in HeLa cells and primary mouse thymocytes treated with etoposide - an agent inducing apoptotic cell death triggered by DNA damage (Jin et al., 2003).

Pseudogene No pseudogenes have been identified.

Protein Note HtrA2 belongs to the HtrA family of evolutionarily conserved ATP-independent serine proteases, homologues of the HtrA (DegP) serine protease from the bacterium Escherichia coli. HtrA proteins are characterized by the presence of a trypsin-like protease domain with the catalytic triad His-Asp-Ser and at least one PDZ domain at the C-terminal end. General function of the HtrA proteins is the defence against cellular stresses (such as heat shock, oxidative stress) causing aberrations in protein structure. At least, four human HtrA proteins have been identified. They are involved in protein quality control, apoptosis and regulation of cell signaling. Disturbances in their functions contribute to neurodegenerative disorders and development of various types of cancer (reviewed by Chien et al., 2009; Clausen et al., 2011; Singh et al., 2011; Zurawa-Janicka et al., 2010).

Description The HTRA2 gene encodes a polypeptide of 458 aa, mass of about 50 kDa. The full-length HtrA2 contains the N-terminal mitochondrial targeting sequence (1-40 aa), a transmembrane domain (105-125 aa), followed by a serine protease domain (150-343 aa) with the catalytic triad His198-Asp228-Ser306, and one PDZ domain (364-445 aa) at the C-terminal end

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