Number 5 May 2014

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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

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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, and also more traditional review articles (“deep insights”) on the above subjects and on surrounding topics. It also present case reports in hematology and educational items in the various related topics for students in Medicine and in Sciences.

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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, Vanessa Le Berre, Anne Malo, Carol Moreau, 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.

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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 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 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 Adriana Zamecnikova (Kuwait) Leukaemia Section

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Volume 18, Number 5, May 2014

Table of contents

Gene Section

BYSL (Bystin-Like) 293 Michiko N Fukuda, Kazuhiro Sugihara DBN1 (drebrin 1) 299 John Chilton NAPA (N-ethylmaleimide-sensitive factor attachment protein, alpha) 301 Nayden G Naydenov, Andrei I Ivanov AUTS2(autism susceptibility candidate 2) 306 Jean-Loup Huret AVEN (apoptosis, caspase activation inhibitor) 311 Inga Maria Melzer, Martin Zörnig FKBP5 (FK506 binding protein 5) 314 Katarzna Anna Ellsworth, Liewei Wang ITGA9 (integrin, alpha 9) 321 Carla Molist, Ana Almazán-Moga, Isaac Vidal, Aroa Soriano, Luz Jubierre, Miguel F Segura, Josep Sánchez de Toledo, Soledad Gallego, Josep Roma KIAA1199 (KIAA1199) 324 Nikki Ann Evensen, Cem Kuscu, Jian Cao MMP19 (matrix metallopeptidase 19) 327 King Chi Chan, Maria Li Lung RPS6KA6 (Ribosomal Protein S6 Kinase, 90kDa, Polypeptide 6) 330 Tuoen Liu, Shousong Cao SIVA1 (SIVA1, Apoptosis-Inducing Factor) 334 João Agostinho Machado-Neto, Fabiola Traina SPRY1 (Sprouty Homolog 1, Antagonist Of FGF Signaling (Drosophila)) 340 Behnam Nabet, Jonathan D Licht TFAP2C (transcription factor AP-2 gamma (activating enhancer binding protein 2 gamma)) 346 Maria V Bogachek, Ronald J Weigel USP1 (ubiquitin specific peptidase 1) 351 Iraia García-Santisteban, Godefridus J Peters, Jose A Rodriguez, Elisa Giovannetti

Leukaemia Section t(3;11)(q12;p15) NUP98/LNP1 356 Jean-Loup Huret t(7;8)(p12;q24) /MYC 358 Jean-Loup Huret

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Deep Insight Section

Adiponectin and cancer 361 Maria Dalamaga, Vassiliki Koumaki

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Gene Section Review

BYSL (Bystin-Like) Michiko N Fukuda, Kazuhiro Sugihara Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA (MNF), Department of Gynecology and Obstetrics, Hamamatsu University School of Medicine, Hamamatsu City, Shizuoka, Japan (KS)

Published in Atlas Database: September 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/BYSLID857ch6p21.html DOI: 10.4267/2042/53636 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract DNA/RNA Review on BYSL, with data on DNA/RNA, on the Description protein encoded and where the gene is implicated. BYSL locates on 6 chromosome 6p21.1 (Pack et al., 1998). Identity It contains 8 exons spanning 10.7 kb of genomic Other names: BYSTIN DNA. HGNC (Hugo): BYSL Protein Location: 6p21.1 Local order: In human chromosome, BYSL gene Description localizes in chromosome 6, between TRFP Human bystin is a 49.6 kDa cytoplasmic protein encoding a transcription mediator, and CCND3 composed of 437 amino acid residues. encoding cyclin D3 (Figure 1). Bystin is a basic protein with isoelectric point 8.10.

Figure 1. Genomic organization of BYSL.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 293 BYSL (Bystin-Like) Fukuda MN, Sugihara K

Figure 2. Blastocyst-dependent localization of bystin protein in the mouse endometrial epithelia. Above: mouse endometrium with implanting blastocyst (Bl) shows bystin protein (red) on the apical side of epithelia. below: mouse endometrium from pseudopregnant female shows bystin at abluminal side of epithelia. Glandular epithelia (ge); luminal epithelia (le).

Bystin protein contains many potential protein proteins localized to the apical side of the epithelia, kinase phosphorylation sites, suggesting an active whereas in their absence bystin protein was role of bystin in signal transduction. localized to the abluminal or basal side of the However, no known structural motif is found in epithelia (Figure 2). This observation suggests the bystin protein. existence of an embryonic factor affecting in a way determining the localization of bystin in the Expression maternal epithelia. The molecular basis underlying BYSL is expressed in trophectoderm cells and apical or basal localization of bystin is presently endometrial epithelial cells during embryo unknown. implantation in human (Aoki and Fukuda, 2000; Bysl is strongly expressed in the adult rat brain Nakayama et al., 2003; Suzuki et al., 1999; Suzuki after injury (Ma et al., 2006; Sheng et al., 2004). et al., 1998). The expression pattern of mouse Bystin is expressed after optic nerve injury in zebra bystin at peri-implantation (Aoki et al., 2006) is fish (Neve et al., 2012). similar to that of mouse trophinin (Nadano et al., Bystin protein was found in mature sperm, of which 2002). function is implicated to sperm motility In the mouse, bystin protein was found in the (Hatakeyama et al., 2008). Bystin is overexpressed blastocyst embryo and endometrial epithelial cells in hepatocellular carcinoma, suggesting its function during peri-implantation period (Aoki et al., 2006). in cell proliferation in liver cancer (Wang et al., Bystin is expressed in mouse endometrial luminal 2009). and glandular epithelial cells throughout hormonal In the Drosophila embryo, bys expression is cycles (Aoki et al., 2006). Bystin in the luminal ubiquitous but relatively weak at early stages, but at epithelia showed a distinct blastocyst-dependent later stages bys expression is strong and specifically pattern: in the presence of blastocysts, bystin localized to larval imaginal discs, suggesting a role

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of bys in cell adhesion. In particular, bys expression suggesting that bystin is essential for mouse is strong in the region of the wing pouch giving rise embryo survival after implantation. However, as to two epithelial sheets of the adult wing that described below, Bysl gene knockdown adhere to one another after the disc everts (Stewart experiments show that bystin is also required for and Nordquist, 2005). survival of pre-implantation stage mouse embryos (Adachi et al., 2007). In the knockout mouse, it is Localisation likely that maternally derived Bysl mRNA masks In 6 weeks human placenta, bystin protein was loss of Bysl at pre-implantation stages. found in the cytoplasm of the syncytiotrophoblast When Bysl siRNAs were microinjected into and cytotrophoblast in the chorionic villi, and in fertilized eggs, compaction at the eight-cell stage endometrial decidual cells at the utero placental occurred normally in vitro (Adachi et al., 2007). interface. In 10 weeks placenta, bystin was Bysl siRNA-injected embryos showed slightly exclusively in the nucli of cytotrophoblast (Suzuki reduced expression of cytokeratin 8 (EndoA), an et al., 1999). In cultured cells, bystin localizes to early trophectoderm marker (Oshima et al., 1983). both the nucleus and cytoplasm (Aoki et al., 2006; While control blastocysts showed assembled Miyoshi et al., 2007). In the nucleus, bystin was cytokeratin structures in the trophectoderm layer, often found in the nucleoli. no organized structures were detected in Bysl siRNA-injected embryos. Consequently, blastocyst Function formation was completely inhibited. These embryos Bystin function in human embryo implantation: failed to hatch from the zona pellucida and could Bystin was originally identified as a cytoplasmic not outgrow in culture, suggesting that the bystin protein that forms a complex with trophinin and functions in trophectoderm differentiation. Bysl tastin in human trophoblastic embryonal carcinoma knockdown also inhibited embryonic stem cell HT-H cells (Fukuda and Nozawa, 1999; Suzuki et proliferation (Adachi et al., 2007). al., 1998). While genes encoding trophinin and Bystin function in stem cells: Mouse bystin gene tastin are only found in mammals, the bystin gene is Bysl has been identified as the stem cell marker conserved across a wide range of eukaryotes, commonly expressed in embryonal, neuronal and including yeast, nematodes, insects, snakes, and hematopoietic stem cells (Ramalho-Santos et al., mammals (Roos et al., 1997; Stewart and Denell, 2002). BYSL is also identified as the major target 1993; Stewart and Nordquist, 2005; Trachtulec and of MYC in B-cells (Basso et al., 2005). Since MYC Forejt, 2001). Trophinin is an intrinsic membrane is one of essential genes for converting somatic protein that mediates cell adhesion by homophilic cells into induced pluripotent stem cell (iPS) trophinin-trophinin binding (Fukuda et al., 1995). (Takahashi and Yamanaka, 2006), these Tastin and bystin are cytoplasmic proteins required observations suggest strongly an essential role of for trophinin to function efficiently as a cell bystin in pluripotent stem cells. Bysl is included in adhesion molecule. In humans, trophinin, tastin and a gene cluster of stem cell markers found on mouse bystin are expressed at the utero-placental interface chromosome 16 (Ramalho-Santos et al., 2002). or at implantation sites (Suzuki et al., 1999). These Bystin function in human sperm motility: Bystin proteins are expressed in human placenta at early regulates sperm motility (Hatakeyama et al., 2008). stages of pregnancy but disappear from the placenta Trophinin plays multiple roles in each cell type after 10 weeks of pregnancy (Aoki and Fukuda, under different conditions. 2000; Fukuda and Nozawa, 1999; Suzuki et al., Bystin function in ribosomal biogenesis: The 1999). yeast bystin homologue ENP1 is essential for In trophoblastic HT-H cells, bystin protein budding yeast to survive (Roos et al., 1997). A associates with trophinin and ErbB4 in the temperature-sensitive ENP1-null mutant showed cytoplasm (Sugihara et al., 2007). When trophinin- defective processing of ribosomal RNA (rRNA) mediated cell adhesion takes place on the cell (Chen et al., 2003). Studies of ribosomal biogenesis surface, bystin dissociates from trophinin and in yeast indicate that Enp1 is required to synthesize tyrosine phosphorylation of ErbB4 takes place, 40S ribosomal subunits by functioning in their suggesting the mechanism underlying the nuclear export (Schafer et al., 2003). trophectoderm cell activation upon human embryo Eukaryotic ribosome formation occurs implantation (Figure 3). Bystin functions as predominantly in nucleoli, but late maturation steps molecular switch in trophinin-mediated signal occur in both the nucleoplasm and cytoplasm. transduction in trophoblastic cells (Fukuda and Location of bystin in the cytoplasm during G1 and Sugihara, 2007; Fukuda and Sugihara,2008; Fukuda its nuclear localization prior to mitosis suggest that and Sugihara,2012). bystin plays dual roles in cell growth and Bystin function in mouse embryo: Bystin null proliferation in mammalian cells. mouse embryos implanted successfully but died Although bystin exhibits activities similar to Enp1, soon after implantation (Aoki et al., 2006), human bystin cannot rescue the lethal phenotype of

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 295 BYSL (Bystin-Like) Fukuda MN, Sugihara K

Enp1-null yeast mutant, suggesting that ribosomal the 40S subunit before translation in human cells RNA processing pathways in multicellular (Miyoshi et al., 2007), bystin may also function in organisms differ from those in yeast and that the final step of 40S subunit synthesis in the bystin's activities may have been modified during cytoplasm. evolution. Bystin associates with undefined nuclear particles Recent studies reveal that maturation of the 40S following actinomycin D treatment of HeLa cells ribosomal subunit precursors in mammals includes (Miyoshi et al., 2007). an additional step during processing of the internal Soluble proteins involved in ribosome biogenesis transcribed spacer 1 (ITS1), and that coordination may shuttle between the nucleolus and nucleoplasm between maturation and nuclear export of pre-40S (Dez and Tollervey, 2004). particles has evolved differently in yeast and Given the dependence of cell proliferation on mammalian cells (Carron et al., 2011). ribosome biogenesis, when biogenesis is halted by In higher organisms, it was long believed that nucleolar stress this system may allow rapid rRNA processing is completed within the nucleus. ribosome re-synthesis following relief from stress However, maturation of the 40S subunit, including (Phipps et al., 2011). final processing of 18S rRNA, occurs in the cytoplasm in human cells (Zemp and Kutay, 2007). Homology Since part of cytoplasmic bystin is associated with None.

Figure 3. Role of bystin protein in signal transduction. Prior to trophinin-mediated cell adhesion or in silent trophectoderm cells, ErbB4 is arrested by trophinin-bystin complex. When trophinin-mediated cell adhesion occurs or trophinin-binding GWRQ peptide mimics trophinin-mediated cell adhesion, bystin dissociates from trophinin leading into tyrosine phosphorylation of ErbB4 (Sugihara et al., 2007).

Figure 4. Ribosomal biogenesis and rRNA processing in eukaryotic cells. The initial pre-rRNA transcript is first transcribed from repetitive ribosomal DNA genes by RNA polymerase I in the nucleolus. rRNA precursors are then processed, chemically modified, and folded in the nucleolus, and ribosomal proteins, which are translated in the cytoplasm and imported into this organelle, concomitantly assemble with pre-rRNAs. There are two alternative pathways for rRNA processing in human HeLa cells. Bystin is likely involved in processing of a 21S intermediate, of which the final product, 18S rRNA, is included in the 40S small subunit. Bystin is involved in 18S rRNA processing.

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Implicated in Oct;99(2):447-55 Stewart MJ, Denell R. Mutations in the Drosophila gene Various cancers encoding ribosomal protein S6 cause tissue overgrowth. Mol Cell Biol. 1993 Apr;13(4):2524-35 Note Fukuda MN, Sato T, Nakayama J, Klier G, Mikami M, Aoki Cancer progression depends on cell growth and cell D, Nozawa S. Trophinin and tastin, a novel cell adhesion cycle progression. molecule complex with potential involvement in embryo Upregulation of BYSL is implicated to following implantation. Genes Dev. 1995 May 15;9(10):1199-210 cancers. Roos J, Luz JM, Centoducati S, Sternglanz R, Lennarz WJ. ENP1, an essential gene encoding a nuclear protein Gastric cancer that is highly conserved from yeast to humans. Gene. 1997 Note Jan 31;185(1):137-46 Genome-wide genomic copy aberration analysis of Pack SD, Pak E, Tanigami A, Ledbetter DH, Fukuda MN. gastric cancer revealed several genes and BYSL Assignment1 of the bystin gene BYSL to human was identified as one of them along with CDC6, chromosome band 6p21.1 by in situ hybridization. Cytogenet Cell Genet. 1998;83(1-2):76-7 SEC61G, ANP32E, BYSL and FDFT1 (Tsukamoto et al., 2008). Suzuki N, Zara J, Sato T, Ong E, Bakhiet N, Oshima RG, Watson KL, Fukuda MN. A cytoplasmic protein, bystin, Hepatocellular carcinoma (HCC) interacts with trophinin, tastin, and cytokeratin and may be involved in trophinin-mediated cell adhesion between Note trophoblast and endometrial epithelial cells. Proc Natl Acad Expression levels of BYSL mRNA and protein in Sci U S A. 1998 Apr 28;95(9):5027-32 human HCC specimens were markedly increased Fukuda MN, Nozawa S. Trophinin, tastin, and bystin: a compared with those seen in adjacent non- complex mediating unique attachment between cancerous tissue (Wang et al., 2009). trophoblastic and endometrial epithelial cells at their BYSL shRNA decreased HCC cell proliferation in respective apical cell membranes. Semin Reprod Endocrinol. 1999;17(3):229-34 vitro, induced apoptosis and partially arrested the cell cycle in the G2/M phase. Suzuki N, Nakayama J, Shih IM, Aoki D, Nozawa S, In vivo, HCC cells treated with BYSL siRNA failed Fukuda MN. Expression of trophinin, tastin, and bystin by trophoblast and endometrial cells in human placenta. Biol to form tumors in nude mice after subcutaneous Reprod. 1999 Mar;60(3):621-7 implantation. Aoki R, Fukuda MN. Recent molecular approaches to BYSL was found at multiple stages during elucidate the mechanism of embryo implantation: trophinin, nucleologenesis, including in nucleolus-derived bystin, and tastin as molecules involved in the initial foci (NDF), perichromosomal regions and the attachment of blastocysts to the uterus in humans. Semin prenucleolar body (PNB) during mitosis. Reprod Med. 2000;18(3):265-71 BYSL depletion remarkably suppressed NDF and Trachtulec Z, Forejt J. Synteny of orthologous genes PNB formation, and disrupted nucleoli assembly conserved in mammals, snake, fly, nematode, and fission after mitosis, resulting in increased apoptosis and yeast. Mamm Genome. 2001 Mar;12(3):227-31 reduced tolerance of HCC cells to serum starvation. Nadano D, Sugihara K, Paria BC, Saburi S, Copeland NG, Gilbert DJ, Jenkins NA, Nakayama J, Fukuda MN. Prostate cancers Significant differences between mouse and human trophinins are revealed by their expression patterns and Note targeted disruption of mouse trophinin gene. Biol Reprod. In prostate cancer cells, which adhere to neurons, 2002 Feb;66(2):313-21 bystin protein is expressed in a manner suggesting a Ramalho-Santos M, Yoon S, Matsuzaki Y, Mulligan RC, role in cell-cell contact and cell growth (Ayala et Melton DA. "Stemness": transcriptional profiling of al., 2006). embryonic and adult stem cells. Science. 2002 Oct 18;298(5593):597-600 B cell lymphoma Chen W, Bucaria J, Band DA, Sutton A, Sternglanz R. Note Enp1, a yeast protein associated with U3 and U14 Indeed BYSL and CCND3 are both elevated in B snoRNAs, is required for pre-rRNA processing and 40S subunit synthesis. Nucleic Acids Res. 2003 Jan cell lymphoma (Bea, 2010; Kasugai et al., 2005), 15;31(2):690-9 which is consistent with close proximity of BYSL Nakayama J, Aoki D, Suga T, Akama TO, Ishizone S, and CCND3 encoding cyclin D3 (Figure 1) Yamaguchi H, Imakawa K, Nadano D, Fazleabas AT, suggesting their co-ordinated role in normal and Katsuyama T, Nozawa S, Fukuda MN. Implantation- malignant cells. dependent expression of trophinin by maternal fallopian tube epithelia during tubal pregnancies: possible role of human chorionic gonadotrophin on ectopic pregnancy. Am References J Pathol. 2003 Dec;163(6):2211-9 Oshima RG, Howe WE, Klier FG, Adamson ED, Shevinsky Schäfer T, Strauss D, Petfalski E, Tollervey D, Hurt E. The LH. Intermediate filament protein synthesis in path from nucleolar 90S to cytoplasmic 40S pre- preimplantation murine embryos. Dev Biol. 1983 ribosomes. EMBO J. 2003 Mar 17;22(6):1370-80

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Dez C, Tollervey D. Ribosome synthesis meets the cell Nozawa S, Nakayama J, Mustelin T, Ruoslahti E, cycle. Curr Opin Microbiol. 2004 Dec;7(6):631-7 Yamaguchi N, Fukuda MN. Trophoblast cell activation by trophinin ligation is implicated in human embryo Sheng J, Yang S, Xu L, Wu C, Wu X, Li A, Yu Y, Ni H, implantation. Proc Natl Acad Sci U S A. 2007 Mar Fukuda M, Zhou J. Bystin as a novel marker for reactive 6;104(10):3799-804 astrocytes in the adult rat brain following injury. Eur J Neurosci. 2004 Aug;20(4):873-84 Zemp I, Kutay U. Nuclear export and cytoplasmic maturation of ribosomal subunits. FEBS Lett. 2007 Jun Basso K, Margolin AA, Stolovitzky G, Klein U, Dalla- 19;581(15):2783-93 Favera R, Califano A. Reverse engineering of regulatory networks in human B cells. Nat Genet. 2005 Hatakeyama S, Sugihara K, Lee SH, Nadano D, Apr;37(4):382-90 Nakayama J, Ohyama C, Fukuda MN. Enhancement of human sperm motility by trophinin binding peptide. J Urol. Kasugai Y, Tagawa H, Kameoka Y, Morishima Y, 2008 Aug;180(2):767-71 Nakamura S, Seto M. Identification of CCND3 and BYSL as candidate targets for the 6p21 amplification in diffuse Tsukamoto Y, Uchida T, Karnan S, Noguchi T, Nguyen LT, large B-cell lymphoma. Clin Cancer Res. 2005 Dec Tanigawa M, Takeuchi I, Matsuura K, Hijiya N, Nakada C, 1;11(23):8265-72 Kishida T, Kawahara K, Ito H, Murakami K, Fujioka T, Seto M, Moriyama M. Genome-wide analysis of DNA copy Stewart MJ, Nordquist EK. Drosophila Bys is nuclear and number alterations and gene expression in gastric cancer. shows dynamic tissue-specific expression during J Pathol. 2008 Dec;216(4):471-82 development. Dev Genes Evol. 2005 Feb;215(2):97-102 Wang H, Xiao W, Zhou Q, Chen Y, Yang S, Sheng J, Yin Aoki R, Suzuki N, Paria BC, Sugihara K, Akama TO, Raab Y, Fan J, Zhou J. Bystin-like protein is upregulated in G, Miyoshi M, Nadano D, Fukuda MN. The Bysl gene hepatocellular carcinoma and required for nucleologenesis product, bystin, is essential for survival of mouse embryos. in cancer cell proliferation. Cell Res. 2009 FEBS Lett. 2006 Nov 13;580(26):6062-8 Oct;19(10):1150-64 Ayala GE, Dai H, Li R, Ittmann M, Thompson TC, Rowley Bea S. Amplifications and target genes in diffuse large B- D, Wheeler TM. Bystin in perineural invasion of prostate cell lymphoma: real targets or consequences of structural cancer. Prostate. 2006 Feb 15;66(3):266-72 features of the genome? Leuk Lymphoma. 2010 Ma L, Yin M, Wu X, Wu C, Yang S, Sheng J, Ni H, Fukuda May;51(5):743-4 MN, Zhou J. Expression of trophinin and bystin identifies Carron C, O'Donohue MF, Choesmel V, Faubladier M, distinct cell types in the germinal zones of adult rat brain. Gleizes PE. Analysis of two human pre-ribosomal factors, Eur J Neurosci. 2006 May;23(9):2265-76 bystin and hTsr1, highlights differences in evolution of Takahashi K, Yamanaka S. Induction of pluripotent stem ribosome biogenesis between yeast and mammals. cells from mouse embryonic and adult fibroblast cultures Nucleic Acids Res. 2011 Jan;39(1):280-91 by defined factors. Cell. 2006 Aug 25;126(4):663-76 Phipps KR, Charette J, Baserga SJ. The small subunit Adachi K, Soeta-Saneyoshi C, Sagara H, Iwakura Y. processome in ribosome biogenesis—progress and Crucial role of Bysl in mammalian preimplantation prospects. Wiley Interdiscip Rev RNA. 2011 Jan- development as an integral factor for 40S ribosome Feb;2(1):1-21 biogenesis. Mol Cell Biol. 2007 Mar;27(6):2202-14 Neve LD, Savage AA, Koke JR, García DM. Activating Miyoshi M, Okajima T, Matsuda T, Fukuda MN, Nadano D. transcription factor 3 and reactive astrocytes following Bystin in human cancer cells: intracellular localization and optic nerve injury in zebrafish. Comp Biochem Physiol C function in ribosome biogenesis. Biochem J. 2007 Jun Toxicol Pharmacol. 2012 Mar;155(2):213-8 15;404(3):373-81 This article should be referenced as such: Sugihara K, Sugiyama D, Byrne J, Wolf DP, Lowitz KP, Kobayashi Y, Kabir-Salmani M, Nadano D, Aoki D, Fukuda MN, Sugihara K. BYSL (Bystin-Like). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):293-298.

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Gene Section Short Communication

DBN1 (drebrin 1) John Chilton Biomedical Neuroscience Research Group, University of Exeter Medical School, Hatherly Laboratories, Prince of Wales Road, Exeter EX4 4PS, UK (JC)

Published in Atlas Database: September 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/DBN1ID51520ch5q35.html DOI: 10.4267/2042/53637 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

acids (DBN1a has 649 amino acids, DBN1b has Abstract 651 amino acids). Review on DBN1, with data on DNA/RNA, on the The N-terminus contains an ADF/Cofilin homology protein encoded and where the gene is implicated. domain (Poukkula et al., 2011) followed by a coiled-coil and a helical domain which each contain Identity an actin-binding site (Worth et al., 2013). The C-terminus contains no identifiable domain Other names: D0S117E structure apart from two Homer binding motifs and HGNC (Hugo): DBN1 can provide intramolecular regulation of F-actin Location: 5q35.3 binding (Worth et al., 2013). In some species (chick, rat) developmental DNA/RNA regulation of the protein occurs such that at the earliest stages of development an embryonic 'E1' Description isoform is expressed. 14 exons. This is then downregulated in favour of an 'E2' isoform containing a 43 amino acid insertion which Transcription itself is subsequently superseded by the adult 'A' Two alternatively spliced isoforms: isoform containing a further 46 amino acids - NCBI LOCUS NM_004395 2942 bp corresponds insertion adjacent to the previous one (Kojima et to DBN1a variant, al., 1993). - NCBI LOCUS NM_080881 3058 bp corresponds In humans E2 appears to be the predominant to DBN1b variant. isoform. Expression Protein DBN1 is widely expressed in the nervous system and is also found in other organs, predominantly Description kidney, stomach, lung and skin (Dun and Chilton, DBN1 encodes a 71 kDa protein of ~650 amino 2010).

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 299 DBN1 (drebrin 1) Chilton J

Localisation Majoul I. Drebrin is a novel connexin-43 binding partner that links gap junctions to the submembrane cytoskeleton. DBN1 localises to actin-rich structures within cells Curr Biol. 2004 Apr 20;14(8):650-8 such as the leading edge of neuronal growth cones Peitsch WK, Hofmann I, Bulkescher J, Hergt M, Spring H, (Geraldo et al., 2008; Dun et al., 2012) and Bleyl U, Goerdt S, Franke WW. Drebrin, an actin-binding, intercellular junctions (Butkevich et al., 2004; cell-type characteristic protein: induction and localization in Rehm et al., 2013). epithelial skin tumors and cultured keratinocytes. J Invest Dermatol. 2005 Oct;125(4):761-74 Function Geraldo S, Khanzada UK, Parsons M, Chilton JK, Gordon- At the molecular level, DBN1 stabilises actin Weeks PR. Targeting of the F-actin-binding protein drebrin filaments (Mikati et al., 2013). It may provide a link by the microtubule plus-tip protein EB3 is required for neuritogenesis. Nat Cell Biol. 2008 Oct;10(10):1181-9 between the actin and microtubule networks (Geraldo et al., 2008) and is required for neuronal Dun XP, Chilton JK. Control of cell shape and plasticity migration (Dun et al., 2012). during development and disease by the actin-binding protein Drebrin. Histol Histopathol. 2010 Apr;25(4):533-40 Drebrin function can be regulated by the phosphorylation state of distinct serine residues due Wang X, Björklund S, Wasik AM, Grandien A, Andersson P, Kimby E, Dahlman-Wright K, Zhao C, Christensson B, to the actions of Cdk5 (Worth et al., 2013) and Sander B. Gene expression profiling and chromatin PTEN (Kreis et al., 2013). immunoprecipitation identify DBN1, SETMAR and HIG2 as direct targets of SOX11 in mantle cell lymphoma. PLoS Homology One. 2010 Nov 22;5(11):e14085 Drebrin is conserved across vertebrates, especially Poukkula M, Kremneva E, Serlachius M, Lappalainen P. in the first 300 amino acids containing the Actin-depolymerizing factor homology domain: a ADF/Cofilin homology, coiled-coil and helical conserved fold performing diverse roles in cytoskeletal domains. The closest relative in invertebrate species dynamics. Cytoskeleton (Hoboken). 2011 Sep;68(9):471- is actin-binding protein 1 (ABP1). 90 Vaskova M, Kovac M, Volna P, Angelisova P, Mejstrikova E, Zuna J, Brdicka T, Hrusak O. High expression of Implicated in cytoskeletal protein drebrin in TEL/AML1pos B-cell precursor acute lymphoblastic leukemia identified by a Mantle cell lymphoma novel monoclonal antibody. Leuk Res. 2011 Note Aug;35(8):1111-3 Drebrin is a direct target of Sox11 in primary Dun XP, Bandeira de Lima T, Allen J, Geraldo S, Gordon- mantle cell lymphomas (Wang et al., 2010). Weeks P, Chilton JK. Drebrin controls neuronal migration through the formation and alignment of the leading B-cell precursor acute lymphoblastic process. Mol Cell Neurosci. 2012 Mar;49(3):341-50 leukemia (BCP-ALL) Kreis P, Hendricusdottir R, Kay L, Papageorgiou IE, van Diepen M, Mack T, Ryves J, Harwood A, Leslie NR, Kann Note O, Parsons M, Eickholt BJ. Phosphorylation of the actin High levels of drebrin protein expression in BCP- binding protein Drebrin at S647 is regulated by neuronal ALL (Vaskova et al., 2011). activity and PTEN. PLoS One. 2013;8(8):e71957 Skin tumours (varied) Mikati MA, Grintsevich EE, Reisler E. Drebrin-induced stabilization of actin filaments. J Biol Chem. 2013 Jul Note 5;288(27):19926-38 Drebrin levels are increased compared to control Rehm K, Panzer L, van Vliet V, Genot E, Linder S. Drebrin skin samples in basal cell carcinoma, squamous cell preserves endothelial integrity by stabilizing nectin at carcinoma, melanoma and leiomyosarcoma (Peitsch adherens junctions. J Cell Sci. 2013 Aug 15;126(Pt et al., 2005). 16):3756-69 Worth DC, Daly CN, Geraldo S, Oozeer F, Gordon-Weeks References PR. Drebrin contains a cryptic F-actin-bundling activity regulated by Cdk5 phosphorylation. J Cell Biol. 2013 Sep Kojima N, Shirao T, Obata K. Molecular cloning of a 2;202(5):793-806 developmentally regulated brain protein, chicken drebrin A and its expression by alternative splicing of the drebrin This article should be referenced as such: gene. Brain Res Mol Brain Res. 1993 Jul;19(1-2):101-14 Chilton J. DBN1 (drebrin 1). Atlas Genet Cytogenet Oncol Butkevich E, Hülsmann S, Wenzel D, Shirao T, Duden R, Haematol. 2014; 18(5):299-300.

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NAPA (N-ethylmaleimide-sensitive factor attachment protein, alpha) Nayden G Naydenov, Andrei I Ivanov Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA (NGN), Department of Human and Molecular Genetics, Virginia Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA (AII)

Published in Atlas Database: September 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/NAPAID44025ch19q13.html DOI: 10.4267/2042/53638 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

19q13 and consists of 11 exons and 10 introns (fig. Abstract 1) with an open reading frame of 1839 bp. Review on NAPA, with data on DNA/RNA, on the The NAPA promoter has not been functionally protein encoded and where the gene is implicated. explored. Identity Transcription Other names: SNAPA The predominant transcript variant (1) of the NAPA gene encodes a functional protein of 295 amino HGNC (Hugo): NAPA acids. Location: 19q13.32 The second transcript of 1521 bp is predicted to Local order: The human NAPA gene maps on encode a 256 amino acid protein. 19q13 between the ZNF541 (zing finger protein This variant (2) uses an alternate splice site in the 3' 541) and the KPTN, (kaptin) (actin binding protein) terminal exon, compared to variant 1. loci. This variant is represented as non-coding because Note: No translocations reported. the use of the alternate splice site renders the resulting transcript a candidate for nonsense- DNA/RNA mediated mRNA decay (NMD). The third transcript, variant (3), is 1668 bp. Variant Description (3) lacks two consecutive internal exons, compared The NAPA gene spans 27,61 kb on chromosome to variant 1.

Figure 1. Schematic representation of the genomic structure of human NAPA gene-transcript variant 1, (ENST00000263354). Exons are represented by red boxes while introns appear as waved black lines. The length of exons in (bp) is shown in the red boxes, and that of the introns is presented at the bottom blue boxes (not to scale). The relative position of ATG start and TAA stop codons are indicated with black arrows.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 301 NAPA (N-ethylmaleimide-sensitive factor attachment protein, alpha) Naydenov NG, Ivanov AI

Figure 2. A model depicting vesicle fusion events according to the SNARE hypothesis. During the initial docking step, v- SNARE and t-SNARE bind creating a complex that drives pore formation and fusion of the two opposing membranes. After the fusion step, NAPA is recruited to the cys-SNARE complex allowing NSF binding. Next the ATPase activity of NSF and conformational changes of both NSF and NAPA disassemble the cys-SNARE complex, and release its components for recycling in subsequent fusion events.

This variant is also represented as non-coding contrast, NAPA and NAPG have only about 25% because the use of the 5'-most expected sequence identity. Structural information is translational start codon, as used in variant 1, also available for the yeast homolog of NAPA, Sec17 makes this transcript a candidate for NMD. (Rice and Brunger, 1999), and zebrafish NAPG Additionally, 2 alternative transcribed variants are (Bitto et al., 2008). Both homologs represent predicted to exist via the automatic annotation elongated proteins comprised of an extended program, Havana. twisted sheet of α-helical hairpins and a helical- However, these predicted transcripts need to be bundle domain at the carboxy-terminal end. experimentally confirmed. Expression Pseudogene NAPA is ubiquitously expressed in various None discovered. mammalian cells and tissues. In mouse tissues, its expression level is highest in the brain, spleen, and Protein testis (Whiteheart et al., 1993). Data from the human gene atlas has shown that NAPA is Description expressed at the highest level in heart, liver, lung, The sequence of the predicted 295-amino acid; and placenta. Regulation of NAPA expression 33233 Da human protein encoded by NAPA shares remains unexplored. One recent report 37%, 60%, and 81% identity with sequences in demonstrated decreased protein levels of NAPA in yeast (Sacharomyces cerevisiae), Drosophila brain synaptosomes of rats subjected to oxidative melanogaster, and zebrafish (Danio rerio). NAPA stress (Kaneai et al., 2013). belongs to a protein family comprised of, in higher eukaryotes, three homologues named NAPA, Localisation soluble NSF attachment protein beta (NAPB), and In polarized epithelial cells such as alveolar type II soluble NSF attachment protein gamma (NAPG) cells, T84, and SK-CO15 human colonic epithelial (Clary et al., 1990). Amino acid sequence cells NAPA predominantly localizes in the plasma comparison of bovine proteins show that NAPA membrane with significant enrichment at the apical and NAPB are most related to each other with 83% junctional complex (Abonyo et al., 2003; Naydenov amino acid identity (Whiteheart et al., 1993). In et al., 2012a). By contrast, in contact-naïve

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 302 NAPA (N-ethylmaleimide-sensitive factor attachment protein, Naydenov NG, Ivanov AI alpha)

epithelial cells, NAPA accumulates in the perinuclear intracellular compartment that Mutations resembles the Golgi complex (Naydenov et al., Note 2012a). A missense G to A transition that leads to a change Function from methionine to isoleucine (M105I) has been detected in mice (Chae et al., 2004; Hong et al., One of the most-studied intracellular functions of 2004). NAPA involves regulation of NSF-dependent This mutation leads to the appearance of the so- vesicle fusion (Andreeva et al., 2006). According to called hyh (hydrocephalus with hop gait) phenotype the so-called "SNARE (soluble NSF attachment and also impairs acrosomal exocytosis in sperm protein receptor) hypothesis" vesicle fusion is (Bátiz et al., 2009). driven by specific associations of complementary Other mutations have not been found associated SNARE proteins residing on the vesicle (v- with this gene potentially because of the multiple SNAREs) and target (t-SNAREs) membranes roles of NAPA in critical cellular functions which (Chen and Scheller, 2001). These proteins form a would prevent survival of cells with dysfunctional core SNARE complex consisting of a parallel four- NAPA mutations. helix bundle. This complex drives the opposing membranes to a close apposition, and subsequently to a complete Implicated in fusion (fig. 2). Eukaryotic cells use an Colorectal cancer evolutionarily-conserved mechanism to disassemble and recycle the cys-SNARE complex Note that is formed after the fusion of two membranes A study utilizing patients with small (Barnard et al., 1997). This mechanism involves a undifferentiated colorectal cancer revealed a hexameric ATPase, NSF, and its adaptor protein, significant increase of NAPA immunoreactivity in NAPA (Vivona et al., 2013; Wilson et al., 1992; cancer cells that correlated with a more aggressive Winter et al., 2009). NAPA interacts with the course of the disease (Grabowski et al., 2002). SNARE complex, recruits NSF, stimulates NSF Down syndrome activity, and transduces a conformational change of Note NSF to drive SNARE disassembly (fig. 2). NAPA One study has analyzed expression of NAPA was implicated in the regulation of numerous protein in fetal cortex samples of patients with trafficking/fusion events in different cellular Down Syndrome. compartments (Andreeva et al., 2006). Examples of The study reported a significant decrease in NAPA this regulation include ER-Golgi transport, intra- expression compared to control samples that Golgi vesicle fusion, trafficking from the trans- correlated with deterioration of the neuronal Golgi network to the plasma membrane, dendritic tree (Weitzdoerfer et al., 2001). Another neuromediator exocytosis, and synaptic vesicle study demonstrated a loss of NAPA homolog, fusion (Barnard et al., 1997; Burgalossi et al., 2010; NAPB, in brain specimens of adult patients with Clary et al., 1990; Low et al., 1998; Peter et al., Down syndrome (Yoo et al., 2001). 1998; Xu et al., 2002). Interestingly, recent studies discovered several NSF-independent activities of Huntington's disease NAPA. These activities involve assembly of Note epithelial junctions (Andreeva et al., 2005; Marked elevation of NAPA expression was Naydenov et al., 2012a), suppression of cell observed by Western blotting of hippocampus apoptosis (Naydenov et al., 2012b; Wu and Chao, samples from patients with Huntington's diseases as 2010), and autophagy (Naydenov et al., 2012c), as compared to age-matched controls (Morton et al., well as regulation of store-operated calcium entry 2001). (Miao et al., 2013). Such NSF-independent functions are likely to Atopic dermatitis depend on NAPA interactions with different Note binding partners. For example, NAPA may A proteomic analysis of peripheral blood suppress apoptosis due to its binding to the ER- leukocytes demonstrated significant resident, pro-apoptotic protein BNIP1 (Nakajima et downregulation of NAPA expression in patients al., 2004). Furthermore, NAPA-dependent with atopic dermatitis as compared to control regulation of autophagy can be mediated by its subjects (Kim et al., 2008). This decrease was ability to interact and dephosphorylate AMP- validated by Western blotting analysis and NAPA activated protein kinase (Wang and Brautigan, level was suggested as a possible biomarker for the 2013). disease.

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alpha-soluble N-ethylmaleimide-sensitive fusion To be noted attachment protein in alveolar type II cells: implications in lung surfactant secretion. Am J Respir Cell Mol Biol. 2003 Acknowledgments: the authors thank Alex Feygin Sep;29(3 Pt 1):273-82 for critical reading of the manuscript. This work Chae TH, Kim S, Marz KE, Hanson PI, Walsh CA. The hyh was supported in part by National Institute of mutation uncovers roles for alpha Snap in apical protein Health grants RO1 DK083968 and R01 DK084953 localization and control of neural cell fate. Nat Genet. 2004 to A.I.I. Mar;36(3):264-70 Hong HK, Chakravarti A, Takahashi JS. The gene for References soluble N-ethylmaleimide sensitive factor attachment protein alpha is mutated in hydrocephaly with hop gait Clary DO, Griff IC, Rothman JE. SNAPs, a family of NSF (hyh) mice. Proc Natl Acad Sci U S A. 2004 Feb attachment proteins involved in intracellular membrane 10;101(6):1748-53 fusion in animals and yeast. Cell. 1990 May 18;61(4):709- 21 Nakajima K, Hirose H, Taniguchi M, Kurashina H, Arasaki K, Nagahama M, Tani K, Yamamoto A, Tagaya M. Wilson DW, Whiteheart SW, Wiedmann M, Brunner M, Involvement of BNIP1 in apoptosis and endoplasmic Rothman JE. A multisubunit particle implicated in reticulum membrane fusion. EMBO J. 2004 Aug membrane fusion. J Cell Biol. 1992 May;117(3):531-8 18;23(16):3216-26 Whiteheart SW, Griff IC, Brunner M, Clary DO, Mayer T, Andreeva AV, Kutuzov MA, Vaiskunaite R, Profirovic J, Buhrow SA, Rothman JE. SNAP family of NSF attachment Meigs TE, Predescu S, Malik AB, Voyno-Yasenetskaya T. proteins includes a brain-specific isoform. Nature. 1993 G alpha12 interaction with alphaSNAP induces VE- Mar 25;362(6418):353-5 cadherin localization at endothelial junctions and regulates barrier function. J Biol Chem. 2005 Aug 26;280(34):30376- Barnard RJ, Morgan A, Burgoyne RD. Stimulation of NSF 83 ATPase activity by alpha-SNAP is required for SNARE complex disassembly and exocytosis. J Cell Biol. 1997 Andreeva AV, Kutuzov MA, Voyno-Yasenetskaya TA. A Nov 17;139(4):875-83 ubiquitous membrane fusion protein alpha SNAP: a potential therapeutic target for cancer, diabetes and Low SH, Chapin SJ, Wimmer C, Whiteheart SW, Kömüves neurological disorders? Expert Opin Ther Targets. 2006 LG, Mostov KE, Weimbs T. The SNARE machinery is Oct;10(5):723-33 involved in apical plasma membrane trafficking in MDCK cells. J Cell Biol. 1998 Jun 29;141(7):1503-13 Bitto E, Bingman CA, Kondrashov DA, McCoy JG, Bannen RM, Wesenberg GE, Phillips GN Jr. Structure and Peter F, Wong SH, Subramaniam VN, Tang BL, Hong W. dynamics of gamma-SNAP: insight into flexibility of Alpha-SNAP but not gamma-SNAP is required for ER- proteins from the SNAP family. Proteins. 2008 Jan Golgi transport after vesicle budding and the Rab1- 1;70(1):93-104 requiring step but before the EGTA-sensitive step. J Cell Sci. 1998 Sep;111 ( Pt 17):2625-33 Kim WK, Cho HJ, Ryu SI, Hwang HR, Kim DH, Ryu HY, Chung JW, Kim TY, Park BC, Bae KH, Ko Y, Lee SC. Rice LM, Brunger AT. Crystal structure of the vesicular Comparative proteomic analysis of peripheral blood transport protein Sec17: implications for SNAP function in mononuclear cells from atopic dermatitis patients and SNARE complex disassembly. Mol Cell. 1999 Jul;4(1):85- healthy donors. BMB Rep. 2008 Aug 31;41(8):597-603 95 Bátiz LF, De Blas GA, Michaut MA, Ramírez AR, Chen YA, Scheller RH. SNARE-mediated membrane Rodríguez F, Ratto MH, Oliver C, Tomes CN, Rodríguez fusion. Nat Rev Mol Cell Biol. 2001 Feb;2(2):98-106 EM, Mayorga LS. Sperm from hyh mice carrying a point Morton AJ, Faull RL, Edwardson JM. Abnormalities in the mutation in alphaSNAP have a defect in acrosome synaptic vesicle fusion machinery in Huntington's disease. reaction. PLoS One. 2009;4(3):e4963 Brain Res Bull. 2001 Sep 15;56(2):111-7 Winter U, Chen X, Fasshauer D. A conserved membrane Weitzdoerfer R, Dierssen M, Fountoulakis M, Lubec G. attachment site in alpha-SNAP facilitates N- Fetal life in Down syndrome starts with normal neuronal ethylmaleimide-sensitive factor (NSF)-driven SNARE density but impaired dendritic spines and synaptosomal complex disassembly. J Biol Chem. 2009 Nov structure. J Neural Transm Suppl. 2001;(61):59-70 13;284(46):31817-26 Yoo BC, Cairns N, Fountoulakis M, Lubec G. Burgalossi A, Jung S, Meyer G, Jockusch WJ, Jahn O, Synaptosomal proteins, beta-soluble N-ethylmaleimide- Taschenberger H, O'Connor VM, Nishiki T, Takahashi M, sensitive factor attachment protein (beta-SNAP), gamma- Brose N, Rhee JS. SNARE protein recycling by αSNAP SNAP and synaptotagmin I in brain of patients with Down and βSNAP supports synaptic vesicle priming. Neuron. syndrome and Alzheimer's disease. Dement Geriatr Cogn 2010 Nov 4;68(3):473-87 Disord. 2001 May-Jun;12(3):219-25 Wu ZZ, Chao CC. Knockdown of NAPA using short-hairpin Grabowski P, Schönfelder J, Ahnert-Hilger G, Foss HD, RNA sensitizes cancer cells to cisplatin: implications to Heine B, Schindler I, Stein H, Berger G, Zeitz M, Scherübl overcome chemoresistance. Biochem Pharmacol. 2010 H. Expression of neuroendocrine markers: a signature of Sep 15;80(6):827-37 human undifferentiated carcinoma of the colon and rectum. Naydenov NG, Brown B, Harris G, Dohn MR, Morales VM, Virchows Arch. 2002 Sep;441(3):256-63 Baranwal S, Reynolds AB, Ivanov AI. A membrane fusion Xu J, Xu Y, Ellis-Davies GC, Augustine GJ, Tse FW. protein αSNAP is a novel regulator of epithelial apical Differential regulation of exocytosis by alpha- and beta- junctions. PLoS One. 2012a;7(4):e34320 SNAPs. J Neurosci. 2002 Jan 1;22(1):53-61 Naydenov NG, Harris G, Brown B, Schaefer KL, Das SK, Abonyo BO, Wang P, Narasaraju TA, Rowan WH 3rd, Fisher PB, Ivanov AI. Loss of soluble N-ethylmaleimide- McMillan DH, Zimmerman UJ, Liu L. Characterization of sensitive factor attachment protein α ( αSNAP) induces

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epithelial cell apoptosis via down-regulation of Bcl-2 Vivona S, Cipriano DJ, O'Leary S, Li YH, Fenn TD, expression and disruption of the Golgi. J Biol Chem. 2012b Brunger AT. Disassembly of all SNARE complexes by N- Feb 17;287(8):5928-41 ethylmaleimide-sensitive factor (NSF) is initiated by a conserved 1:1 interaction between α-soluble NSF Naydenov NG, Harris G, Morales V, Ivanov AI. Loss of a attachment protein (SNAP) and SNARE complex. J Biol membrane trafficking protein αSNAP induces non- Chem. 2013 Aug 23;288(34):24984-91 canonical autophagy in human epithelia. Cell Cycle. 2012c Dec 15;11(24):4613-25 Wang L, Brautigan DL. α-SNAP inhibits AMPK signaling to reduce mitochondrial biogenesis and dephosphorylates Kaneai N, Fukui K, Koike T, Urano S. Vitamin E prevents Thr172 in AMPK α in vitro. Nat Commun. 2013;4:1559 hyperoxia-induced loss of soluble N-ethylmaleimide- sensitive fusion protein attachment protein receptor This article should be referenced as such: proteins in the rat neuronal cytoplasm. Biol Pharm Bull. 2013;36(9):1500-2 Naydenov NG, Ivanov AI. NAPA (N-ethylmaleimide- sensitive factor attachment protein, alpha). Atlas Genet Miao Y, Miner C, Zhang L, Hanson PI, Dani A, Vig M. An Cytogenet Oncol Haematol. 2014; 18(5):301-305. essential and NSF independent role for α-SNAP in store- operated calcium entry. Elife. 2013;2:e00802

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AUTS2 (autism susceptibility candidate 2) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: October 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/AUTS2ID51794ch7q11.html DOI: 10.4267/2042/53639 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract and proximal to- POM121 (another gene involved in PAX5 translocations in leukemia), and to the Review on AUTS2, with data on DNA/RNA, on the Williams-Beuren syndrome critical region. protein encoded and where the gene is implicated. DNA/RNA Identity Description Other names: FBRSL2 The gene spans 1.19 Mb. 19 coding exons. HGNC (Hugo): AUTS2 Transcription Location: 7q11.22 There are 16 transcripts (splice variants). Six Local order: AUTS2 is close to (about 2.1 Mb) – transcripts contains an open reading frame.

AUTS2 protein and domains.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 306 AUTS2 (autism susceptibility candidate 2) Huret JL

Enhancers that were mutated in patients with Protein dyslexia or with autism spectrum disorder were Description described; AUTS2 has been found as a rapidly evolving gene in homo sapiens sapiens, compared 1259 amino acids (aa); from N-term to C-term, to Neanderthals, and non-human primates. It is AUTS2 contains: nuclear localization sequences suggested that AUTS2 has an important role in the (aa: 11-27; 70-79; 120-141); Pro-rich regions (aa: evolution of human cognitive traits (Oksenberg et 288-471; 544-646); a Dwarfin consensus sequence al., 2013). (aa: 325-453); a Ser-rich region (aa: 383-410); a PY motif (aa: 515-519); a hexanucleotide repeat (aa: Implicated in 524-540; (cagcac/cagcac/cagcac/cagcac/acc/cac/cagcac/cagca t(7;9)(q11;p13) PAX5/AUTS2 c/cagcac) at nucleotide 1901-1949 (exon 9)); His- Note rich regions (aa: 525-548, 1122-1181); a Fibrosin homology region (aa: 645-798); a topoisomerase PAX5 is involved in B-cell differentiation. Entry of homology region (aa: 880-920); a trinucleotide common lymphoid progenitors into the B cell repeat (aa: 1126-1133 (cac)8, at nucleotide 3701- lineage depends on E2A, EBF1, and PAX5. Genes 3732 (exon 19)), and also N-glycosylation sites (aa repressed by PAX5 expression in early B cells are 395-398, 785-788, 955-958, 1009-1012), cAMP restored in their function in mature B cells and and cGMP- dependent protein kinase plasma cells, and PAX5 repressed (Medvedovic et phosphorylation sites (aa: 13-16, 77-80, 116-119, al., 2011). 832-835, 849-852, 975-978, 1235-1238), SH3 Disease interaction domains (P67, P72, P73, P266, P332, Pediatric B-cell precursor acute lymphoblastic P361, P364, P467, P468, P471, P638, P806, leukemia (BCP-ALL). P1234), and a SH2 interaction domain (Y971) Prognosis (Sultana et al., 2002; Bedogni et al., 2010b; Three cases to date, two boys and one girl, aged Oksenberg and Ahituv, 2013). 0.6, 2.8, and 3.1 years (Kawamata 2008; Coyaud et Expression al., 2010; Denk et al., 2012). Two patients AUTS2 is primarily expressed in the central presented with a high WBC, and also had a central nervous system, and also in skeletal muscle and nervous system involvement at a time during course kidney, and with lower expression in other tissues of the disease. Patients were assigned to different (placenta, lung, and leukocytes) (Sultana et al., risk arms of the respective clinical trials, as noted 2002). AUTS2 is highly expressed in the embryo, by Denk et al., 2012. The three patients achieved and in more restricted areas in the adult (Oksenberg complete remission (CR), but two (those with high and Ahituv, 2013). risk features) relapsed and died at 1.7 and 3.4 years Auts2 in the mouse embryo is expressed in the after diagnosis, indicating a rather poor outcome cortical preplate, in frontal cortex, hippocampus (Denk et al., 2012). Only one patient is still in CR and cerebellum, including Purkinje cells and deep and well 2.2 years after diagnosis. nuclei, in developing dorsal thalamus, olfactory Cytogenetics bulb, inferior colliculus and substantia nigra The t(7;9)(q11;p13) was the sole abnormality in (Bedogni et al., 2010a). one case. Unbalanced translocation in two cases, Localisation due to the loss of the der(7)t(7;9). Hybrid/Mutated gene AUTS2 is a nuclear protein. 5' PAX5-3' AUTS2. Fusion of PAX5 exon 6 to Function AUTS2 exon 4 or 6. TBR1, a postmitotic projection-neuron specific Abnormal protein transcription factor, binds the AUTS2 promoter and 1289 or 1311 amino acids depending on whether activates AUTS2 in developing neocortex in vivo exon 6 or 4 of AUTS2 is fused to PAX5. The (Bedogni et al., 2010b; Srinivasan et al., 2012). predicted fusion protein contains the paired domain, Suppression of auts2 in zebrafish embryos caused the octapeptide, and the homeodomain of PAX5 microcephaly, and a reduction in developing and the proline rich, the Dwarfin consensus midbrain neurons and also in sensory and motor sequence, the serine rich, the PY motif, the neurons (Beunders et al., 2013; Oksenberg et al., hexanucleotide repeat, the histidine rich, the 2013). ZMAT3 (a target gene of TP53) fibrosin homology region, the topoisomerase downregulation produced significant reductions in homology region, and the trinucleotide repeat of AUTS2 mRNA levels (Sedaghat et al., 2012). AUTS2.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 307 AUTS2 (autism susceptibility candidate 2) Huret JL

Fusion protein PAX5/AUTS2.

Other cancers Mental retardation: A patient with developmental delay had an intragenic deletion within AUTS2 Disease (Jolley et al., 2013). Loss of heterozygocity was found in an Three unrelated mentally disabled patients were adenocarcinoma of the lung, but more data is found to carry a balanced translocation that needed (Weir et al., 2007). truncates AUTS2. Patients were borderline or Copy number variation was found in a single case severely mentally retarded and carried different of mixed germ cell tumor containing yolk sac tumor deletions in AUTS2 (Kalscheuer et al., 2007). and teratoma (Stadler et al., 2012). AUTS2 has been found disrupted in balanced chromosomal abnormality in patients with Syndromic phenotype, mental abnormal neurodevelopment (Huang et al., 2010; retardation, neurodevelopmental and Talkowski et al., 2012). psychiatric disorders, including Autism spectrum disorder (ASD): Small copy- autism spectrum disorder number variations (CNVs) that disrupt AUTS2 (duplications or deletions of exons) were found in A review in Oksenberg and Ahituv, 2013 shows a two patients with developmental delay, and two map of the gene with the structural variants and with autism spectrum disorder (Nagamani et al., abnormalities in relation to the various phenotypes 2013). AUTS2 has been found disrupted in a described. monozygotic twin pair concordant for autism Disease (Sultana et al., 2002). Duplication in the AUTS2 Syndromic phenotype: A study on 24 patients gene was identified in a family with ASD (Ben- with deletions of part of AUTS2 allowed the David et al., 2011). identification of a variable syndromic phenotype Pathological behaviour: A variant in AUTS2 was including intellectual disability, autism, short associated with excessive alcohol consumption stature, microcephaly, cerebral palsy, and facial (Edenberg and Foroud, 2013; Kapoor et al., 2013). dysmorphisms. AUTS2 variants (rs6943 allele A) are correlated The authors delineated an "AUTS2 syndrome with heroin dependence, and reduced AUTS2 gene severity score" of the phenotypic diversity, that expression might confer increased susceptibility correlated with genotypic data: individuals with (Chen et al., 2013). rs6943555 A allele was also deletions in the 5' part of the gene showed a milder found associated with alcohol consumption phenotype than those with a deletion in the 3' part (Schumann et al., 2011), and with suicide of the gene (Beunders et al., 2013). committed after drinking (Chojnicka et al., 2013).

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Amino acids sequence variant in AUTS2 were Huang XL, Zou YS, Maher TA, Newton S, Milunsky JM. A found in a large family with high risk for suicide, de novo balanced translocation breakpoint truncating the autism susceptibility candidate 2 (AUTS2) gene in a but also with a significant co-morbidity for patient with autism. Am J Med Genet A. 2010 affective disorders, alcohol disorders, psychotic Aug;152A(8):2112-4 disorders, and drug abuse disorders (Coon et al., Mefford HC, Muhle H, Ostertag P, von Spiczak S, Buysse 2013). K, Baker C, Franke A, Malafosse A, Genton P, Thomas P, Epilepsy: AUTS2 deletions were identified in one Gurnett CA, Schreiber S, Bassuk AG, Guipponi M, patient with juvenile myoclonic epilepsy and in Stephani U, Helbig I, Eichler EE. Genome-wide copy number variation in epilepsy: novel susceptibility loci in another patient with an unclassified 'non-lesional idiopathic generalized and focal epilepsies. PLoS Genet. epilepsy with features of atypical benign partial 2010 May 20;6(5):e1000962 epilepsy' (Mefford et al., 2010). Ben-David E, Granot-Hershkovitz E, Monderer-Rothkoff G, Lerer E, Levi S, Yaari M, Ebstein RP, Yirmiya N, Shifman References S. Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression. Hum Mol Sultana R, Yu CE, Yu J, Munson J, Chen D, Hua W, Estes Genet. 2011 Sep 15;20(18):3632-41 A, Cortes F, de la Barra F, Yu D, Haider ST, Trask BJ, Green ED, Raskind WH, Disteche CM, Wijsman E, Medvedovic J, Ebert A, Tagoh H, Busslinger M. Pax5: a Dawson G, Storm DR, Schellenberg GD, Villacres EC. master regulator of B cell development and Identification of a novel gene on chromosome 7q11.2 leukemogenesis. Adv Immunol. 2011;111:179-206 interrupted by a translocation breakpoint in a pair of Schumann G, Coin LJ, Lourdusamy A, Charoen P, Berger autistic twins. Genomics. 2002 Aug;80(2):129-34 KH, Stacey D, Desrivières S, Aliev FA, Khan AA, Amin N, Kalscheuer VM, FitzPatrick D, Tommerup N, Bugge M, Aulchenko YS, Bakalkin G, Bakker SJ, Balkau B, Beulens Niebuhr E, Neumann LM, Tzschach A, Shoichet SA, JW, Bilbao A, de Boer RA, Beury D, Bots ML, Breetvelt EJ, Menzel C, Erdogan F, Arkesteijn G, Ropers HH, Ullmann Cauchi S, Cavalcanti-Proença C, Chambers JC, Clarke R. Mutations in autism susceptibility candidate 2 (AUTS2) TK, Dahmen N, de Geus EJ, Dick D, Ducci F, Easton A, in patients with mental retardation. Hum Genet. 2007 Edenberg HJ, Esko T, Fernández-Medarde A, Foroud T, May;121(3-4):501-9 Freimer NB, Girault JA, Grobbee DE, Guarrera S, Gudbjartsson DF, Hartikainen AL, Heath AC, Hesselbrock Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim V, Hofman A, Hottenga JJ, Isohanni MK, Kaprio J, Khaw R, Lin WM, Province MA, Kraja A, Johnson LA, Shah K, KT, Kuehnel B, Laitinen J, Lobbens S, Luan J, Mangino M, Sato M, Thomas RK, Barletta JA, Borecki IB, Broderick S, Maroteaux M, Matullo G, McCarthy MI, Mueller C, Navis G, Chang AC, Chiang DY, Chirieac LR, Cho J, Fujii Y, Gazdar Numans ME, Núñez A, Nyholt DR, Onland-Moret CN, AF, Giordano T, Greulich H, Hanna M, Johnson BE, Kris Oostra BA, O'Reilly PF, Palkovits M, Penninx BW, Polidoro MG, Lash A, Lin L, Lindeman N, Mardis ER, McPherson S, Pouta A, Prokopenko I, Ricceri F, Santos E, Smit JH, JD, Minna JD, Morgan MB, Nadel M, Orringer MB, Soranzo N, Song K, Sovio U, Stumvoll M, Surakk I, Osborne JR, Ozenberger B, Ramos AH, Robinson J, Roth Thorgeirsson TE, Thorsteinsdottir U, Troakes C, JA, Rusch V, Sasaki H, Shepherd F, Sougnez C, Spitz Tyrfingsson T, Tönjes A, Uiterwaal CS, Uitterlinden AG, MR, Tsao MS, Twomey D, Verhaak RG, Weinstock GM, van der Harst P, van der Schouw YT, Staehlin O, Wheeler DA, Winckler W, Yoshizawa A, Yu S, Zakowski Vogelzangs N, Vollenweider P, Waeber G, Wareham NJ, MF, Zhang Q, Beer DG, Wistuba II, Watson MA, Garraway Waterworth DM, Whitfield JB, Wichmann EH, Willemsen LA, Ladanyi M, Travis WD, Pao W, Rubin MA, Gabriel SB, G, Witteman JC, Yuan X, Zhai G, Zhao JH, Zhang W, Gibbs RA, Varmus HE, Wilson RK, Lander ES, Meyerson Martin NG, Metspalu A, Doering A, Scott J, Spector TD, M. Characterizing the cancer genome in lung Loos RJ, Boomsma DI, Mooser V, Peltonen L, Stefansson adenocarcinoma. Nature. 2007 Dec 6;450(7171):893-8 K, van Duijn CM, Vineis P, Sommer WH, Kooner JS, Kawamata N, Ogawa S, Zimmermann M, Niebuhr B, Spanagel R, Heberlein UA, Jarvelin MR, Elliott P. Stocking C, Sanada M, Hemminki K, Yamatomo G, Genome-wide association and genetic functional studies Nannya Y, Koehler R, Flohr T, Miller CW, Harbott J, identify autism susceptibility candidate 2 gene (AUTS2) in Ludwig WD, Stanulla M, Schrappe M, Bartram CR, the regulation of alcohol consumption. Proc Natl Acad Sci Koeffler HP. Cloning of genes involved in chromosomal U S A. 2011 Apr 26;108(17):7119-24 translocations by high-resolution single nucleotide Denk D, Nebral K, Bradtke J, Pass G, Möricke A, polymorphism genomic microarray. Proc Natl Acad Sci U S Attarbaschi A, Strehl S. PAX5-AUTS2: a recurrent fusion A. 2008 Aug 19;105(33):11921-6 gene in childhood B-cell precursor acute lymphoblastic Bedogni F, Hodge RD, Nelson BR, Frederick EA, Shiba N, leukemia. Leuk Res. 2012 Aug;36(8):e178-81 Daza RA, Hevner RF. Autism susceptibility candidate 2 Srinivasan K, Leone DP, Bateson RK, Dobreva G, Kohwi (Auts2) encodes a nuclear protein expressed in developing Y, Kohwi-Shigematsu T, Grosschedl R, McConnell SK. A brain regions implicated in autism neuropathology. Gene network of genetic repression and derepression specifies Expr Patterns. 2010a Jan;10(1):9-15 projection fates in the developing neocortex. Proc Natl Bedogni F, Hodge RD, Elsen GE, Nelson BR, Daza RA, Acad Sci U S A. 2012 Nov 20;109(47):19071-8 Beyer RP, Bammler TK, Rubenstein JL, Hevner RF. Tbr1 Sedaghat Y, Mazur C, Sabripour M, Hung G, Monia BP. regulates regional and laminar identity of postmitotic Genomic analysis of wig-1 pathways. PLoS One. neurons in developing neocortex. Proc Natl Acad Sci U S 2012;7(2):e29429 A. 2010b Jul 20;107(29):13129-34 Stadler ZK, Esposito D, Shah S, Vijai J, Yamrom B, Levy Coyaud E, Struski S, Dastugue N, Brousset P, Broccardo D, Lee YH, Kendall J, Leotta A, Ronemus M, Hansen N, C, Bradtke J. PAX5-AUTS2 fusion resulting from Sarrel K, Rau-Murthy R, Schrader K, Kauff N, Klein RJ, t(7;9)(q11.2;p13.2) can now be classified as recurrent in B Lipkin SM, Murali R, Robson M, Sheinfeld J, Feldman D, cell acute lymphoblastic leukemia. Leuk Res. 2010 Bosl G, Norton L, Wigler M, Offit K. Rare de novo germline Dec;34(12):e323-5

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copy-number variation in testicular cancer. Am J Hum H, Jerominski L, Hansen J, Klein M, Callor WB, Byrd J, Genet. 2012 Aug 10;91(2):379-83 Bakian A, Crowell SE, McMahon WM, Rajamanickam V, Camp NJ, McGlade E, Yurgelun-Todd D, Grey T, Gray D. Talkowski ME, Rosenfeld JA, Blumenthal I, Pillalamarri V, Genetic risk factors in two Utah pedigrees at high risk for Chiang C, Heilbut A, Ernst C, Hanscom C, Rossin E, suicide. Transl Psychiatry. 2013 Nov 19;3:e325 Lindgren AM, Pereira S, Ruderfer D, Kirby A, Ripke S, Harris DJ, Lee JH, Ha K, Kim HG, Solomon BD, Gropman Edenberg HJ, Foroud T. Genetics and alcoholism. Nat Rev AL, Lucente D, Sims K, Ohsumi TK, Borowsky ML, Gastroenterol Hepatol. 2013 Aug;10(8):487-94 Loranger S, Quade B, Lage K, Miles J, Wu BL, Shen Y, Neale B, Shaffer LG, Daly MJ, Morton CC, Gusella JF. Jolley A, Corbett M, McGregor L, Waters W, Brown S, Sequencing chromosomal abnormalities reveals Nicholl J, Yu S. De novo intragenic deletion of the autism neurodevelopmental loci that confer risk across diagnostic susceptibility candidate 2 (AUTS2) gene in a patient with boundaries. Cell. 2012 Apr 27;149(3):525-37 developmental delay: a case report and literature review. Am J Med Genet A. 2013 Jun;161A(6):1508-12 Beunders G, Voorhoeve E, Golzio C, Pardo LM, Rosenfeld JA, Talkowski ME, Simonic I, Lionel AC, Vergult S, Pyatt Kapoor M, Wang JC, Wetherill L, Le N, Bertelsen S, RE, van de Kamp J, Nieuwint A, Weiss MM, Rizzu P, Hinrichs AL, Budde J, Agrawal A, Bucholz K, Dick D, Verwer LE, van Spaendonk RM, Shen Y, Wu BL, Yu T, Yu Harari O, Hesselbrock V, Kramer J, Nurnberger JI Jr, Rice Y, Chiang C, Gusella JF, Lindgren AM, Morton CC, van J, Saccone N, Schuckit M, Tischfield J, Porjesz B, Binsbergen E, Bulk S, van Rossem E, Vanakker O, Edenberg HJ, Bierut L, Foroud T, Goate A. A meta- Armstrong R, Park SM, Greenhalgh L, Maye U, Neill NJ, analysis of two genome-wide association studies to identify Abbott KM, Sell S, Ladda R, Farber DM, Bader PI, novel loci for maximum number of alcoholic drinks. Hum Cushing T, Drautz JM, Konczal L, Nash P, de Los Reyes Genet. 2013 Oct;132(10):1141-51 E, Carter MT, Hopkins E, Marshall CR, Osborne LR, Gripp Nagamani SC, Erez A, Ben-Zeev B, Frydman M, Winter S, KW, Thrush DL, Hashimoto S, Gastier-Foster JM, Astbury Zeller R, El-Khechen D, Escobar L, Stankiewicz P, Patel A, C, Ylstra B, Meijers-Heijboer H, Posthuma D, Menten B, Cheung SW. Detection of copy-number variation in AUTS2 Mortier G, Scherer SW, Eichler EE, Girirajan S, Katsanis gene by targeted exonic array CGH in patients with N, Groffen AJ, Sistermans EA. Exonic deletions in AUTS2 developmental delay and autistic spectrum disorders. Eur cause a syndromic form of intellectual disability and J Hum Genet. 2013 Mar;21(3):343-6 suggest a critical role for the C terminus. Am J Hum Genet. 2013 Feb 7;92(2):210-20 Oksenberg N, Ahituv N. The role of AUTS2 in neurodevelopment and human evolution. Trends Genet. Chen YH, Liao DL, Lai CH, Chen CH. Genetic analysis of 2013 Oct;29(10):600-8 AUTS2 as a susceptibility gene of heroin dependence. Drug Alcohol Depend. 2013 Mar 1;128(3):238-42 Oksenberg N, Stevison L, Wall JD, Ahituv N. Function and regulation of AUTS2, a gene implicated in autism and Chojnicka I, Gajos K, Strawa K, Broda G, Fudalej S, human evolution. PLoS Genet. 2013;9(1):e1003221 Fudalej M, Stawi ński P, Pawlak A, Krajewski P, Wojnar M, Płoski R. Possible association between suicide committed This article should be referenced as such: under influence of ethanol and a variant in the AUTS2 gene. PLoS One. 2013;8(2):e57199 Huret JL. AUTS2 (autism susceptibility candidate 2). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5): 306-310. Coon H, Darlington T, Pimentel R, Smith KR, Huff CD, Hu

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Gene Section Short Communication

AVEN (apoptosis, caspase activation inhibitor) Inga Maria Melzer, Martin Zörnig Institute for Biomedical Research Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt, Germany (IMM, MZ)

Published in Atlas Database: October 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/AVENID43158ch15q14.html DOI: 10.4267/2042/53640 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

exons, ranging in length between 70 and appr. 500 Abstract bp and 5 introns varying largely in size (from few Review on AVEN, with data on DNA/RNA, on the 100 bp to some Mb). According to the Ensembl protein encoded and where the gene is implicated. genome browser database (ENSG00000169857), there are three transcript variants of AVEN of Identity which only one leads to the translation of a functional protein whereas the other two are Other names: PDCD12 degraded by nonsense-mediated decay or do not HGNC (Hugo): AVEN encode for a functional protein product. Location: 15q14 Transcription According to the NCBI database, the human AVEN DNA/RNA gene encodes for a 1551 bp mRNA transcript, the Description coding sequence ranging from bp 57 to 1145. The CDS in the Ensembl genome browser database The human AVEN gene is located on the reverse (ENSG00000169857) is identical to the NCBI CDS strand of chromosome 15 (bases 34158428 to (NM_020371.2). The transcript NM_020371.2 is 34331303; according to NCBI RefSeq gene also included in the human CCDS set and encodes database (gene ID: 57099; Refseq ID: for a protein of 362 aa. NM_020371.2), genome assembly GRCh37 from February 2009) of the human genome and is Pseudogene comprised of 172876 bp. AVEN consists of 6 None known.

AVEN protein: 1-362 aa. Cathepsin D cleavage sites: L144 and L196; putative BH3 domain: aa141-153; NES: aa282-293. ATM kinase phosphorylation sites: S 135 and S 308.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 311 AVEN (apoptosis, caspase activation inhibitor) Melzer IM, Zörnig M

Xenopus laevis egg extracts induced a cell cycle Protein arrest at G2/M which is in large part ATM Description dependent, whereas the absence of AVEN impaired ATM-mediated checkpoint function. An intrinsic The AVEN protein possesses no predicted domains loop of activation exists between AVEN and ATM: according to the NCBI database. However, a AVEN binds to the kinase domain of ATM (appr. sequential proteolytic processing of AVEN by the aa 2500-3000) and, in turn, is phosphorylated by lysosomal protease cathepsin D has been published ATM at S135 and S308. (Melzer et al., 2012), leading to the cleavage of This phosphorylation seems to enhance AVEN's AVEN at aa 144 and 196 and the generation of a activating influence on ATM. Esmaili et al. (2010) shorter isoform (deltaN Aven) that is supposed to were able to demonstrate that AVEN possesses a be associated with the antiapoptotic function. nuclear export signal (NES) which is located Moreover, AVEN is able to bind to the DNA between aa 282 and 293. Under normal damage response regulating kinase ATM (ataxia physiological conditions, AVEN is shuttled outside telangiectasia mutated) and is phosphorylated by of the nucleus by Exportin-1/CRM1 whereas ATM at S135 and S308 (Guo et al., 2008). In inhibition of CRM1 by leptomycin or mutation of addition, a potential nuclear export sequence (NES) the AVEN NES leads to nuclear accumulation of to exists between aa 282-293 (Esmaili et al., 2010) the protein. The NES/nuclear-cytosolic shuttling of and a putative BH3 motif (for binding to Bcl-xL) AVEN might be important for its cell cycle has been predicted to be located between aa 141- regulatory functions and its role in DNA damage 153 (Hawley et al., 2012). repair. Expression Depending on the degree of DNA damage, AVEN Widely expressed throughout the human organism is possibly a multifunctional protein, finetuning the (Chau et al., 2000). cellular decisions of cell cycle arrest and apoptosis in the DNA damage response. Localisation Homology Mostly cytosolic, punctuate, reticular pattern (associated with intracellular membrane No close orthologs of AVEN in humans are known. localization, lysosomal?) in the cytosol (Chau et al., However, Hawley et al. (2010) note homology to 2000), diffuse nuclear staining (Esmaili et al., Bik (58% homology over a 77 aa region 2010). encompassing the putative BH3 homology domain). Homologs of AVEN can be found in several Function species, like mouse (NCBI acc. Nr. NP_083120), Antiapoptotic: Drosophila (NP_572817), rat (NP_001101227), AVEN was first discovered as an interactor of the chicken (NP_001005791; Vezyri et al., 2011) and antiapoptotic BCl-xL protein by Chau et al. (2000). Xenopus (NP_001090621; Guo et al., 2008). Of It was also shown to bind to the proapoptotic note, two isoforms are postulated to exist in mouse, APAF-1 protein and postulated to prevent the the second one (NP_001159407) possessing a oligomerization of APAF-1 (apoptosome distinctly shorter N-terminus than the full length formation) in the intrinsic apoptosis pathway and to protein. However, nothing is known about the stabilize the Bcl-xL protein by binding to it (Kutuk function or biological relevance of this predicted et al., 2010). Putative binding sites in Bcl-xL are second isoform. Functional similarity to the human predicted to be located in the Bcl-xL BH1 and BH4 protein in its cell cycle regulatory properties has domains (Hawley et al., 2012). Recently, it was been published for the Drosophila (Zou et al., 2011) shown that AVEN can be processed by the and the Xenopus homologs (Guo et al., 2008). lysosomal protease Cathepsin D at aa 144 and 196, and that this processing is neccessary to activate Implicated in AVEN's antiapoptotic function (Melzer et al., 2012). It is still unclear whether it is the Acute leukemias stabilization of Bcl-xL, the interference with Note apoptosome assembly or another feature of AVEN AVEN is a putative oncogene which is that is responsible for the antiapoptotic capacity of overexpressed in T- cell acute lymphoblastic this protein. leukemia. DNA damage repair: First reports that AVEN is overexpressed on It was shown by Guo et al. (2008) that AVEN, in mRNA level in acute leukemias were published by addition to binding to the apoptotic machinery, is Paydas et al. in 2003. also able to bind one of the key players in DNA The authors investigated a study group consisting damage repair, the ataxia telangiectasia mutated of 37 acute myeloblastic leukemias (AML) and 28 (ATM) kinase. Overexpression of AVEN in acute lymphoblastic leukemia (ALL) patients.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 312 AVEN (apoptosis, caspase activation inhibitor) Melzer IM, Zörnig M

Details regarding the number of ALL patients who were either of the frequent B-cell type or had References developed T-cell acute lymphoblastic Chau BN, Cheng EH, Kerr DA, Hardwick JM. Aven, a leukemia/lymphoma (T-ALL) were not given. novel inhibitor of caspase activation, binds Bcl-xL and In this study, elevated Aven mRNA expression Apaf-1. Mol Cell. 2000 Jul;6(1):31-40 levels were noted in acute leukemias, and the Paydas S, Tanriverdi K, Yavuz S, Disel U, Sahin B, Burgut authors suggest that AVEN could be a new R. Survivin and aven: two distinct antiapoptotic signals in acute leukemias. Ann Oncol. 2003 Jul;14(7):1045-50 prognostic marker in this cancer entity. Choi et al. (2006) describe a positive correlation Choi J, Hwang YK, Sung KW, Kim DH, Yoo KH, Jung HL, between Aven mRNA overexpression and poor Koo HH. Aven overexpression: association with poor prognosis in childhood acute lymphoblastic leukemia. Leuk prognosis in childhood ALL. Res. 2006 Aug;30(8):1019-25 A recent study by Eissmann et al. (2013) shows Guo JY, Yamada A, Kajino T, Wu JQ, Tang W, Freel CD, proof that overexpression of AVEN contributes to Feng J, Chau BN, Wang MZ, Margolis SS, Yoo HY, Wang increased malignancy in hematopoietic neoplasms. XF, Dunphy WG, Irusta PM, Hardwick JM, Kornbluth S. Here, the authors confirm overexpression of AVEN Aven-dependent activation of ATM following DNA damage. in T-ALL patient samples compared to healthy T Curr Biol. 2008 Jul 8;18(13):933-42 cells on protein level. Esmaili AM, Johnson EL, Thaivalappil SS, Kuhn HM, Furthermore, using a transgenic mouse model with Kornbluth S, Irusta PM. Regulation of the ATM-activator T-cell specific overexpression of AVEN, an protein Aven by CRM1-dependent nuclear export. Cell Cycle. 2010 Oct 1;9(19):3913-20 oncogenic cooperation of AVEN with heterozygous loss of p53 is shown. Kutuk O, Temel SG, Tolunay S, Basaga H. Aven blocks DNA damage-induced apoptosis by stabilising Bcl-xL. Eur Additionally, in subcutaneous mouse xenograft J Cancer. 2010 Sep;46(13):2494-505 models, the authors show that downregulation of AVEN expression via shRNA leads to significantly Vezyri E, Mikrou A, Athanassiadou A, Zarkadis IK. Molecular cloning and expression of Aven gene in chicken. decreased, if not halted, tumor growth indicating Protein J. 2011 Jan;30(1):72-6 AVEN as a putative novel therapy target for T-ALL and AML. Zou S, Chang J, LaFever L, Tang W, Johnson EL, Hu J, Wilk R, Krause HM, Drummond-Barbosa D, Irusta PM. Breast cancer Identification of dAven, a Drosophila melanogaster ortholog of the cell cycle regulator Aven. Cell Cycle. 2011 Note Mar 15;10(6):989-98 Two other studies implicate AVEN in breast cancer Hawley RG, Chen Y, Riz I, Zeng C. An Integrated (Kutuk et al., 2010; Ouzounova et al., 2013). Bioinformatics and Computational Biology Approach Kutuk et al. describe decreased nuclear expression Identifies New BH3-Only Protein Candidates. Open Biol J. of AVEN in breast cancer tissue microarrays, in 2012 May 4;5:6-16 particular in infiltrative ductal carcinoma and Melzer IM, Fernández SB, Bösser S, Lohrig K, papillary carcinoma compared to non-neoplastic Lewandrowski U, Wolters D, Kehrloesser S, Brezniceanu breast tissue and infiltrating lobular breast cancer. ML, Theos AC, Irusta PM, Impens F, Gevaert K, Zörnig M. The Apaf-1-binding protein Aven is cleaved by Cathepsin They suggest that AVEN might be an important D to unleash its anti-apoptotic potential. Cell Death Differ. mediator in DNA damage-induced apoptotic 2012 Sep;19(9):1435-45 signalling and its nuclear downregulation in breast Eißmann M, Melzer IM, Fernández SB, Michel G, Hrab ě cancer can lead to genomic instability. de Angelis M, Hoefler G, Finkenwirth P, Jauch A, Schoell A recent study by Ouzounova et al. shows that B, Grez M, Schmidt M, Bartholomae CC, Newrzela S, AVEN is an inversely regulated downstream target Haetscher N, Rieger MA, Zachskorn C, Mittelbronn M, Zörnig M. Overexpression of the anti-apoptotic protein of the miR-30 family which is important for AVEN contributes to increased malignancy in regulation of breast cancer cells under non- hematopoietic neoplasms. Oncogene. 2013 May attachment conditions. 16;32(20):2586-91 Overexpression of miR-30 family members reduces Ouzounova M, Vuong T, Ancey PB, Ferrand M, Durand G, breast tumor progression and tumorsphere Le-Calvez Kelm F, Croce C, Matar C, Herceg Z, formation (and AVEN expression), an effect which Hernandez-Vargas H. MicroRNA miR-30 family regulates could be partially rescued by AVEN re- non-attachment growth of breast cancer cells. BMC Genomics. 2013 Feb 28;14:139 /overexpression, suggesting, in contrast to the other study, that rather overexpression (than This article should be referenced as such: downregulation or nuclear depletion) of AVEN is Melzer IM, Zörnig M. AVEN (apoptosis, caspase activation important for breast tumor growth. inhibitor). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):311-313.

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Gene Section Review

FKBP5 (FK506 binding protein 5) Katarzyna Anna Ellsworth, Liewei Wang Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA (KAE, LW)

Published in Atlas Database: October 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/FKBP5ID40578ch6p21.html DOI: 10.4267/2042/53641 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Description FKBP51 is a member of immunophilin family, Review on FKBP5, with data on DNA/RNA, on the proteins characterized by their ability to bind protein encoded and where the gene is implicated. immunosuppresive drugs. Additionally, immunophilins are peptidylprolyl isomerases Identity (PPIase) that catalyze the cis-trans conversion of Other names: AIG6, FKBP51, FKBP54, P54, peptidylprolyl bonds, a reaction important for PPIase, Ptg-10 protein folding (Fischer et al., 1984). Sinars et al. HGNC (Hugo): FKBP5 (Sinars et al., 2003) initially showed the structure of FKBP51 and the orientation of its domains. The N- Location: 6p21.31 terminal domain, FK1, is an active rotamase domain (peptidyl-prolyl isomerase; PPIase) which DNA/RNA is required to bind immunosuppressive drugs, such Description as FK506 (tacrolimus). In addition, it is responsible for binding to the FKBP5 gene is located on short arm of kinase Akt (Pei et al., 2009). The FK2 domain, chromosome 6 (6p21.31). needed for interaction with some binding partners FKBP5 gene ranges from 35541362 to 35696360 (Figure 2), does not show measurable PPIase on reverse strand with a total length of 154999 bp activity. The TRP domain consists of three highly including 10 coding exons. degenerate 34 amino acid repeats TPR repeats, and Transcription is responsible for multiple protein-protein This gene has been found to have multiple interactions (figure 2), for example with Hsp90 polyadenylation sites. (Cheung-Flynn et al., 2003), progesterone receptor Transcription of FKBP5 gene produces 4 different (PR) (Barent et al., 1998), PH domain and leucine transcript variants due to alternative splicing rich repeat protein phosphatase (PHLPP) (Pei et al., (RefSeq, Mar 2009). 2009). NM_004117 is the transcript most widely referred Expression to, and its mRNA is 3803 bp long. FKBP5 is ubiquitously expressed with different Protein levels of distribution in various tissues. Tissue examples include amygdala, kidney, heart, Note hippocampus, liver skeletal muscle, peripheral Protein name: FK506 binding protein 51, FKBP51, blood, placenta, thymus, testis, uterus, and others, Peptidyl-prolyl cis-trans isomerase (PPIase). It is with lower levels of expression in pancreas, spleen, encoded by the FKBP5 gene (Nair et al., 1997). and stomach (Baughman et al., 1997).

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 314 FKBP5 (FK506 binding protein 5) Ellsworth KA, Wang L

Figure 1. (A) Schematic diagram of FKBP5 location on chromosome 6. FKBP5 localizes to chromosome 6p21.31, which is represented graphically. FKBP5 gene spans over 154 kbp from 35541362 to 35696360 on reverse strand. The region surrounding FKBP5 gene is enlarged. (B) Schematic representation of FKBP5 mRNA structure, with indicated ATG translation start site in exon 2.

Up to date it has been established that FKBP5 2010), NF κB pathway (Bouwmeester et al., 2004), expression is regulated by glucocorticoids, as well as Akt pathway (Pei et al., 2009). Moreover, progestins, and androgens (Hubler et al., 2003; FKBP5 plays a role in regulating drug responses Hubler and Scammell, 2004; Makkonen et al., (Jiang et al., 2008; Li et al., 2008; Hou and Wang, 2009; Paakinaho et al., 2010). 2012; Binder et al., 2004). Localisation FKBP5 localizes to cytoplasm and nucleus. Mutations Function Note FKBP5 plays multiple important roles in cellular Next Generation resequencing of FKBP5 gene was process. Since it has peptidyl-prolyl isomerase performed using 96 Caucasian American samples (PPIase) activity, it regulates protein folding (Galat, and identified 657 single nucleotide polymorphisms 1993; Fruman et al., 1994). In addition, FKBP5 can (SNPs) (Ellsworth et al., 2013b). In addition, Next associate with chaperones, thus playing a role in Generation resequencing was also performed using cell trafficking (Schiene-Fischer and Yu, 2001). 60 samples from pancreatic cancer patients and Also, it influences steroid receptor signaling identified 404 SNPs (Ellsworth et al., 2013a). All of (Denny et al., 2000; Barent et al., 1998; Ni et al., these polymorphisms are germinal SNPs.

Figure 2. Functional domains of FKBP51. FKBP1 consists of 457 amino acids with three functional domains, as shown. FKBP51 binding proteins are indicated and listed by domain they interact with.

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Figure 3. Importance of FKBP5 in regulating activity of Akt pathway. FKBP5 acts as a scaffolding protein, enhancing the interaction of PHLPP and Akt, therefore promoting de-phosphorylation of Akt's Serine residue 473. That in turn eventually leads to inactivation of Akt pathway. FKBP5 expression and interaction with PHLPP is especially important upon chemotherapy treatment, because it inactivation of Akt leads to chemotoxic stress and directs cells towards apoptosis, rather than survival pathway.

Somatic Pancreatic cancer It has been reported that four confirmed somatic Note mutations in various cancer tissues has been The Akt pathway is one of the most important identified (V37V: silent (ovary) M97I: missense signaling pathways, playing a role in regulation of (breast) (Cancer Genome Atlas Research Network, many cellular processes, including cell 2011), Y113Y: silent (pancreas) (Biankin et al., proliferation, growth, and other processes that 2012), S309L: missense (endometrium, lung, large crucial for cell survival (Manning and Cantley, intestine) (Liu et al., 2012). 2007). Akt is a serine/threonine kinase that in order to Implicated in become fully activated needs its residues: Ser473 Cancer and response to and Thr308 to be phosphorylated. This is facilitated by phosphoinositide 3-kinase chemotherapy (PIP3), as well as PDK1, and mTOR complex 2 Note (Alessi et al., 1996; Engelman et al., 2006; FKBP51 is an important protein involved in the Sarbassov et al., 2005). regulation of many key signaling cascades in the Conversely, phosphatases, such as PP2 cell, such as Akt (Pei et al., 2009), NF κB holoenzymes and PHLPP de-phosphorylate Akt, (Bouwmeester et al., 2004), and androgen receptor halting its activity (Brognard et al., 2007; pathways (Ni et al., 2010). Carracedo and Pandolfi, 2008; Gao et al., 2005; All of these signalling pathways are implicated in Padmanabhan et al., 2009). tumorigenesis and response to drug treatment. The balance in phosphorylation levels of Akt It has been suggested that the contribution of determines its pathway activity, therefore affecting FKBP5 in tumorgenesis and antineoplastic therapy all the downstream cellular events. is tissue-specific. If Akt pathway becomes highly up-regulated, it Depending on the cellular context, FKBP5 can potentially could lead to tumor development, either promote or inhibit tumor progression and progression and eventually to chemotherapy chemoresistance. resistance (Pei et al., 2010).

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Figure 4. FKBP5 enzymatic activity regulates NF-κB pathway activation. Peptidylprolyl isomerase enzymatic activity of FKBP5 is required for IKKa activation and further phosphorylation of NF κB, which promotes cell survival and chemoresistance. Rapamycin can specifically inhibit FKBP5 enzymatic activity, which leads to decrease in NF κB pathway activation and increase in apoptosis upon chemotherapy treatment.

Genome-wide association studies of cytidine activity, to anthracycline treatment of blasts from analogues identified FKBP5 low expression levels chronic childhood acute lymphoblastic leukemia to be associated with resistance to many (ALL) patients would sensitize these cells to chemotherapeutic drugs (Li et al., 2008; Pei et al., anthracyclines (Avellino et al., 2005). These 2009). Functional studies of FKBP5 demonstrated experiments suggested that the combination that FKBP51 acts as a scaffolding protein treatment of rapamycin and doxorubicin inhibits the increasing interaction between Akt's phosphatase - activation of the NF-κB pathway, which leads to an PHLPP and Akt, thus decreasing the increase in apoptosis, and, in turn, an increase in phosphorylation of Akt-Ser473 (Pei et al., 2009). It sensitivity to chemotherapy (Avellino et al., 2005). was shown, that in pancreatic and breast cancer Since NF-κB pathway activation leads to anti- cells FKBP5 expression levels are decreased, while apoptotic signals, therefore, in this case, FKBP5 the phosphorylation of Akt-Ser473 is increased, plays a role in chemoresistance to drugs such as which could lead to chemoresistance. Also, it anthracyclines. In addition, in glioma cells, FKBP5 suggested that FKBP5 might function as a tumor expression contributes to glioma cells growth and suppressor gene through the down-regulation of sensitivity to rapamycin through regulation of the Akt activation (Pei et al., 2009, Hou and Wang, NF-κB pathway (Jiang et al., 2008). FKBP5 was 2012). also described to influence radioresistance in Acute lymphoblastic leukemia, melanoma cells (Romano et al., 2010). Specifically, it was found that in melanoma samples FKBP51 glioma, melanoma controlled radioresistance through the activation of Note NF-κB pathway, and by silencing expression of FKBP5 plays a pivotal role in regulating NF-κB FKBP5 in tumors in vitro and in vivo, it contributed pathway (Bouwmeester et al., 2004). Specifically, to an increase in apoptosis after irradiation. FKBP51 interacts with several members of the NF- κB pathway including inhibitors of NF-κB kinase: Prostate cancer IKK α, IKK ε, TAK1 and MEKK1. It was shown, Note that FKBP51 enzymatic activity is required for IKK FKBP5 influences androgen receptor signaling in activation, which suggested that FKBP5 plays an prostate cancer. Androgen receptor (AR) is a important role in this pathway. Avellino et al. transcription factor, regulating expression of demonstrated, that the addition of rapamycin, a multiple genes, including FKBP5 (Makkonen et al., known inhibitor of FKBP51 enzymatic (PPIase) 2009).

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Figure 5. Prostate cancer cell growth promotion under low-androgen conditions. Formation of ATP-bound Hsp90-FKBP5- p23 superchaperone complex allows for increased androgen and androgen receptor binding which promotes cell growth.

Additionally, FKBP5 is a part of a positive Depression, post-traumatic stress feedback loop that not only is having its expression regulated by AR and androgen binding, but it also disorder facilitates androgen-dependent transcription. Note Ni et al. (Ni et al., 2010) reported that FKBP5 It has been established that one of the major forms a superchaperone complex with ATP-bound functions of FKBP51 is to co-chaperone with HSP Hsp90 and p23 that increases binding of androgen family members steroid receptors: glucocorticoid to its receptor. This allows for androgen-dependent (GR) (Denny et al., 2000), progesterone (PR) gene transcription activation and promotes cell (Barent et al., 1998), and androgen (AR) (Ni et al., growth, which is especially important during 2010). In addition, FKBP5 intronic regions contain prostate cancer progression to the androgen- hormone response elements (HRE) that upon GR, independent state during disease progression and PR, or AR activation bind their respective tumor growth (Ni et al., 2010). hormones.

Figure 6. Negative feedback loop on GR sensitivity. When HSP90-GR is bound to the FKBP51, it has a lower affinity for GR ligand (glucocorticoids). However, once glucocorticoids bind to the complex, FKBP51 dissociates from the complex and FKBP52 binds instead. That allows for the GR translocation into the nucleus and exertion of its action as a transcription factor. GR also acts on FKBP5 via its glucocorticoid response elements (GREs), increasing its transcription, which leads to an increase in amount of FKBP51 protein in the cell. That, in turn, decreases the GR affinity for its ligand, completing this negative feedback loop on GR sensitivity.

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That, in turn, induces the FKBP5 gene transcription chimeras and mutants for Hsp90 binding and association (Hubler et al., 2003; Hubler and Scammell, 2004; with progesterone receptor complexes. Mol Endocrinol. 1998 Mar;12(3):342-54 Makkonen et al., 2009; Paakinaho et al., 2010) leading to increases in the amount of FKBP51 Denny WB, Valentine DL, Reynolds PD, Smith DF, Scammell JG. Squirrel monkey immunophilin FKBP51 is a protein in the cell. FKBP5 modulates steroid potent inhibitor of glucocorticoid receptor binding. hormones binding affinity; therefore it affects their Endocrinology. 2000 Nov;141(11):4107-13 signaling pathways. Schiene-Fischer C, Yu C. Receptor accessory folding For example FKBP51 plays an important role in helper enzymes: the functional role of peptidyl prolyl regulating the activity of the glucocorticoid receptor cis/trans isomerases. FEBS Lett. 2001 Apr 20;495(1-2):1-6 (Davies et al., 2005). Cheung-Flynn J, Roberts PJ, Riggs DL, Smith DF. C- When FKBP51 is bound to the GR-complex, the terminal sequences outside the tetratricopeptide repeat receptor has lower affinity for glucocorticoids, domain of FKBP51 and FKBP52 cause differential binding which causes an increase of glucocorticoids in the to Hsp90. J Biol Chem. 2003 May 9;278(19):17388-94 intercellular environment. Hubler TR, Denny WB, Valentine DL, Cheung-Flynn J, On the other hand, once glucocorticoid is bound, Smith DF, Scammell JG. The FK506-binding immunophilin FKBP51 dissociate from the complex and is FKBP51 is transcriptionally regulated by progestin and attenuates progestin responsiveness. Endocrinology. 2003 exchanged with FKBP52. Jun;144(6):2380-7 That allows for the translocation of GR into the nucleus and interaction with DNA. Once, in the Sinars CR, Cheung-Flynn J, Rimerman RA, Scammell JG, Smith DF, Clardy J. 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Atlas of Genetics and Cytogenetics

in Oncology and Haematology

OPEN ACCESS JOURNAL INIST -CNRS

Gene Section Short Communication

ITGA9 (integrin, alpha 9) Carla Molist, Ana Almazán-Moga, Isaac Vidal, Aroa Soriano, Luz Jubierre, Miguel F Segura, Josep Sánchez de Toledo, Soledad Gallego, Josep Roma Laboratory of Translational Research in Paediatric Cancer, Vall d'Hebron Research Institute, Barcelona, Spain (CM, AAM, IV, AS, LJ, MFS, JSdT, SG, JR), Paediatric Oncology and Haematology, Vall d'Hebron Hospital, Barcelona, Spain (JSdT, SG)

Published in Atlas Database: October 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/ITGA9ID41010ch3p22.html DOI: 10.4267/2042/53642 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

4 splice variants described (7889, 2282, 609 and Abstract 428 bp), three of which with protein translation Review on ITGA9, with data on DNA/RNA, on the (1035, 632 and 69 aa). protein encoded and where the gene is implicated. Protein Identity Note Other names: ALPHA-RLC, ITGA4L, RLC Alpha9-Integrin. HGNC (Hugo): ITGA9 Description Location: 3p22.2 Alpha-integrins, such as Alpha9-Integrin, are cell DNA/RNA surface glycoproteins that contain a large N- terminal extracellular domain with 7 conserved Description repeats of putative metal-binding domains, a Chromosome 3: 37493606-37865005; forward transmembrane segment, and a short C-terminal strand. Segons omim: 3:37493812 - 37861280. cytoplasmic tail. ITGA9, like ITGA4, lacks the domain I and the post-translational cleavage that Transcription usually occurs in the rest of alpha-integrins. Exons: 28; Coding exons: 28; Transcript length: Alpha9-Integrin forms a functional heterodimer 7889 bps; Translation length: 1035 residues. with beta1-integrin.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 321 ITGA9 (integrin, alpha 9) Molist C, et al.

Expression Homology ITGA9 expression is widely distributed in normal Alpha- and beta-integrins are completely distinct, human epithelia and muscle. with no detectable homology between them. For instance, it has been found in airway Sequence identity among alpha-integrins is around epithelium, basal layer of squamous epithelium, 45%. smooth muscle and skeletal muscle. All alpha-integrins are thought to have evolved Furthermore, its expression has been found in from a common ancestor. hepatocytes, breast tissue, neutrophils and Among all alpha-subunits, alpha-9 shows the polymorphonuclear leukocytes. greatest homology with alpha-4. Localisation Cell membrane. Mutations Function Adhesion with extracellular-matrix proteins, cell- cell interactions and signal transduction. ITGA9 has been shown to bind a plethora of ligands: tenascin, VCAM-1, osteopontin, uPAR, plasmin, angiostatin, several ADAMs (ADAM1, ADAM2, ADAM3, ADAM7, ADAM8, ADAM9, ADAM12, ADAM15, ADAM28 and ADAM33), EMILIN1, fibronectin, VEGF-A, VEGF-C and VEGF-D. Alpha9 knockout mice died from respiratory failure before day 12 after birth and showed chylothorax, defective lymphatic and venous valve morphogenesis, impaired development of neutrophils, improper re-epithelialisation during Implicated in cutaneous wound-healing, impaired bone resorption Small cell lung cancer (SCLC) and abnormal osteoclasts. In cancer, the heterodimer alpha9-beta1 has Note recently been shown to have an oncogenic role by Yamakawa et al. (1993) identified a region of inducing epithelial-mesenchymal transition and cell homozygous deletions in chromosome 3p21.3 in migration and metastatic ability in several cancers lung cancer cell lines, where the ITGA9 gene is such as glioma, breast, colon and located. rhabdomyosarcoma. Furthermore, Hibi et al. (1994) reported an However, other authors have reported a tumour upregulation of the ITGA9 gene in SCLC cell lines suppressor function for ITGA9 in a wide variety of and primary tumours, suggesting that an altered tumours based on deletion or methylation states in expression of the ITGA9 may contribute to the varying percentages of patients. phenotype of this cancer. Furthermore, a very small percentage of patients An activation of ITGA9 expression has been shown (1%) with point mutations has also been reported. in different human tumours and cancer cells, for

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 322 ITGA9 (integrin, alpha 9) Molist C, et al.

example small cell lung cancer, medulloblastoma, alternative splicing. J Biol Chem. 2002 Apr astrocytoma and glioblastoma. 26;277(17):14467-74 On the other hand, several genetic and epigenetic Takada Y, Ye X, Simon S. The integrins. Genome Biol. aberrations (deletions and methylations) of ITGA9 2007;8(5):215 have been described in several types of cancer such Mambole A, Bigot S, Baruch D, Lesavre P, Halbwachs- as kidney, lung, breast, ovarian, cervical, prostate Mecarelli L. Human neutrophil integrin alpha9beta1: up- and colorectal. regulation by cell activation and synergy with beta2 integrins during adhesion to endothelium under flow. J References Leukoc Biol. 2010 Aug;88(2):321-7 Mostovich LA, Prudnikova TY, Kondratov AG, Loginova D, Palmer EL, Rüegg C, Ferrando R, Pytela R, Sheppard D. Vavilov PV, Rykova VI, Sidorov SV, Pavlova TV, Kashuba Sequence and tissue distribution of the integrin alpha 9 VI, Zabarovsky ER, Grigorieva EV. Integrin alpha9 (ITGA9) subunit, a novel partner of beta 1 that is widely distributed expression and epigenetic silencing in human breast in epithelia and muscle. J Cell Biol. 1993 Dec;123(5):1289- tumors. Cell Adh Migr. 2011 Sep-Oct;5(5):395-401 97 Høye AM, Couchman JR, Wewer UM, Fukami K, Yoneda Yamakawa K, Takahashi T, Horio Y, Murata Y, Takahashi A. The newcomer in the integrin family: integrin α9 in E, Hibi K, Yokoyama S, Ueda R, Takahashi T, Nakamura biology and cancer. Adv Biol Regul. 2012 May;52(2):326- Y. Frequent homozygous deletions in lung cancer cell lines 39 detected by a DNA marker located at 3p21.3-p22. Majumder M, Tutunea-Fatan E, Xin X, Rodriguez-Torres Oncogene. 1993 Feb;8(2):327-30 M, Torres-Garcia J, Wiebe R, Timoshenko AV, Hibi K, Yamakawa K, Ueda R, Horio Y, Murata Y, Tamari Bhattacharjee RN, Chambers AF, Lala PK. Co-expression M, Uchida K, Takahashi T, Nakamura Y, Takahashi T. of α9β1 integrin and VEGF-D confers lymphatic metastatic Aberrant upregulation of a novel integrin alpha subunit ability to a human breast cancer cell line MDA-MB-468LN. gene at 3p21.3 in small cell lung cancer. Oncogene. 1994 PLoS One. 2012;7(4):e35094 Feb;9(2):611-9 Masià A, Almazán-Moga A, Velasco P, Reventós J, Torán Shang T, Yednock T, Issekutz AC. alpha9beta1 integrin is N, Sánchez de Toledo J, Roma J, Gallego S. Notch- expressed on human neutrophils and contributes to mediated induction of N-cadherin and α9-integrin confers neutrophil migration through human lung and synovial higher invasive phenotype on rhabdomyosarcoma cells. Br fibroblast barriers. J Leukoc Biol. 1999 Nov;66(5):809-16 J Cancer. 2012 Oct 9;107(8):1374-83 Taooka Y, Chen J, Yednock T, Sheppard D. The integrin Veeravalli KK, Ponnala S, Chetty C, Tsung AJ, Gujrati M, alpha9beta1 mediates adhesion to activated endothelial Rao JS. Integrin α9β1-mediated cell migration in cells and transendothelial neutrophil migration through glioblastoma via SSAT and Kir4.2 potassium channel interaction with vascular cell adhesion molecule-1. J Cell pathway. Cell Signal. 2012 Jan;24(1):272-81 Biol. 1999 Apr 19;145(2):413-20 Gupta SK, Oommen S, Aubry MC, Williams BP, Vlahakis Eto K, Huet C, Tarui T, Kupriyanov S, Liu HZ, Puzon- NE. Integrin α9β1 promotes malignant tumor growth and McLaughlin W, Zhang XP, Sheppard D, Engvall E, Takada metastasis by potentiating epithelial-mesenchymal Y. Functional classification of ADAMs based on a transition. Oncogene. 2013 Jan 10;32(2):141-50 conserved motif for binding to integrin alpha 9beta 1: implications for sperm-egg binding and other cell This article should be referenced as such: interactions. J Biol Chem. 2002 May 17;277(20):17804-10 Molist C, Almazán-Moga A, Vidal I, Soriano A, Jubierre L, Liao YF, Gotwals PJ, Koteliansky VE, Sheppard D, Van De Segura MF, Sánchez de Toledo J, Gallego S, Roma J. Water L. The EIIIA segment of fibronectin is a ligand for ITGA9 (integrin, alpha 9). Atlas Genet Cytogenet Oncol integrins alpha 9beta 1 and alpha 4beta 1 providing a Haematol. 2014; 18(5):321-323. novel mechanism for regulating cell adhesion by

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Gene Section Short Communication

KIAA1199 (KIAA1199) Nikki Ann Evensen, Cem Kuscu, Jian Cao Stony Brook University, Stony Brook, New York, USA (NAE, CK, JC)

Published in Atlas Database: October 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/KIAA1199ID51053ch15q25.html DOI: 10.4267/2042/53643 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

introns. The transcriptional start site is within the Abstract second exon. There is a canonical TATA-box Review on KIAA1199, with data on DNA/RNA, on present in the KIAA1199 promoter region at -31 to the protein encoded and where the gene is -27 base pairs, as well as a GC-box at -248 to -243 implicated. base pairs. However, this GC-box was not found to be required for transcriptional activation of Identity KIAA1199, nor was there any methylation of the cytosines found within this region, which is often Other names: CCSP1, TMEM2L an important feature of GC-boxes. KIAA1199 also HGNC (Hugo): KIAA1199 contains a CpG island within the first intron (+525 Location: 15q25.1 50 +1025). The methylation status of this CpG island was found to effect the expression level of Note KIAA1199, with high levels of DNA methylation Reported in the Human Unidentified Gene-Encoded found in non-aggressive, low expressing, cancer Large Proteins (HUGE) database as KIAA1199. cell lines (Kuscu et al., 2012). DNA/RNA Transcription An AP-1 binding site, located between -48 and -45 Description within the KIAA1199 promoter, was found to be The human KIAA1199 transcript spans 7080 base important for KIAA1199 promoter activity. AP-1 pairs on chromosome 15 in the region 15q25.1. It was found to directly bind to this region in order to contains 29 exons, 28 of which are coding, and 28 activate transcription of KIAA1199.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 324 KIAA1199 (KIAA1199) Evensen NA, et al.

AP-1 transcription factors have been associated (BiP)/glucose-regulated protein (GRP-78), which with increased promoter activity of genes further supports the ER localization of KIAA1199 associated with cancer. Additionally, among four (Evensen et al., 2013). Secretion of KIAA1199 has potential NF-κB binding sites, the site furthest from also been demonstrated for certain cell types the transcriptional start site (-1345 to -1333) was (Tiwari et al., 2013). found to play a role in KIAA1199 promoter Function activation. NF-κB was found to directly bind to this site to increase transcription of KIAA1199 (Kuscu KIAA1199 plays a key role in cancer progression et al., 2012). via increasing cancer cell migration and invasion, which are necessary steps for cancer metastasis. Protein Expression of KIAA1199 in non-aggressive cancer cell lines leads to an epithelial-to-mesenchymal Description transition along with increased migratory The KIAA1199 open reading frame consists of capabilites. Furthermore, knockdown of KIAA1199 4083 base pairs, which encodes a protein 1361 leads to a loss of mesenchymal characteristics with amino acids in length. It has a predicted molecular decreased invasive and migratory abilities, as well weight of approximately 163 kDa. The KIAA1199 as reduced metastastic potential (Evensen et al., protein has a G8 domain between a.a. 44-166, 2013). which is a novel domain that contains eight A role for KIAA1199 in maintaining ion conserved glycines and consists of five β-strand homeostasis, and more specifically calcium pairs (He et al., 2006). Several disease related signaling, has also been suggested (Abe et al., proteins contain this domain, including polyductin 2003; Tiwari et al., 2013). KIAA1199-mediated protein (PKHD1) and transmembrane protein 2 migration was found to involve elevated cytosolic (TMEM2), although the exact function of the G8 calcium levels followed by protein kinase C alpha motif remains unclear (He et al., 2006). A GG (PKC α) translocation/activation. This change in domain, characterized by seven β-strands and two cytosolic calcium is due to increased release of α-helices, can also be found within the KIAA1199 calcium from the ER via an unknown mechanism protein (Guo et al., 2006). This novel domain also induced by KIAA1199 (Evensen et al., 2013). has no known function. KIAA1199 is also predicted Additional studies revealed an interaction with KIAA1199 and inositol 1,4,5-triphosphate receptor to have a cleavable signal peptide at its NH 2- terminus (Sabates-Bellver et al., 2007). KIAA1199 3 (ITPR3) which is a ligand-gated ion channel has been demonstrated to be N-linked glycosylated located on the ER membrane that is known to (Tiwari et al., 2013). mediate the release of calcium from the ER (Tiwari et al., 2013). Expression KIAA1199 is thought to be a target of the Wnt Northern blot analysis of normal human tissues signaling pathway and a potential player in the revealed expression of KIAA1199 mRNA in progression of colorectal adenomatous (Sabates- various tissues, with the highest levels found in the Bellver et al., 2007; Tiwari et al., 2013). brain, placenta, lung, and testis (Michishita et al., Additionally, silencing of KIAA1199 was shown to 2006). KIAA1199 is also expressed in various cell alter the expression of genes known to be involved types found in the inner ear (Abe et al., 2003; in the Wnt/ β-catenin pathway and decrease cell Usami et al., 2008), and in dermal fibroblasts of the proliferation (Birkenkamp-Demtroder et al., 2011). skin (Yoshida et al., 2013). Increased levels of In human skin fibroblasts, KIAA1199 expression KIAA1199 have also been demonstrated in was found to cause increased degradation of numerous cancer tissues compared to normal hyaluronan (HA), which is a glycosaminoglycan tissues, including colorectal adenomas (Sabates- found in the extracellular matrix surrounding Bellver et al., 2007). tissues. It acts as a structural component and can affect cell signaling and cellular behavior, including Localisation angiogenesis and cell migration (Yoshida et al., Cytoplasmic and nuclear staining for KIAA1199 2013). has been observed in gastric and colon cancer tissue samples (Sabates-Bellver et al., 2007; Matsuzaki et Homology al., 2009; Birkenkamp-Demtroder et al., 2011). The KIAA1199 gene product shares 38% identity More detailed subcellular localization revealed (63% similarity) with transmembrane protein 2 expression of exogenous and endogenous (TMEM2). A small region within the KIAA1199 KIAA1199 within the endoplasmic reticulum (ER) gene product (aa 55-155) also shares 38% identity of various cell types (Evensen et al., 2013; Tiwari (57% similarity) with polyductin protein (PKHD1) et al., 2013). KIAA1199 was found to interact with (Abe et al., 2003). However, none of these the ER chaperone binding immunoglobulin protein homologies revealed any functional information.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 325 KIAA1199 (KIAA1199) Evensen NA, et al.

non-syndromic hearing loss diseases. FEBS Lett. 2006 Mutations Jan 23;580(2):581-4 Somatic He QY, Liu XH, Li Q, Studholme DJ, Li XW, Liang SP. G8: a novel domain associated with polycystic kidney disease Nine DNA variants of the KIAA1199 gene were and non-syndromic hearing loss. Bioinformatics. 2006 Sep identified, six of which were missense (R187C, 15;22(18):2189-91 R187H, H783R, H783Y, V1109I, and P1169A) and Michishita E, Garcés G, Barrett JC, Horikawa I. three of which were synonymous substitutions Upregulation of the KIAA1199 gene is associated with (L532L, P619P, D800D). R187C, R187H, H783Y, cellular mortality. Cancer Lett. 2006 Jul 28;239(1):71-7 and V1109I were found only in families with Sabates-Bellver J, Van der Flier LG, de Palo M, Cattaneo nonsyndromic hearing loss, suggesting a potential E, Maake C, Rehrauer H, Laczko E, Kurowski MA, Bujnicki role for these specific mutations in this disease state JM, Menigatti M, Luz J, Ranalli TV, Gomes V, Pastorelli A, Faggiani R, Anti M, Jiricny J, Clevers H, Marra G. (Abe et al., 2003). Transcriptome profile of human colorectal adenomas. Mol Cancer Res. 2007 Dec;5(12):1263-75 Implicated in Usami S, Takumi Y, Suzuki N, Oguchi T, Oshima A, Suzuki H, Kitoh R, Abe S, Sasaki A, Matsubara A. The Gastric and colorectal cancers localization of proteins encoded by CRYM, KIAA1199, Prognosis UBA52, COL9A3, and COL9A1, genes highly expressed in the cochlea. Neuroscience. 2008 Jun 12;154(1):22-8 Numerous studies have implicated KIAA1199 expression with cancer progression. Gastric cancer Matsuzaki S, Tanaka F, Mimori K, Tahara K, Inoue H, Mori M. Clinicopathologic significance of KIAA1199 patients with low expression of KIAA1199 were overexpression in human gastric cancer. Ann Surg Oncol. found to have significantly better overall 5-year 2009 Jul;16(7):2042-51 survival rates as compared to those expressing Chivu Economescu M, Necula LG, Dragu D, Badea L, higher levels. Furthermore, lymph node metastasis, Dima SO, Tudor S, Nastase A, Popescu I, Diaconu CC. distant metastasis, and peritoneal dissemination Identification of potential biomarkers for early and were more often observed in the patients with advanced gastric adenocarcinoma detection. higher levels of KIAA1199 (Matsuzaki et al., Hepatogastroenterology. 2010 Nov-Dec;57(104):1453-64 2009). Birkenkamp-Demtroder K, Maghnouj A, Mansilla F, Additionally, there is evidence to suggest that Thorsen K, Andersen CL, Øster B, Hahn S, Ørntoft TF. Repression of KIAA1199 attenuates Wnt-signalling and KIAA1199 could potentially be used as a decreases the proliferation of colon cancer cells. Br J biomarker for cancer. Higher levels of KIAA1199 Cancer. 2011 Aug 9;105(4):552-61 transcripts were found in the serum of patients with Kuscu C, Evensen N, Kim D, Hu YJ, Zucker S, Cao J. adenoma and colorectal cancer as compared to Transcriptional and epigenetic regulation of KIAA1199 neoplasia free controls (LaPointe et al., 2012). gene expression in human breast cancer. PLoS One. KIAA1199 was also found to be upregulated in 2012;7(9):e44661 cancerous tissues from gastric adenocarcinoma LaPointe LC, Pedersen SK, Dunne R, Brown GS, Pimlott patients, further supporting the idea of using L, Gaur S, McEvoy A, Thomas M, Wattchow D, Molloy PL, KIAA1199 for diagnostics, early detection, or as a Young GP. Discovery and validation of molecular biomarkers for colorectal adenomas and cancer with predictor of cancer progression (Chivu Economescu application to blood testing. PLoS One. 2012;7(1):e29059 et al., 2010). Evensen NA, Kuscu C, Nguyen HL, Zarrabi K, Dufour A, Nonsyndromic hearing loss Kadam P, Hu YJ, Pulkoski-Gross A, Bahou WF, Zucker S, Cao J. Unraveling the role of KIAA1199, a novel Prognosis endoplasmic reticulum protein, in cancer cell migration. J Several mutations within KIAA1199 were found in Natl Cancer Inst. 2013 Sep 18;105(18):1402-16 patients with nonsyndromic hearing loss but not in Tiwari A, Schneider M, Fiorino A, Haider R, Okoniewski control subjects. Based on the expression pattern of MJ, Roschitzki B, Uzozie A, Menigatti M, Jiricny J, Marra KIAA1199 in the cells of the inner ear, it is thought G. Early insights into the function of KIAA1199, a markedly that it could play a role in normal auditory overexpressed protein in human colorectal tumors. PLoS development with these particular mutations having One. 2013;8(7):e69473 a negative impact (Abe et al., 2003). Yoshida H, Nagaoka A, Kusaka-Kikushima A, Tobiishi M, Kawabata K, Sayo T, Sakai S, Sugiyama Y, Enomoto H, Okada Y, Inoue S. KIAA1199, a deafness gene of References unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization. Proc Natl Acad Abe S, Usami S, Nakamura Y. Mutations in the gene Sci U S A. 2013 Apr 2;110(14):5612-7 encoding KIAA1199 protein, an inner-ear protein expressed in Deiters' cells and the fibrocytes, as the cause of nonsyndromic hearing loss. J Hum Genet. This article should be referenced as such: 2003;48(11):564-70 Evensen NA, Kuscu C, Cao J. KIAA1199 (KIAA1199). Guo J, Cheng H, Zhao S, Yu L. GG: a domain involved in Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):324- phage LTF apparatus and implicated in human MEB and 326.

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Gene Section Short Communication

MMP19 (matrix metallopeptidase 19) King Chi Chan, Maria Li Lung Department of Clinical Oncology and Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong, P.R. China (KCC, MLL)

Published in Atlas Database: October 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/MMP19ID41395ch12q13.html DOI: 10.4267/2042/53644 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Transcription The MMP-19 promoter contains a TATA-box at Review on MMP19, with data on DNA/RNA, on position -29 and AP-1 binding site at position -73. the protein encoded and where the gene is Potential binding sites for other transcription factors implicated. such as NF κB, AP-2, and SP-1 also exist (Mueller Identity et al., 2000). Other names: MMP18, RASI-1 Protein HGNC (Hugo): MMP19 Description Location: 12q13.2 MMP-19 is a secreted protein. It contains a signal DNA/RNA peptide for targeting to secretory vesicles. Like most secreted MMPs, MMP-19 is translated and Description secreted as catalytic inactive proproteins MMP-19 can be found at chromosome 12q13.2 at (zymogens), which needed to be activated by location 56229214-56236767. The DNA sequence proteolytic cleavage of the propeptide region by contains nine exons and eight introns, spanning other extracellular matrix (EMC) proteinases (Ra 7,55 kb. and Parks, 2007).

Alternative splicing results in multiple transcript variants for this gene (provided by RefSeq, Jan 2013). With reference to UniProtKB database, variant 1 represents the longest transcript and encodes isoform 1 (508 aa, 57 kDa, also known as RASI-1). Variant 2 encoded protein isoform 2 (222 aa, 25 kDa, also known as RASI-9). Variant 3 encoded protein isoform 3 (63 aa, 6 kDa, also known as RASI-6). Isoform 1 has been described as the canonical sequence and all the information described here, unless stated, refers to isoform 1.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 327 MMP19 (matrix metallopeptidase 19) Chan KC, Lung ML

MMP-19 shares a typical MMP structural domain, containing the signal peptide, propeptide, catalytic domain, hinge region, and four hemopexin repeats (Pendás et al., 1997).

MMP-19 is a zinc-dependent endopeptidase. progression and repression, the role of MMP-19 in The catalytic domain contains the active site for cancer development is as controversial as for all zinc ion binding and functions in catalytic activity other MMPs. such as substrate degradation. MMP-19 is reported to cleave insulin-like growth The hemopexin domain is responsible for substrate factor binding protein-3 (IGFBP-3), thereby recognition (Ra and Parks, 2007). causing the release of IGF-1 and enhanced human The catalytic activities of MMPs were reported to keratinocyte cell proliferation, migration, and be regulated by tissue inhibitor of adhesion on type I collagen (Sadowski et al., 2003). metalloproteinases (TIMPs). MMP-19 is reported to Also, MMP-19 was reported to process the laminin- be strongly inhibited by TIMP-2, TIMP-3, and 5-gamma-2-chain in keratinocyte cells, which leads TIMP-4, and less efficiently by TIMP-1 (Clark et to the integrin switch favoring epithelial cell al., 2008). migration (Sadowski et al., 2005). Expression On the other hand, a MMP-19 deficiency mouse model increased the onset of skin tumor invasion MMP-19 was found to be expressed in a wide range and vascularization, implicating the role of MMP- of normal tissue types, such as nasopharyngeal 19 in inhibition of tumor invasion and anti- epithelial cells, lung, breast, skin, intestine, angiogenesis (Jost et al., 2006). pancreas, spleen, and ovary. MMP-19 was down- The anti-angiogenic role of MMP-19 was regulated or lost during neoplastic progression in demonstrated in the tube formation assay in human nasopharyngeal carcinoma (NPC), mammary gland microvascular endothelial cells (HMEC-1). MMP- tumor, skin neoplasm, intestine, and colon cancers 19 inhibited tube formation by degradation of (Pendás et al., 1997; Djonov et al., 2001; Impola et nidogen-1, which is a scaffolding protein required al., 2003; Bister et al., 2004; Chan et al., 2011). for stabilizing new capillary formation (Titz et al., Localisation 2004). Further studies of MMP-19 on endothelial cells suggested other mechanisms of MMP-19 in MMP-19 is located in the cytoplasm and secreted inhibition of angiogenesis. MMP-19 digests into the extracellular matrix. plasminogen to generate angiostatin-like fragments, Function which are antagonists of angiogenesis and inhibit MMP-19 is a member of the MMP family of zinc- migration and proliferation of endothelial cells dependent endopeptidases. The catalytic domain (Brauer et al., 2011). responsible for degradation of various components Functional studies of MMP-19 demonstrated its of the ECM includes collagen type IV, nidogen-1, tumor suppressive and anti-angiogenesis functions fibronectin, tenascin-C isoform, aggrecan, and in nasopharyngeal carcinoma (NPC). MMP-19 laminin-5-gamma-2-chain (Stracke et al., 2000; reduces colony-forming ability of NPC cells and Shiomi et al., 2010). MMP-19 is involved in many suppresses tumor formation in nude mice. Also, physiological activities such as cell proliferation, MMP-19 reduces tube-forming ability in human migration, and anti-angiogenesis. umbilical vein endothelial cells (HuVEC) and human microvascular endothelial cells (HMEC-1). Implicated in The anti-angiogenic activity of MMP-19 in NPC is associated with reduction of secreted vascular Various cancers endothelial growth factor (VEGF) in the Note conditioned media (Chan et al., 2011). Recent study Due to the ability of MMPs to degrade a variety of in NPC cells demonstrated MMP-19 increased substrates, which may be involved in both cancer cisplatin sensitivity through production of γ-H2AX

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 328 MMP19 (matrix metallopeptidase 19) Chan KC, Lung ML

and attenuation of NER activity to repair cisplatin- Lohi J, Puolakkainen P, Lopez-Otin C, Saarialho-Kere U. induced DNA damage, therefore increasing the Differential expression of three matrix metalloproteinases, MMP-19, MMP-26, and MMP-28, in normal and inflamed cisplatin-induced apoptosis in NPC (Liu et al., intestine and colon cancer. Dig Dis Sci. 2004 2013). Apr;49(4):653-61 Rheumatoid arthritis (RA) Titz B, Dietrich S, Sadowski T, Beck C, Petersen A, Sedlacek R. Activity of MMP-19 inhibits capillary-like Note formation due to processing of nidogen-1. Cell Mol Life MMP-19 was first isolated as an autoantigen from Sci. 2004 Jul;61(14):1826-33 the synovium of a rheumatoid arthritis patient Sadowski T, Dietrich S, Koschinsky F, Ludwig A, Proksch suggesting its role in RA-associated joint tissue E, Titz B, Sedlacek R. Matrix metalloproteinase 19 destruction (Sedlacek et al., 1998). processes the laminin 5 gamma 2 chain and induces epithelial cell migration. Cell Mol Life Sci. 2005 Apr;62(7- References 8):870-80 Jost M, Folgueras AR, Frérart F, Pendas AM, Blacher S, Pendás AM, Knäuper V, Puente XS, Llano E, Mattei MG, Houard X, Berndt S, Munaut C, Cataldo D, Alvarez J, Apte S, Murphy G, López-Otín C. Identification and Melen-Lamalle L, Foidart JM, López-Otín C, Noël A. characterization of a novel human matrix Earlier onset of tumoral angiogenesis in matrix metalloproteinase with unique structural characteristics, metalloproteinase-19-deficient mice. Cancer Res. 2006 chromosomal location, and tissue distribution. J Biol May 15;66(10):5234-41 Chem. 1997 Feb 14;272(7):4281-6 Ra HJ, Parks WC. Control of matrix metalloproteinase Sedlacek R, Mauch S, Kolb B, Schätzlein C, Eibel H, Peter catalytic activity. Matrix Biol. 2007 Oct;26(8):587-96 HH, Schmitt J, Krawinkel U. Matrix metalloproteinase MMP-19 (RASI-1) is expressed on the surface of activated Clark IM, Swingler TE, Sampieri CL, Edwards DR. The peripheral blood mononuclear cells and is detected as an regulation of matrix metalloproteinases and their inhibitors. autoantigen in rheumatoid arthritis. Immunobiology. 1998 Int J Biochem Cell Biol. 2008;40(6-7):1362-78 Feb;198(4):408-23 Shiomi T, Lemaître V, D'Armiento J, Okada Y. Matrix Mueller MS, Mauch S, Sedlacek R. Structure of the human metalloproteinases, a disintegrin and metalloproteinases, MMP-19 gene. Gene. 2000 Jul 11;252(1-2):27-37 and a disintegrin and metalloproteinases with thrombospondin motifs in non-neoplastic diseases. Pathol Stracke JO, Fosang AJ, Last K, Mercuri FA, Pendás AM, Int. 2010 Jul;60(7):477-96 Llano E, Perris R, Di Cesare PE, Murphy G, Knäuper V. Matrix metalloproteinases 19 and 20 cleave aggrecan and Brauer R, Beck IM, Roderfeld M, Roeb E, Sedlacek R. cartilage oligomeric matrix protein (COMP). FEBS Lett. Matrix metalloproteinase-19 inhibits growth of endothelial 2000 Jul 28;478(1-2):52-6 cells by generating angiostatin-like fragments from plasminogen. BMC Biochem. 2011 Jul 25;12:38 Djonov V, Högger K, Sedlacek R, Laissue J, Draeger A. MMP-19: cellular localization of a novel metalloproteinase Chan KC, Ko JM, Lung HL, Sedlacek R, Zhang ZF, Luo within normal breast tissue and mammary gland tumours. DZ, Feng ZB, Chen S, Chen H, Chan KW, Tsao SW, Chua J Pathol. 2001 Sep;195(2):147-55 DT, Zabarovsky ER, Stanbridge EJ, Lung ML. Catalytic activity of Matrix metalloproteinase-19 is essential for Impola U, Toriseva M, Suomela S, Jeskanen L, Hieta N, tumor suppressor and anti-angiogenic activities in Jahkola T, Grenman R, Kähäri VM, Saarialho-Kere U. nasopharyngeal carcinoma. Int J Cancer. 2011 Oct Matrix metalloproteinase-19 is expressed by proliferating 15;129(8):1826-37 epithelium but disappears with neoplastic dedifferentiation. Int J Cancer. 2003 Mar 1;103(6):709-16 Liu RY, Dong Z, Liu J, Zhou L, Huang W, Khoo SK, Zhang Z, Petillo D, Teh BT, Qian CN, Zhang JT. Overexpression Sadowski T, Dietrich S, Koschinsky F, Sedlacek R. Matrix of asparagine synthetase and matrix metalloproteinase 19 metalloproteinase 19 regulates insulin-like growth factor- confers cisplatin sensitivity in nasopharyngeal carcinoma mediated proliferation, migration, and adhesion in human cells. Mol Cancer Ther. 2013 Oct;12(10):2157-66 keratinocytes through proteolysis of insulin-like growth factor binding protein-3. Mol Biol Cell. 2003 This article should be referenced as such: Nov;14(11):4569-80 Chan KC, Lung ML. MMP19 (matrix metallopeptidase 19). Bister VO, Salmela MT, Karjalainen-Lindsberg ML, Uria J, Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):327- 329.

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Gene Section Review

RPS6KA6 (Ribosomal Protein S6 Kinase, 90kDa, Polypeptide 6) Tuoen Liu, Shousong Cao Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri, United States (TL), Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, United States (SC)

Published in Atlas Database: October 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/RPS6KA6ID43481chXq21.html DOI: 10.4267/2042/53645 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

contains 22 exons that span approximately 75 kb of Abstract genomic DNA and are located on cosmids E1, H22 Review on RPS6KA6, with data on DNA/RNA, on and G9 in a telomeric to centromeric orientation the protein encoded and where the gene is (Yntema et al, 1999; Dümmler et al., 2005; implicated. Kantojärvi et al., 2011). Identity Protein Other names: PP90RSK4, RSK4 Note HGNC (Hugo): RPS6KA6 Human RPS6KA6 gene codes for the protein Location: Xq21.1 RSK4, a serine- threonine kinase with 745 amino acids, also a member of the 90 kDa ribosomal S6 DNA/RNA kinase (RSK) family which includes other three members RSK1, RSK2 and RSK3 (Yntema et al., Description 1999; Dümmler et al., 2005; Anjum and Blenis, The human RPS6KA6 gene is located at Xq21, and 2008; Serra et al., 2013).

The basic structure of the RSK4. The RSK4 protein includes two kinases domains: amino-terminal kinase domain (NTKD) and carboxyl-terminal kinase domain (CTKD), a linker region and amino- and carboxyl-terminal tails. The NTKD is responsible for substrate phosphorylation and CTKD regulates sutophosphorylation of the RSK4. The two kinase domains are connected by a linker region which is about 100 amino acids containing essential regulatory domains including hydrophobic and turn motifs, involved in the activation of NTKD. An ERK-docking motif, known also as the D domain, is located in the carboxyl-terminal tail (Dümmler et al., 2005; Anjum and Blenis, 2008; Romeo et al., 2012).

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The activation of the RSK4 family protein. All RSK family membranes including RSK4 are involved in MAPK pathways and can be activated by various molecules including growth factors, neurotransmitters, hormones, phorbol esters. First, activation of cell surface receptors creates docking site for adaptor molecules like growth factor receptor-bound protein-2 (GRB2). GRB2 links the receptor to the guanine nucleotide-exchange factor son of sevenless (SOS). SOS catalyses GDP release and GTP binding to the small G-protein Ras. The GTP-bound Ras then binds to the Raf protein kinases. Upon the activation of Raf, it activates MAPK kinase (MEK), then downstream extracellular signal-regulated kinase (ERK). All four RSK family members are directly phosphorylated and activated by ERK1/2. RSKs are also phosphorylated by 3'-phosphoinositide-dependent kinase-1 (PDK1) which is a serine-threonine kinase. Activated RSKs can then phosphorylate their substrates via serine and threonine sites (Anjum and Blenis, 2008).

Description Expression RSK4 is a serine- threonine kinase and there are six RSK4 expression is low in both mouse and human phosphorylation sites in RSK4: Ser232, Thr368, embryonic and adult tissues compared with other Ser372, Ser389, Thr581, and Ser742. Upon three RSK family members. RSK4 mRNA was activation of the cell surface receptors, ERK first detected in the brain, cerebellum, heart, kidney and bound to the ERK-docking motif in the carboxyl- skeletal muscle, but not in other tissues such as terminal and phosphorylates Ser372 in the linker lung, liver, pancreas and adipose. Specifically, region and Thr581 in the CTKD. Phosphorylation RSK4 was found to be ubiquitously expressed at a of Thr581 activates CTK which autophosphorylates low level through mouse development, and it is RSK4 at Ser389 in the linker region. more highly expressed in specific phases of Phosphorylation of Ser389 recruites and activiates embryogenesis such as egg cylinder, gastrula and PDK1 which phosphorylates Ser232 in NTKD. organ genesis (Kohn et al., 2003; Lleonart et al., After dissociation of PDK1 from RSK, the Ser386 2006; Romeo et al., 2012). phosphorylated motif interacts with NTKD and activates the NTK in synergy with phosphor- Localisation Ser232. The phosphorylation of Ser372 increases RSK is predominantly located in cytosol, and the activity of NTK. Thr368 is phosphorylated by contrary to other RSKs, its expression is relatively ERK and Ser742 can be phosphorylated by low and does not significantly accumulate in the activated NTK, which leads to the association of nucleus after mitogenic stimulation (Dümmler et RSK and ERK, serving as an inhibitory feedback al., 2005; Romeo et al., 2012). mechanism to "shut off" the process (Dümmler et Function al., 2005). The CTKD activity of RSK1, RSK2 and RSK4 can be regulated by the irreversible inhibitor, Recent studies showed RSK4 can be either pyrrolopyrimidine FMK (Z-VAD-FMK, oncogenic or tumor suppressive depending on many benzyloxycarbonyl-Val-Ala-DL-Asp- factors, and Cyclin D1 inhibited RSK4 expression fluoromethylketone) (Romeo et al., 2012). and serum starvation enhanced the inhibition.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 331 RPS6KA6 (Ribosomal Protein S6 Kinase, 90kDa, Polypeptide Liu T, Cao S 6)

RSK4 can induce cellular senescence which is pathway inhibitors may overcome the resistance mediated by p21. mediated by RSK4 in breast cancer (Serra et al., Also, inhibition of RSK4 causes bypass of cellular 2013). senescence induced by stress or oncogene, Colon, kidney cancer and melanoma suggesting RSK4 inhibition may be an important factor in facilitating cell transformation. (López- Note Vicente et al., 2011). RSK4 is down-regulated in colon carcinomas, renal shRNA against RPS6KA6 bypassed p53-dependent cell carcinomas and colon adenomas. G1 cell cycle arrest and suppressed mRNA Overexpression of RSK4 induced cell arrest and expression of cyclin-dependent kinase inhibitor senescence features in normal fibroblasts and p21 cip1 , suggesting RSK4 is needed for growth malignant colon carcinoma cell lines. arrest induced by p53 (Berns et al., 2004). In addition, RSK4 is up-regulated in both In addition, RSK4 is identified to be an inhibitor of replicative and stress-induced senescence and fibroblast growth factor (FGF)-Ras-ERK signal RSK4 inhibition induces senescence resistance in transduction. RSK4 plays an inhibitory role during colon carcinoma cells, suggesting RSK4 may be a embryogenesis by suppressing receptor tyrosine tumor suppressor gene by regulating senescence kinase signaling (López-Vicente et al., 2009). induction and inviting cell proliferation in colon carcinogenesis and renal cell carcinomas (Myers et Homology al., 2004). The RSK family members share 73-80% amino RSK4 expression causes Sunitinib resistance in acids similarity to each other and are mostly kidney carcinoma and melanoma cells, thus, RSK4 different in their amino- and carboxyl-terminal may be a potential resistance marker in Sunitinib sequences (Romeo et al., 2012). therapy and a potential target for new drug Difference from other RSK members whose development to overcome Sunitinib resistance activation needs the stimulation by growth factors, (Llenaont et al., 2006; Bender and Ullrich, 2012). RSK4 can be constitutively activated under serum- starved condition without growth factor. Endometrial cancer The constitutive activation is due to constitutive Note phosphorylation of Ser232, Ser372 and Ser389 RSK4 is frequently hypermethylated in endometrial (Dümmler et al., 2005). cancer and RSK4 methylation is significantly PDK1 is required for mitogenic stimulation of associated with tumor grade, with higher grade RSK1-3, however, RSK4 does not appear to require tumors having lower levels of methylation. PDK1 to maintain its high basal activity (Romeo et Thus, RSK4 appears to be epigenetically silenced in al., 2012). endometrial cancer as evidenced by Unlike other three family members, RSK4 hypermethylation (Dewdney et al., 2011). expression can disrupt mouse mesoderm formation induced by the FGF-Ras-ERK signaling pathway X-linked mental retardation (Myers et al., 2004). Note RPS6KA6 gene is commonly deleted in complex Implicated in X-linked mental retardation patients (Yntema et al., 1999). Breast cancer Autism spectrum disorder Note RSK4 is highly expressed and has anti-invasive and Note anti-metastatic activities in breast cancer. RPS6KA6 plays a role in brain development and Exogenous expression of RSK4 resulted in could be associated with mental retardation. decreased breast cancer cell proliferation and RSP6KA6 is located in the chromosomal region, increased accumulation of cells in G0-G1 phase of which is commonly deleted in males with mental the cell cycle, also with enhanced expression retardation. several tumor suppressor genes: retinoblastoma Its mutation may be associated with autism protein, retinoblastoma-associated 46 kDa protein spectrum disorders (Kantojärvi et al., 2011). (RbAp46), and p21 protein (Thakur et al., 2007; Thakur et al., 2008). In addition, RSK4 expression AIDS enhances breast cancer cell survival upon Note PI3K/mTOR inhibitors treatment through inhibition SNP rs5968255, located at human Xq21.1 in a of apoptosis and up-regulation of protein conserved sequence element near the RPS6KA6 translation. Adding MEK- or RSK-specific and CYLC1 genes, was identified as a significant inhibitors can overcome the RSK4 mediated genetic determinant of AIDS progression in HIV resistance, thus, combination of RSK and PI3K infected women.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 332 RPS6KA6 (Ribosomal Protein S6 Kinase, 90kDa, Polypeptide Liu T, Cao S 6)

However, whether RPS6KA6 gene is functionally activities of ribosomal protein S6 kinase 4 in breast cancer involved in the observed phenotype is not clear cells. Clin Cancer Res. 2008 Jul 15;14(14):4427-36 (Siddiqui et al., 2009). López-Vicente L, Armengol G, Pons B, Coch L, Argelaguet E, Lleonart M, Hernández-Losa J, de Torres I, Ramon y Cajal S. Regulation of replicative and stress-induced References senescence by RSK4, which is down-regulated in human Yntema HG, van den Helm B, Kissing J, van Duijnhoven tumors. Clin Cancer Res. 2009 Jul 15;15(14):4546-53 G, Poppelaars F, Chelly J, Moraine C, Fryns JP, Hamel Siddiqui RA, Sauermann U, Altmüller J, Fritzer E, BC, Heilbronner H, Pander HJ, Brunner HG, Ropers HH, Nothnagel M, Dalibor N, Fellay J, Kaup FJ, Stahl-Hennig Cremers FP, van Bokhoven H. A novel ribosomal S6- C, Nürnberg P, Krawczak M, Platzer M. X chromosomal kinase (RSK4; RPS6KA6) is commonly deleted in patients variation is associated with slow progression to AIDS in with complex X-linked mental retardation. Genomics. 1999 HIV-1-infected women. Am J Hum Genet. 2009 Dec 15;62(3):332-43 Aug;85(2):228-39 Kohn M, Hameister H, Vogel M, Kehrer-Sawatzki H. Dewdney SB, Rimel BJ, Thaker PH, Thompson DM Jr, Expression pattern of the Rsk2, Rsk4 and Pdk1 genes Schmidt A, Huettner P, Mutch DG, Gao F, Goodfellow PJ. during murine embryogenesis. Gene Expr Patterns. 2003 Aberrant methylation of the X-linked ribosomal S6 kinase May;3(2):173-7 RPS6KA6 (RSK4) in endometrial cancers. Clin Cancer Berns K, Hijmans EM, Mullenders J, Brummelkamp TR, Res. 2011 Apr 15;17(8):2120-9 Velds A, Heimerikx M, Kerkhoven RM, Madiredjo M, Kantojärvi K, Kotala I, Rehnström K, Ylisaukko-Oja T, Nijkamp W, Weigelt B, Agami R, Ge W, Cavet G, Linsley Vanhala R, von Wendt TN, von Wendt L, Järvelä I. Fine PS, Beijersbergen RL, Bernards R. A large-scale RNAi mapping of Xq11.1-q21.33 and mutation screening of screen in human cells identifies new components of the RPS6KA6, ZNF711, ACSL4, DLG3, and IL1RAPL2 for p53 pathway. Nature. 2004 Mar 25;428(6981):431-7 autism spectrum disorders (ASD). Autism Res. 2011 Myers AP, Corson LB, Rossant J, Baker JC. Jun;4(3):228-33 Characterization of mouse Rsk4 as an inhibitor of López-Vicente L, Pons B, Coch L, Teixidó C, Hernández- fibroblast growth factor-RAS-extracellular signal-regulated Losa J, Armengol G, Ramon Y Cajal S. RSK4 inhibition kinase signaling. Mol Cell Biol. 2004 May;24(10):4255-66 results in bypass of stress-induced and oncogene-induced Dümmler BA, Hauge C, Silber J, Yntema HG, Kruse LS, senescence. Carcinogenesis. 2011 Apr;32(4):470-6 Kofoed B, Hemmings BA, Alessi DR, Frödin M. Functional Bender C, Ullrich A. PRKX, TTBK2 and RSK4 expression characterization of human RSK4, a new 90-kDa ribosomal causes Sunitinib resistance in kidney carcinoma- and S6 kinase, reveals constitutive activation in most cell melanoma-cell lines. Int J Cancer. 2012 Jul 15;131(2):E45- types. J Biol Chem. 2005 Apr 8;280(14):13304-14 55 LLeonart ME, Vidal F, Gallardo D, Diaz-Fuertes M, Rojo F, Romeo Y, Zhang X, Roux PP. Regulation and function of Cuatrecasas M, López-Vicente L, Kondoh H, Blanco C, the RSK family of protein kinases. Biochem J. 2012 Jan Carnero A, Ramón y Cajal S. New p53 related genes in 15;441(2):553-69 human tumors: significant downregulation in colon and lung carcinomas. Oncol Rep. 2006 Sep;16(3):603-8 Serra V, Eichhorn PJ, García-García C, Ibrahim YH, Prudkin L, Sánchez G, Rodríguez O, Antón P, Parra JL, Thakur A, Rahman KW, Wu J, Bollig A, Biliran H, Lin X, Marlow S, Scaltriti M, Pérez-Garcia J, Prat A, Arribas J, Nassar H, Grignon DJ, Sarkar FH, Liao JD. Aberrant Hahn WC, Kim SY, Baselga J. RSK3/4 mediate resistance expression of X-linked genes RbAp46, Rsk4, and Cldn2 in to PI3K pathway inhibitors in breast cancer. J Clin Invest. breast cancer. Mol Cancer Res. 2007 Feb;5(2):171-81 2013 Jun 3;123(6):2551-63 Anjum R, Blenis J. The RSK family of kinases: emerging roles in cellular signalling. Nat Rev Mol Cell Biol. 2008 This article should be referenced as such: Oct;9(10):747-58 Liu T, Cao S. RPS6KA6 (Ribosomal Protein S6 Kinase, Thakur A, Sun Y, Bollig A, Wu J, Biliran H, Banerjee S, 90kDa, Polypeptide 6). Atlas Genet Cytogenet Oncol Sarkar FH, Liao DJ. Anti-invasive and antimetastatic Haematol. 2014; 18(5):330-333.

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Atlas of Genetics and Cytogenetics

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Gene Section Review

SIVA1 (SIVA1, Apoptosis-Inducing Factor) João Agostinho Machado-Neto, Fabiola Traina Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciencia e Tecnologia do Sangue, Campinas, Sao Paulo, Brazil (JAMN, FT), Hematology/Oncology Division, Department of Internal Medicine, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil (FT)

Published in Atlas Database: October 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/SIVA1ID42301ch14q32.html DOI: 10.4267/2042/53646 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Two alternatively-spliced transcript variants Abstract encoding distinct proteins have been described, Review on SIVA1, with data on DNA/RNA, on the SIVA1 transcript variant 1, which is the protein encoded and where the gene is implicated. predominant transcript variant with a cDNA containing 790 bp (codifying the SIVA1 protein), Identity and the SIVA1 transcript variant 2 lacking the exon 2 with a cDNA containing 595 bp (codifying the Other names: CD27BP, SIVA, Siva-1, Siva-2 SIVA2 protein). HGNC (Hugo): SIVA1 Protein Location: 14q32.33 Description DNA/RNA SIVA1 contains a unique amphipathic helical region (SAH) in the N-terminal region, a death Description domain homology region (DDHR) in the central The entire SIVA1 gene is about 15.3 Kb and part of the protein, and a Zinc finger-like structure contains 4 exons (Start: 105219437 bp and End: at its C-terminal region. The SIVA2 isoform lacks 105234831; Orientation: plus strand). the DDHR domain (Figure 1).

Figure 1. Schematic structure of SIVA1 and SIVA2 proteins. The amphipathic helical region (SAH) at the N-terminal region, a death domain homology region (DDHR) in the central section, and a Zinc finger-like (ZF) structure at its C-terminal region are illustrated. The amino acids (aa) positions are indicated.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 334 SIVA1 (SIVA1, Apoptosis-Inducing Factor) Machado-Neto JA, Traina F

Figure 2. Intracellular localization of SIVA1 protein in a prostate cancer cell line. Confocal analysis of LNCaP cells displaying SIVA (green), DAPI (blue) and Actin (red) staining; MERGE shows the overlapped images. Scale bar, 10 µm. Note the cytoplasmatic and nuclear localization of SIVA1. Anti-SIVA1 (sc-7436) was from Santa Cruz Biotechnology, (Santa Cruz, CA, USA), Phalloidin (A12379) and DAPI (P-36931) were from Invitrogen (Carlsbad, CA, USA). Personal data.

Expression upregulated under stress or following DNA damage (Ray et al., 2011; Fortin et al., 2004). Ubiquitous. Recently, novel partners and functions have been Localisation attributed to SIVA1. SIVA1 binds to and regulates SIVA1 is found in the nucleus and cytoplasm p53 stability by acting as an adapter protein (Figure 2). between p53 and MDM2, and participates in an auto-regulatory feedback loop between p53 and Function SIVA1 (Du et al., 2009; Mei and Wu, 2012). The proapoptotic function of SIVA1 is well SIVA1 associates with ARF, enabling its elucidated and characterized. SIVA1 binds to death ubiquitination and degradation; this mechanisms receptors, including CD27 and TNFRSF18, and also regulates the p53/MDM2 signaling pathway plays a role in the transduction of the proapoptotic (Wang et al., 2013). signal by the extrinsic pathway (Prasad et al., 1997; Finally, SIVA1 is a novel adaptor protein that Spinicelli et al., 2002). SIVA1 interacts with BCL2 promotes Stathmin 1/CaMKII interaction. and BCL-XL, abrogates their antiapoptotic SIVA1 inhibits Stathmin 1 activity through functions and modulates the intrinsic apoptosis Stathmin 1 phosphorylation at serine 16, which pathway (Chu et al., 2004; Chu et al., 2005). In results in reduced cell migration and metastasis by addition, SIVA1 associates with XIAP and stabilizing microtubules of tumor cells (Li et al., regulates the apoptosis mediated by NFkB and JNK 2011). signaling (Resch et al., 2009). The SIVA gene is a The main functions and signaling pathways of transcription target of p53, p73 and E2F1 and is SIVA1 are illustrated in Figure 3.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 335 SIVA1 (SIVA1, Apoptosis-Inducing Factor) Machado-Neto JA, Traina F

Figure 3. SIVA1 signaling pathway. (1) SIVA1 binds to death receptors and modulates the extrinsic apoptosis pathway. (2) SIVA 1 binds to BCL2 proteins family, inhibits the antiapoptotic proteins, BCL2 and BCL-XL, and leads to proapoptotic BAD protein oligomerization, and modulates the intrinsic apoptosis pathway. (3) SIVA1 binds to the XIAP protein and balances the proapoptotic and antiapoptotic signaling through the JNK and NFkB pathway, respectively, and modulates the extrinsic apoptosis pathway. (4) SIVA1 promotes Stathmin 1/CaMKII interaction, Stathmin 1 phosphorylation and inhibition, and modulates microtubule dynamics. (5) The SIVA1 gene is a transcription target of p53, p73 and E2F1. (6) SIVA1 protein acts as an adapter protein between p53 and MDM2, and promotes p53 ubiquitination. (7) SIVA1 acts as an ARF E3 ubiquitin ligase and regulates cell proliferation by the ARF/p53/MDM2 pathway. Abbreviations: P, phosphorylation; Ac, acetylation; Ub, ubiquitination. Figure was produced using Servier Medical Art.

The binding partners of SIVA1 are: cells expressing the GFP-BCL-XL protein (Xue et CD27: SIVA1 was initially identified by two- al., 2002). Later on, Chu et al. reported that the hybrid (Y2H) screening using CD27 as a bait, and SAH region of SIVA1 was sufficient to specifically its interaction was confirmed by interact with BCL-XL (Chu et al., 2004). immunoprecipitation (IP) of 293 cells co- B-cell CLL/lymphoma 2 (BCL2): The association expressing both proteins (Prasad et al., 1997). In of BCL2 and SIVA1 was verified using GST pull agreement, Yoon et al. found that murine Siva1 and down assays with GST-SIVA in Cos-7 cells Siva2 also bind to CD27 (Yoon et al., 1999). overexpressing full-length BCL2 protein, and this c-abl oncogene 2, non-receptor tyrosine kinase interaction occurred at the SAH region of SIVA1 (ABL2): Y2H screening using ABL2 (previously (Chu et al., 2004). known as ARG) as the bait identified SIVA1 as a CD4: Y2H screen using cytoplasmic domain of binding partner. This protein association was CD4 as the bait identified SIVA1. This protein confirmed by IP of MCF7 cells co-expressing interaction was confirmed by in vitro binding FLAG-ABL2 and GFP-SIVA1 (Cao et al., 2001). assays with GST-SIVA1. The interaction was Tumor necrosis factor receptor superfamily, mapped through GST pull-down assay using GST member 18 (TNFRSF18): TNFRSF18 (previously tagged deletion mutants of SIVA1; the C-terminal known as GITR) presents high homology with region of SIVA1 binds to the cytoplasmic domain CD27. The interaction between TNFRSF18 and of CD4 (Py et al., 2007). SIVA1 was identified using GST pull down and IP Lysophosphatidic acid receptor 2 (LPAR2): Y2H assays (Spinicelli et al., 2002). screening using the C-terminal region of LPAR2 as BCL2-like 1 (BCL-XL): The association of BCL- the bait identified SIVA1. GST pull-down assays XL and SIVA1 was first identified using purified confirmed this protein association and the SIVA1 GST-SIVA and BCL-XL proteins and confirmed by C-terminal region (aa 139-175) is required for this GST pull down assays using GST-SIVA1 in 293 interaction (Lin et al., 2007).

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 336 SIVA1 (SIVA1, Apoptosis-Inducing Factor) Machado-Neto JA, Traina F

Table 1. Comparative identity of human SIVA1 with other species. Source: homologene.

Pyrin (MEFV): Y2H screening using Pyrin as the exogenous or endogenous SIVA1 and Stathmin 1 bait identified SIVA1 binding, and this association proteins (Li et al., 2011). was confirmed by IP. Using deletion mutants of Cyclin-dependent kinase inhibitor 2A Pyrin and of SIVA1 or SIVA2, the C-terminal, rfp (CDKN2A) , also known as ARF: The ARF and and SRPY domain of pyrin were found to interact SIVA interaction was tested by IP assays of H1229 with the N-terminal region of SIVA (Balci- cells containing FLAG-SIVA1 and GFP-ARF, and Peynircioglu et al., 2008). purified recombinant proteins were used for X-linked inhibitor of apoptosis (XIAP): Y2H confirmation. The protein interaction mapping was screening using XIAP as the bait identified SIVA1 performed by GST pull down assays using deletion binding, and this protein association was confirmed mutants of SIVA1 and ARF overexpressed in 293 by IP of 293 cells co-expressing both proteins cells. SIVA1 binds to ARF by its N-terminal region (Resch et al., 2009). and DDHR, while the residue aa 21-64 of ARF is FHL1 four and a half LIM domains 1 (FHL1): required (Wang et al., 2013). Y2H screening using the SLIMMER isoform of Homology FHL1 as the bait identified SIVA; and this protein association was confirmed by IP. Three different SIVA1 shares high homology (around 40%) in its isoforms of FHL1 were used in a Y2H assay for DDHR domain with the FADD and RIP proteins. protein interaction mapping, SIVA1 binds only SIVA1 also shares a high homology with different with the SLIMMER and not with FHL1 and KyoT2 species (Table 1). isoforms (Cottle et al., 2009). p53: The interaction between p53 and SIVA1 was Mutations tested by IP using H1229 cells co-expressing FLAG-p53 and GFP-SIVA1 and confirmed by IP Mutations in the SIVA1 gene are rare, only six using endogenous proteins from A549 cells. GST missense and one nonsense mutations are reported pull-down assays indicate that SIVA1 binds to p53 at COSMIC (Catalogue of somatic mutations in using its N-terminal region and DDHR, while p53 cancer). binds to SIVA1 via its DBD domain (Du et al., 2009). Implicated in Tyrosine kinase 2 (TYK2): Y2H screening using Breast cancer TYK2 as the bait identified SIVA1 binding, and this association was confirmed by IP of 293 cells Note co-expressing FLAG-SIVA1 and full-length TYK2. In breast cancer cells, SIVA1 acts synergistically The SIVA1 N-terminal region binds to TYK2, as with cisplatin in inducing apoptosis (Chu et al., demonstrated by IP of 293T cells overexpressing 2005). Recently, SIVA1 protein has been reported GFP tagged deletion mutants of SIVA1 and FLAG- to be downregulated in primary and metastatic TYK2 (Shimoda et al., 2010). breast cancer tumors and SIVA 1 negatively Stathmin 1: Y2H screening using SIVA1 as bait correlates with Stathmin 1 activity (Li et al., 2011). identified Stathmin 1, and this association was SIVA1 silencing augments metastasis in a confirmed by IP of U2OS cells co-expressing xenograft breast cancer model (Li et al., 2011).

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 337 SIVA1 (SIVA1, Apoptosis-Inducing Factor) Machado-Neto JA, Traina F

Acute lymphoid leukemia Lin S, Ying SY. Differentially expressed genes in activin- induced apoptotic LNCaP cells. Biochem Biophys Res Note Commun. 1999 Apr 2;257(1):187-92 In acute lymphoid leukemia cell lines, SIVA1 Yoon Y, Ao Z, Cheng Y, Schlossman SF, Prasad KV. overexpression induces apoptosis (Py et al., 2004), Murine Siva-1 and Siva-2, alternate splice forms of the while SIVA1 inhibition reduces apoptosis (Resch et mouse Siva gene, both bind to CD27 but differentially al., 2009). transduce apoptosis. Oncogene. 1999 Nov 25;18(50):7174-9 Colorectal cancer Cao C, Ren X, Kharbanda S, Koleske AJ, Prasad KV, Kufe Note D. The ARG tyrosine kinase interacts with Siva-1 in the apoptotic response to oxidative stress. J Biol Chem. 2001 In colorectal cancer samples, using a DNA array Apr 13;276(15):11465-8 approach, SIVA1 has been shown to be downregulated when compared to normal tissue Okuno K, Yasutomi M, Nishimura N, Arakawa T, Shiomi M, Hida J, Ueda K, Minami K. Gene expression analysis in (Okuno et al., 2001). In colon cancer cell lines, colorectal cancer using practical DNA array filter. Dis SIVA1 was found to be a transcriptional target of Colon Rectum. 2001 Feb;44(2):295-9 p53 and E2F1 and to participate in the apoptosis Spinicelli S, Nocentini G, Ronchetti S, Krausz LT, Bianchini induced by MDM2 inhibition (Ray et al., 2011). In R, Riccardi C. GITR interacts with the pro-apoptotic protein addition, SIVA1 silencing reduces apoptosis in a Siva and induces apoptosis. Cell Death Differ. 2002 p53-dependent manner in colon cancer cells treated Dec;9(12):1382-4 with cisplatin (Barkinge et al., 2009). Xue L, Chu F, Cheng Y, Sun X, Borthakur A, Ramarao M, Pandey P, Wu M, Schlossman SF, Prasad KV. Siva-1 Osteosarcoma binds to and inhibits BCL-X(L)-mediated protection against Note UV radiation-induced apoptosis. Proc Natl Acad Sci U S A. 2002 May 14;99(10):6925-30 In a xenograft osteosarcoma model, SIVA1 silencing increases p53 stability and augments the Chu F, Borthakur A, Sun X, Barkinge J, Gudi R, Hawkins tumor growth (Du et al., 2009). In osteosarcoma S, Prasad KV. The Siva-1 putative amphipathic helical region (SAH) is sufficient to bind to BCL-XL and sensitize cell lines, SIVA1 silencing increases cell migration cells to UV radiation induced apoptosis. Apoptosis. 2004 and metastasis, while SIVA1 overexpression has an Jan;9(1):83-95 opposite effect (Li et al., 2011). Fortin A, MacLaurin JG, Arbour N, Cregan SP, Kushwaha Prostate cancer N, Callaghan SM, Park DS, Albert PR, Slack RS. The proapoptotic gene SIVA is a direct transcriptional target for Note the tumor suppressors p53 and E2F1. J Biol Chem. 2004 In a study focused on the identification of genes Jul 2;279(27):28706-14 modulated in prostate cancer cells under apoptosis, Py B, Slomianny C, Auberger P, Petit PX, Benichou S. SIVA1 transcripts were found to be upregulated. Siva-1 and an alternative splice form lacking the death This finding indicates a possible role of SIVA1 in domain, Siva-2, similarly induce apoptosis in T lymphocytes via a caspase-dependent mitochondrial the apoptotic pathway of prostate cancer cells (Lin pathway. J Immunol. 2004 Apr 1;172(7):4008-17 and Ying, 1999). Chu F, Barkinge J, Hawkins S, Gudi R, Salgia R, Kanteti PV. Expression of Siva-1 protein or its putative To be noted amphipathic helical region enhances cisplatin-induced apoptosis in breast cancer cells: effect of elevated levels of Note BCL-2. Cancer Res. 2005 Jun 15;65(12):5301-9 SIVA1 was initially identified as a potent protein in Py B, Bouchet J, Jacquot G, Sol-Foulon N, the induction of apoptosis, which led it to be given Basmaciogullari S, Schwartz O, Biard-Piechaczyk M, a similar name to the Hindu god of destruction, Benichou S. The Siva protein is a novel intracellular ligand Shiva (Prasad et al., 1997). In 2009, the paradigm of the CD4 receptor that promotes HIV-1 envelope-induced apoptosis in T-lymphoid cells. Apoptosis. 2007 that SIVA1 has a function strictly related to Oct;12(10):1879-92 apoptosis was broken when its role in p53 stability was reported. More recently, among the new roles Lin FT, Lai YJ, Makarova N, Tigyi G, Lin WC. The lysophosphatidic acid 2 receptor mediates down-regulation proposed for SIVA1 are cell proliferation, of Siva-1 to promote cell survival. J Biol Chem. 2007 Dec migration and metastasis (Du et al., 2009; Mei and 28;282(52):37759-69 Wu, 2012). Balci-Peynircioglu B, Waite AL, Hu C, Richards N, Staubach-Grosse A, Yilmaz E, Gumucio DL. Pyrin, product References of the MEFV locus, interacts with the proapoptotic protein, Siva. J Cell Physiol. 2008 Sep;216(3):595-602 Prasad KV, Ao Z, Yoon Y, Wu MX, Rizk M, Jacquot S, Schlossman SF. CD27, a member of the tumor necrosis Barkinge JL, Gudi R, Sarah H, Chu F, Borthakur A, factor receptor family, induces apoptosis and binds to Siva, Prabhakar BS, Prasad KV. The p53-induced Siva-1 plays a proapoptotic protein. Proc Natl Acad Sci U S A. 1997 Jun a significant role in cisplatin-mediated apoptosis. J 10;94(12):6346-51 Carcinog. 2009;8:2

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Cottle DL, McGrath MJ, Wilding BR, Cowling BS, Kane metastasis of tumor cells by inhibiting stathmin and JM, D'Arcy CE, Holdsworth M, Hatzinisiriou I, Prescott M, stabilizing microtubules. Proc Natl Acad Sci U S A. 2011 Brown S, Mitchell CA. SLIMMER (FHL1B/KyoT3) interacts Aug 2;108(31):12851-6 with the proapoptotic protein Siva-1 (CD27BP) and delays skeletal myoblast apoptosis. J Biol Chem. 2009 Sep Ray RM, Bhattacharya S, Johnson LR. Mdm2 inhibition 25;284(39):26964-77 induces apoptosis in p53 deficient human colon cancer cells by activating p73- and E2F1-mediated expression of Du W, Jiang P, Li N, Mei Y, Wang X, Wen L, Yang X, Wu PUMA and Siva-1. Apoptosis. 2011 Jan;16(1):35-44 M. Suppression of p53 activity by Siva1. Cell Death Differ. 2009 Nov;16(11):1493-504 Mei Y, Wu M. Multifaceted functions of Siva-1: more than an Indian God of Destruction. Protein Cell. 2012 Resch U, Schichl YM, Winsauer G, Gudi R, Prasad K, de Feb;3(2):117-22 Martin R. Siva1 is a XIAP-interacting protein that balances NFkappaB and JNK signalling to promote apoptosis. J Cell Wang X, Zha M, Zhao X, Jiang P, Du W, Tam AY, Mei Y, Sci. 2009 Aug 1;122(Pt 15):2651-61 Wu M. Siva1 inhibits p53 function by acting as an ARF E3 ubiquitin ligase. Nat Commun. 2013;4:1551 Shimoda HK, Shide K, Kameda T, Matsunaga T, Shimoda K. Tyrosine kinase 2 interacts with the proapoptotic protein This article should be referenced as such: Siva-1 and augments its apoptotic functions. Biochem Biophys Res Commun. 2010 Sep 17;400(2):252-7 Machado-Neto JA, Traina F. SIVA1 (SIVA1, Apoptosis- Inducing Factor). Atlas Genet Cytogenet Oncol Haematol. Li N, Jiang P, Du W, Wu Z, Li C, Qiao M, Yang X, Wu M. 2014; 18(5):334-339. Siva1 suppresses epithelial-mesenchymal transition and

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 339

Atlas of Genetics and Cytogenetics

in Oncology and Haematology

OPEN ACCESS JOURNAL INIST -CNRS

Gene Section Review

SPRY1 (Sprouty Homolog 1, Antagonist Of FGF Signaling (Drosophila)) Behnam Nabet, Jonathan D Licht Feinberg School of Medicine, Northwestern University, Hematology/Oncology Division, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA (BN, JDL)

Published in Atlas Database: October 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/SPRY1ID51064ch4q28.html DOI: 10.4267/2042/53647 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Protein Review on SPRY1, with data on DNA/RNA, on the Description protein encoded and where the gene is implicated. SPRY1 is a member of the SPRY gene family, which is composed of four genes (SPRY1, SPRY2, Identity SPRY3, and SPRY4). SPRY1 protein is composed Other names: hSPRY1 of 319 amino acids, which include a conserved HGNC (Hugo): SPRY1 serine-rich motif and a conserved cysteine-rich domain (Figure 1C). The C-terminal cysteine-rich Location: 4q28.1 domain of SPRY1 contains 23 cysteine residues, 19 DNA/RNA of which are shared among the four family members (reviewed in Guy et al., 2009). This Description cysteine-rich domain facilitates homo- and SPROUTY1 (SPRY1) is located on the plus strand heterodimer formation between SPRY proteins of chromosome 4 (124319541-124324915) and (Ozaki et al., 2005). contains three exons (Figure 1A). SPRY1 functions as a regulator of fundamental The third exon is the coding exon. signaling pathways and its activity is regulated by post-translational modifications. Spry1 is Transcription phosphorylated in response to the growth factors, Four transcript variants exist for SPRY1, all of fibroblast growth factor (FGF) and platelet-derived which encode the same protein (according to UCSC growth factor (PDGF) (Mason et al., 2004). genome browser (hg19)). Xenopus xSpry1 is phosphorylated on the tyrosine Transcript variant 1 contains three exons, the last of 53 (Tyr53) residue in response to FGF treatment which is the coding exon. (Hanafusa et al., 2002). The xSpry1 Y53F mutant, Transcript variant 2 lacks exon 2 but retains the which prevents this phosphorylation event, same coding exon as transcript variant 1. functions as a dominant-negative suggesting that Transcript variants 3 and 4 also lack exon 2, have phosphorylation is required for xSpry1 inhibitory alternative promoters, and retain the same third activity toward growth signaling pathways coding exon (Figure 1B). (Hanafusa et al., 2002).

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Figure 1. SPROUTY1 (SPRY1) genomic context, transcript variants, and protein structure. (A) UCSC genome browser (hg19) snapshot of SPRY1 genomic context on chromosome 4q28.1. Image modified from: UCSC genome Bioinformatics. (B) UCSC genome browser (hg19) snapshot of the four SPRY1 transcripts. All transcripts retain the same coding exon. Image modified from: UCSC genome Bioinformatics. (C) Schematic of SPRY1 protein. Highlighted is the conserved N-terminal tyrosine 53 (Y53) that is phosphorylated in response to growth factor treatment, the serine-rich motif (SRM) that is phosphorylated upon growth factor treatment, and the conserved C-terminal cysteine-rich domain (CRD).

Serine residues of Spry1 are also phosphorylated in cell line or stimulus used. Serum starved NIH-3T3 response to FGF (Impagnatiello et al., 2001). cells treated with FGF, PDGF, epidermal growth Finally, Spry1 can be palmitoylated, and serves as a factor (EGF) or phorbol 12-myristate-13-acetate possible mechanism of membrane localization (PMA), upregulate Spry1 mRNA expression 30-60 (Impagnatiello et al., 2001). minutes after stimulation (Ozaki et al., 2001). However, at time-points beyond 2 hours, Spry1 Expression mRNA expression is downregulated in serum- Spry1 is expressed in localized domains throughout starved NIH-3T3 cells treated with FGF (Gross et organogenesis in the developing mouse embryo and al., 2001). in adult tissues (Minowada et al., 1999). Spry1 is Taken together these results may reflect a transient expressed during the development of the brain, burst of Spry1 mRNA induction in response to salivary gland, lung, digestive tract, lens, and growth factor signaling. In mouse microvascular kidney (Minowada et al., 1999, Zhang et al., 2001, endothelial cells (1G11), Spry1 mRNA expression Boros et al., 2006). Notably, Spry1 is expressed in is modulated as cells are serum deprived and the developing mouse kidney at the condensing stimulated with FGF. mesenchyme and the ureteric tree (Gross et al., Spry1 expression increases upon serum starvation, 2003). During mouse embryonic development decreases after 2 hours of FGF treatment, and then Spry1 expression patterns strongly correlate with increases after 6-18 hours of FGF treatment regions of FGF expression, which may directly (Impagnatiello et al., 2001). promote Spry1 gene activation (Minowada et al., Spry1 mRNA expression is increased in Th1 cells 1999). For example, Spry1 expression is induced in upon activation of T-cell receptor (TCR) signaling response to FGF8 in explant cultures of the mouse pathways (Choi et al., 2006). mandibular arch (Minowada et al., 1999). SPRY1 protein expression increases in U937 cells Spry1 expression is dynamically regulated in upon interferon α or β treatment (Sharma et al., response to environmental stimuli, although the 2012). Finally, SPRY1 mRNA expression increases kinetics of activation vary depending on the specific when human umbilical vein endothelial cells

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(HUVECs) are subject to hypoxic conditions (Lee al., 2010; Chakkalakal et al., 2012). Studies et al., 2010). conditionally deleting both Spry1 and Spry2 Spry1 activity is also regulated by transcription revealed that Spry1 and Spry2 are also critical factors such as Wilms Tumor 1 (WT1), which binds regulators of proper lens and cornea, as well as directly to the Spry1 promoter to activate its brain development. The conditional deletion of the expression (Gross et al., 2003). Furthermore, Spry1 combination of Spry1 and Spry2 results in lens and expression is directly repressed by microRNA-21 cornea defects, and cataract formation (Kuracha et (miR-21) (Thum et al., 2008). Importantly, miR-21 al., 2011; Shin et al., 2012). Spry1 and Spry2 mediated repression of Spry1 leads to increased conditional double knockout mutants lack proper Ras-extracellular signal regulated kinase (Erk) patterning of the murine brain, and altered gene signaling pathway activation causing cardiac expression downstream of Fgf signaling pathway fibrosis and dysfunction (Thum et al., 2008). activation (Faedo et al., 2010). SPRY family members including SPRY1 function Localisation as inhibitors of Ras-Erk signaling, although the SPRY1 is primarily expressed in the cytoplasm and point at which SPRY inhibits pathway activation its localization to the plasma membrane is remains controversial (reviewed in Mason et al., modulated upon serum deprivation and growth 2006). In the developing mouse kidney, Spry1 factor treatment. Impagnatiellio et al. demonstrated antagonizes the glial cell line-derived neurotrophic that in freely growing HUVECs, SPRY1 is factor (GDNF)/Ret signaling pathway to control localized to perinuclear and vesicular structures as Erk activation (Basson et al., 2005). Similarly, well as the plasma membrane. Upon serum conditional deletion of the combination of Spry1 deprivation, SPRY1 remains cytoplasmic but is no and Spry2 in the murine lens leads to elevated Erk longer detected at the plasma membrane. In activation, as well as activation of downstream FGF response to FGF treatment, SPRY1 is again target genes (Kuracha et al., 2011; Shin et al., localized to the plasma membrane (Impagnatiello et 2012). In cell lines, Spry1 regulates signaling al., 2001). Similarly, ectopic Spry1 in COS-1 cells pathway activation in response to various defined translocates to membrane ruffles upon EGF stimuli. Spry1 inhibits Ras-Erk pathway activation treatment (Lim et al., 2002). in response to growth factors including FGF, PDGF, and VEGF, correlating with the ability of Function Spry1 to control cell proliferation and Elegant studies in Drosophila identified dSpry as a differentiation (Gross et al., 2001; Impagnatiello et novel inhibitor of FGF and EGF signaling pathway al., 2001). By contrast, overexpression of SPRY1 in activation during tracheal branching, oogenesis, and HeLa cells leads to increased Ras-Erk pathway eye development, with specificity towards activation in response to EGF (Egan et al., 2002). regulating the Ras-Erk cascade (Hacohen et al., Recent evidence demonstrates that SPRY1 is 1998; Casci et al., 1999; Kramer et al., 1999; Reich involved in inhibiting ERK and p38 MAPK et al., 1999). Similarly, subsequent studies using activation in response to interferons, limiting mammalian cell lines and mouse models revealed expression of interferon-stimulated genes and that SPRY1 negatively regulates receptor tyrosine decreasing interferon-mediated biologic responses kinase (RTK) signaling pathway activation in (Sharma et al., 2012). various cellular contexts. As a result, SPRY1 Growing evidence also links the SPRY family as controls organ development and fundamental critical regulators of phosphoinositide 3-kinase biologic processes including cell proliferation, (PI3K)-protein kinase B (PKB, also known as differentiation, survival, and angiogenesis AKT) and phospholipase C gamma (PLC γ)- protein (reviewed in Mason et al., 2006; Edwin et al., kinase C (PKC) pathway activation. In an inner 2009). medullary collecting duct cell line, Spry1 In vivo loss-of-function experiments in mice knockdown results in enhanced and prolonged demonstrated that Spry1 is a key regulator of proper phosphorylated, activated Akt in response to GDNF organ and tissue development. Spry1 knockout treatment (Basson et al., 2006). Spry1 binds to (Spry1 -/-) mice have striking defects in branching PLC γ and inhibits PLC γ pathway activation, morphogenesis of the kidney, develop kidney resulting in decreased inositol triphosphate (IP3), epithelial cysts, and a disease resembling the human calcium, and diacylglycerol (DAG) production condition known as congenital anomalies of the (Akbulut et al., 2010). kidney and urinary track (Basson et al., 2005; SPRY1 regulates TCR signaling pathway activation Basson et al., 2006). Conditional deletion of Spry1 in a cell-type specific manner. In Th1 cells (Choi et in satellite cells demonstrated that Spry1 is required al., 2006) and CD4+ cells (Collins et al., 2012), for the muscle stem cell quiescence during muscle Spry1 inhibits signaling pathway activation, while cell regeneration as well as the maintenance of in naïve T-cells Spry1 potentiates signaling muscle stem cell quiescence during ageing (Shea et pathway activation (Choi et al., 2006).

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Spry1 binds to numerous signaling intermediates Hepatocellular carcinoma including linker of activated T-cells (LAT), PLC γ1, Note and c-Cbl to suppress Ras-Erk, nuclear factor of An initial study comparing hepatocellular activated T-cells (NFAT) and nuclear factor kappa- carcinoma tumors with non-tumor livers, found that light-chain-enhancer of activated B cells (NF-kB) SPRY2 was significantly downregulated, while pathway activation (Lee et al., 2009). SPRY1 was not significantly downregulated in tumor tissue (Fong et al., 2006). Implicated in qRT-PCR analysis of tissues from hepatocellular Breast cancer carcinoma patients revealed that SPRY1 expression levels are upregulated in 68% of patients, while Note SPRY2 and SPRY4 are commonly downregulated SPRY1 is significantly downregulated in the (79% and 75%, respectively). majority of breast cancer cases. The upregulated SPRY1 levels were found in This down-regulation was observed by comparing patients that did not display cirrhosis in their non- the expression of SPRY1 in breast cancer tumors tumor tissue (Sirivatanauksorn et al., 2012). and matched normal tissues using cDNA arrays Recent evidence suggests that downregulation of (39/50 (78%) of paired samples) and quantitative SPRY1 in liver cancers occurs through miR-21 real-time PCR (qRT-PCR) (18/19 (94%) of paired mediated repression (Jin et al., 2013). samples) (Lo et al., 2006). This data suggests that SPRY1 has tumor suppressive activity in breast Medullary thyroid carcinoma (MTC) cancer. Note Clear cell renal cell carcinoma SPRY1 has been proposed to have tumor (ccRCC) suppressive activity in MTC. Spry1 -/- mice display evidence of thyroid cell hyperplasia. Note Overexpression of Spry1 in an MTC cell line with Gene expression profiling of 29 ccRCC patient low Spry1 expression reduces cell proliferation and tumors revealed that SPRY1 expression serves as a tumor formation in xenografts through activation of prognostic biomarker associated with good the CDKN2A locus. outcome (Takahashi et al., 2001). The majority of human MTC samples tested display Embryonal rhabdomyosarcoma promoter methylation and downregulation of subtype (ERMS) SPRY1 expression, in line with the proposed tumor suppressive role of SPRY1 in MTC (Macia et al., Note 2012). cDNA microarray and Affymetrix microarray experiments revealed that SPRY1 mRNA Non-small cell lung cancer (NSCLC) expression is elevated in ERMS tumors compared Note to alveolar rhabdomyosarcoma subtype (RMS) SPRY1 mRNA expression is upregulated in tumors. NSCLC tumors compared to matched normal lung Oncogenic Ras mutations leading to elevated Ras- tissues, while SPRY2 mRNA expression is Erk pathway activation in ERMS cell lines, result in commonly downregulated (Sutterluty et al., 2007). increased SPRY1 protein expression. Inhibition of SPRY1 in ERMS cell lines decreases cell growth, Ovarian cancer survival and xenograft formation (Schaaf et al., Note 2010). SPRY1 mRNA and protein expression varies in This data suggests that in ERMS tumors driven by ovarian cancer cell lines. 4/7 cell lines (SKOV-3, oncogenic Ras with elevated SPRY1 expression, CAOV-3, OV-90, and IGROV-1) display targeting SPRY1 may prove to be efficacious. significantly lower SPRY1 protein expression, 1/7 Glioma cell lines (OVCAR-3) display significantly higher SPRY1 protein expression, and 2/7 cell lines (1A9 Note and A2780) display equivalent SPRY1 expression, Analysis of a glioma dataset containing expression as compared to normal primary human ovarian cells data from 276 tumor samples revealed that (Moghaddam et al., 2012). SPROUTY (SPRY1, SPRY2, and SPRY4) genes are coordinately upregulated in EGFR amplified Prostate cancer gliomas (Ivliev et al., 2010). Note The role and significance of SPRY1 in glioma has SPRY1 expression is downregulated in prostate not been functionally addressed. cancer.

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This downregulation was observed by comparing Reich A, Sapir A, Shilo B. Sprouty is a general inhibitor of prostate cancer tissue to normal tissues using receptor tyrosine kinase signaling. Development. 1999 Sep;126(18):4139-47 immunohistochemistry (40% of 407 of paired samples) and qRT-PCR (16/20 of samples assessed) Gross I, Bassit B, Benezra M, Licht JD. Mammalian sprouty proteins inhibit cell growth and differentiation by (Kwabi-Addo et al., 2004). Moderate down- preventing ras activation. J Biol Chem. 2001 Dec regulation of SPRY1 mRNA expression was also 7;276(49):46460-8 detected in an independent study (Fritzsche et al., Impagnatiello MA, Weitzer S, Gannon G, Compagni A, 2006). In addition, SPRY1 protein levels are Cotten M, Christofori G. Mammalian sprouty-1 and -2 are significantly decreased in prostate cancer cell lines membrane-anchored phosphoprotein inhibitors of growth (LNCaP, Du145, and PC-3) compared to prostatic factor signaling in endothelial cells. J Cell Biol. 2001 Mar epithelial cell lines. Overexpression of SPRY1 in 5;152(5):1087-98 LNCaP and PC-3 cells significantly inhibits cell Ozaki K, Kadomoto R, Asato K, Tanimura S, Itoh N, Kohno growth (Kwabi-Addo et al., 2004). Increased M. ERK pathway positively regulates the expression of methylation of the SPRY1 promoter and miR-21 Sprouty genes. Biochem Biophys Res Commun. 2001 Aug 3;285(5):1084-8 mediated repression are in part responsible for abnormal SPRY1 silencing that occurs in prostate Takahashi M, Rhodes DR, Furge KA, Kanayama H, Kagawa S, Haab BB, Teh BT. Gene expression profiling of cancer (Kwabi-Addo et al., 2009; Darimipourain et clear cell renal cell carcinoma: gene identification and al., 2011). More recently, it was confirmed in vivo prognostic classification. Proc Natl Acad Sci U S A. 2001 that Spry1 and Spry2 function together to inhibit Aug 14;98(17):9754-9 prostate cancer progression (Schutzman and Martin, Zhang S, Lin Y, Itäranta P, Yagi A, Vainio S. Expression of 2012). The conditional deletion of both Spry1 and Sprouty genes 1, 2 and 4 during mouse organogenesis. Spry2 in mouse prostate epithelium results in ductal Mech Dev. 2001 Dec;109(2):367-70 hyperplasia and low-grade prostatic intraepithelial Egan JE, Hall AB, Yatsula BA, Bar-Sagi D. The bimodal neoplasia. Notably, the deletion of Spry1 and Spry2 regulation of epidermal growth factor signaling by human synergizes with reduction of Pten to increase the Sprouty proteins. Proc Natl Acad Sci U S A. 2002 Apr grade and invasiveness of prostate tumorigenesis 30;99(9):6041-6 through increased PI3K-Akt and Ras-Erk signaling Hanafusa H, Torii S, Yasunaga T, Nishida E. Sprouty1 and pathway activation (Schutzman and Martin, 2012). Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat Cell Biol. 2002 Nov;4(11):850-8 To be noted Lim J, Yusoff P, Wong ES, Chandramouli S, Lao DH, Fong CW, Guy GR. The cysteine-rich sprouty translocation Note domain targets mitogen-activated protein kinase inhibitory proteins to phosphatidylinositol 4,5-bisphosphate in Acknowledgements: This work was supported by plasma membranes. Mol Cell Biol. 2002 Nov;22(22):7953- the National Institutes of Health grant CA59998 66 (J.D.L.) and the Lynn Sage and Northwestern Gross I, Morrison DJ, Hyink DP, Georgas K, English MA, Memorial Foundations (J.D.L.). B.N. is supported Mericskay M, Hosono S, Sassoon D, Wilson PD, Little M, by a National Institutes of Health Cellular and Licht JD. The receptor tyrosine kinase regulator Sprouty1 Molecular Basis of Disease Training Grant is a target of the tumor suppressor WT1 and important for (GM08061) and a Malkin Scholars Award from the kidney development. J Biol Chem. 2003 Oct 17;278(42):41420-30 Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Kwabi-Addo B, Wang J, Erdem H, Vaid A, Castro P, Ayala G, Ittmann M. 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Endocr Relat Cancer. 2006 Sep;13(3):839-49 Kuracha MR, Burgess D, Siefker E, Cooper JT, Licht JD, Robinson ML, Govindarajan V. Spry1 and Spry2 are Lo TL, Fong CW, Yusoff P, McKie AB, Chua MS, Leung necessary for lens vesicle separation and corneal HY, Guy GR. Sprouty and cancer: the first terms report. differentiation. Invest Ophthalmol Vis Sci. 2011 Aug Cancer Lett. 2006 Oct 28;242(2):141-50 29;52(9):6887-97 Mason JM, Morrison DJ, Basson MA, Licht JD. Sprouty Chakkalakal JV, Jones KM, Basson MA, Brack AS. The proteins: multifaceted negative-feedback regulators of aged niche disrupts muscle stem cell quiescence. Nature. receptor tyrosine kinase signaling. Trends Cell Biol. 2006 2012 Oct 18;490(7420):355-60 Jan;16(1):45-54 Collins S, Waickman A, Basson A, Kupfer A, Licht JD, Sutterlüty H, Mayer CE, Setinek U, Attems J et al.. Down- Horton MR, Powell JD. Regulation of CD4 ⁺ and CD8 ⁺ regulation of Sprouty2 in non-small cell lung cancer effector responses by Sprouty-1. PLoS One. contributes to tumor malignancy via extracellular signal- 2012;7(11):e49801 regulated kinase pathway-dependent and -independent mechanisms. Mol Cancer Res. 2007 May;5(5):509-20 Macià A, Gallel P, Vaquero M et al.. Sprouty1 is a candidate tumor-suppressor gene in medullary thyroid Thum T, Gross C, Fiedler J, Fischer T, Kissler S et al.. carcinoma. Oncogene. 2012 Aug 30;31(35):3961-72 MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature. Moghaddam SM, Amini A, Wei AQ, Pourgholami MH, 2008 Dec 18;456(7224):980-4 Morris DL. Initial report on differential expression of sprouty proteins 1 and 2 in human epithelial ovarian Edwin F, Anderson K, Ying C, Patel TB. Intermolecular cancer cell lines. J Oncol. 2012;2012:373826 interactions of Sprouty proteins and their implications in development and disease. Mol Pharmacol. 2009 Schutzman JL, Martin GR. Sprouty genes function in Oct;76(4):679-91 suppression of prostate tumorigenesis. Proc Natl Acad Sci U S A. 2012 Dec 4;109(49):20023-8 Guy GR, Jackson RA, Yusoff P, Chow SY. Sprouty proteins: modified modulators, matchmakers or missing Sharma B, Joshi S, Sassano A, Majchrzak B et al.. links? J Endocrinol. 2009 Nov;203(2):191-202 Sprouty proteins are negative regulators of interferon (IFN) signaling and IFN-inducible biological responses. J Biol Kwabi-Addo B, Ren C, Ittmann M. DNA methylation and Chem. 2012 Dec 7;287(50):42352-60 aberrant expression of Sprouty1 in human prostate cancer. Epigenetics. 2009 Jan;4(1):54-61 Shin EH, Basson MA, Robinson ML, McAvoy JW, Lovicu FJ. Sprouty is a negative regulator of transforming growth Lee JS, Lee JE, Oh YM, Park JB, Choi H, Choi CY, Kim factor β-induced epithelial-to-mesenchymal transition and IH, Lee SH, Choi K. Recruitment of Sprouty1 to immune cataract. Mol Med. 2012 Jul 18;18:861-73 synapse regulates T cell receptor signaling. J Immunol. 2009 Dec 1;183(11):7178-86 Sirivatanauksorn Y, Sirivatanauksorn V, Srisawat C, Khongmanee A, Tongkham C. Differential expression of Akbulut S, Reddi AL, Aggarwal P, Ambardekar C et al.. sprouty genes in hepatocellular carcinoma. J Surg Oncol. Sprouty proteins inhibit receptor-mediated activation of 2012 Mar;105(3):273-6 phosphatidylinositol-specific phospholipase C. Mol Biol Cell. 2010 Oct 1;21(19):3487-96 Jin XL, Sun QS, Liu F, Yang HW, Liu M, Liu HX, Xu W, Jiang YY. microRNA 21-mediated suppression of Sprouty1 Faedo A, Borello U, Rubenstein JL. Repression of Fgf by Pokemon affects liver cancer cell growth and signaling by sprouty1-2 regulates cortical patterning in two proliferation. J Cell Biochem. 2013 Jul;114(7):1625-33 distinct regions and times. J Neurosci. 2010 Mar 17;30(11):4015-23 This article should be referenced as such: Ivliev AE, 't Hoen PA, Sergeeva MG. Coexpression Nabet B, Licht JD. SPRY1 (Sprouty Homolog 1, Antagonist network analysis identifies transcriptional modules related Of FGF Signaling (Drosophila)). Atlas Genet Cytogenet to proastrocytic differentiation and sprouty signaling in Oncol Haematol. 2014; 18(5):340-345.

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TFAP2C (transcription factor AP-2 gamma (activating enhancer binding protein 2 gamma)) Maria V Bogachek, Ronald J Weigel Department of Surgery, Carver College of Medicine, University of Iowa, 5269 CBRB, 500 Newton Road, Iowa City, Iowa 52242, USA (MVB), Department of Surgery, Carver College of Medicine, University of Iowa, 200 Hawkins Drive Room 1509 JCP, Iowa City, Iowa 52242, USA (RJW)

Published in Atlas Database: October 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/TFAP2CID42528ch20q13.html DOI: 10.4267/2042/53648 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

associated genes and repression of genes Abstract characteristic of the basal subtype. Review on TFAP2C, with data on DNA/RNA, on the protein encoded and where the gene is DNA/RNA implicated. Description Identity TFAP2C consists of 7 encoding exons. The open reading frame of the coding region is 1353 bp. Other names: AP2-GAMMA, ERF1, TFAP2G, TFAP2C cDNA was isolated in 1996 (Williamson hAP-2g et al., 1996) and predicted protein was conserved HGNC (Hugo): TFAP2C with TFAP2A DNA-binding and dimerization domains, and differs in the N-terminal activation Location: 20q13.31 domain. Note: TFAP2C is a member of the retinoic acid- The promoter lacks canonical binding sites for inducible, developmentally regulated family of AP- basal transcription factors such as TATA and 2 factors. TFAP2C regulates cell growth and CCAAT boxes, but contains a cluster of CpG differentiation during ectodermal development islands and may rely on an initiator element for (Qiao et al., 2012; Hoffman et al., 2007). transcription (Li et al., 2002). A potential It plays a critical role in establishing the luminal trophoblast cell-specific regulatory element located phenotype of normal mammary cells during their approximately 6 kb upstream of the murine Tfap2c differentiation process. gene transcription start site (Li and Kellems, 2003). TFAP2C was shown to be involved in regulation of Transcription ESR1 and luminal - associated genes in breast 3 splice variants are described (Ensembl). cancer (Woodfield et al., 2010). TFAP2C maintains breast cancer luminal Pseudogene phenotype through the induction of luminal- No pseudogenes are reported.

TFAP2C human gene including promoter, 7 exons (blue rectangles) and 6 introns. Modified from Entrez Gene (Genomic DNA).

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 346 TFAP2C (transcription factor AP-2 gamma (activating Bogachek MV, Weigel RJ enhancer binding protein 2 gamma))

Assignment of TFAP2C functional domains. AA: aminoacids, K10: SUMOylation site, AD: activation domain, Di/DBD: dimerization domain/DNA binding domain (adapted from Williams and Tjian, 1991).

TFAP2C silencing coincided with acquisition of an Protein active chromatin conformation at the CDKN1A Note locus and increased gene expression (Gee et al., Active TFAP2C forms consist of homo - and 2009). heterodimers and play an important role in TFAP2C SUMOylation modification was described activation of retinoic acid-mediated differentiation in mammalian cells and SUMO site was mapped to including development of the eyes, face, body wall, conserved lysine 10 (Eloranta and Hurst, 2002). limbs, neural tube (Hoffman et al., 2007; Li and Epithelial hyperplasia and impaired differentiation Cornell, 2007). were reported in Tfap2c overexpressing transgenic Placental defect and embryonic death were reported mice (Jäger et al., 2003). as results of TFAP2C total knockdown. TFAP2C protein was purified in 1997 (McPherson Description et al., 1997) from ESR1 - positive cell line, was A helixloop-helix motif in the DNA binding designed as ERF1. TFAP2C, 450-aa protein, has 48 domain binds to GC-rich consensus site, kDa molecular mass. SCCTSRGGS (S=G/C, R=A/G) (Woodfield et al., TFAP2C has 65% sequence homology to TFAP2A 2010), in the promoters of target genes and overall and 76% identity in C-terminal part. mediates TFAP2C specific transcriptional activity. The consensus site from the ChIP-seq data, SCCTSRGGS (S=G/C, r=A/G), is consistent with Expression the optimal binding site, GCCTGAGGG, which TFAP2C is widely expressed within secondary was determined by in vitro PCR-assisted binding outgrowths in the human mammary gland by 19 site selection (Woodfield et al., 2010). weeks gestation. Estrogen receptor-alpha (ESR1) and HER2/c-erbB2 In the adult mammary gland TFAP2C expression genes are regulated by TFAP2C (Bosher et al., can be found in epithelial and myoepithelial 1995; McPherson et al., 1997; Delacroix et al., compartments. 2005; Woodfield et al., 2007) along with genes TFAP2C expression was reported in 16-40 weeks associated with luminal phenotype of breast cancer placenta, 5-10 weeks decidu and chorion (Li et al., (Woodfield et al., 2010). 2002). Activity of TFAP2C at specific target genes TFAP2C is expressed in gonocytes at weeks 12-37 depends upon epigenetic chromatin structure. of gestation, indicating a role of this transcription The combination of increasing chromatin factor in fetal germ cell development. accessibility and inducing TFAP2C provides a TFAP2C and c-KIT, a known target of AP-2 more robust activation of the ESR1 gene in ESR1- transcription factors, were coexpressed in negative breast cancer cells (Woodfield et al., gonocytes, making a direct regulation possible. 2009). With increasing differentiation of fetal testis, TFAP2C repressed CD44 expression in basal- gradual downregulation of TFAP2C from the 12 th derived breast cancer (Spanheimer et al., 2013a). to 37 th week of gestation was observed. TFAP2C regulates the expression of GPX1, which Furthermore, TFAP2C was expressed abundantly in influences the redox state and sensitivity to 25/25 IGCNUs, 52/53 testicular seminomas, 10/10 oxidative stress induced by peroxides (Kulak et al., metastatic seminomas, 9/9 extragonadal seminomas 2013). and 5/5 dysgerminomas (Pauls et al., 2005). Wwox tumor suppressor protein inhibits TFAP2C Normal tissues with TFAP2C expression: colon, oncogenic activity by sequestering it in the lymph node, brain, heart, kidney, liver, lung, cytoplasm (Aqeilan et al., 2004). thyroid, adrenal gland, ovary, prostate, testis. Reporter and chromatin immunoprecipitation assays demonstrated a direct, functional interaction Localisation by TFAP2C at the CDKN1A proximal promoter. Nuclear.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 347 TFAP2C (transcription factor AP-2 gamma (activating Bogachek MV, Weigel RJ enhancer binding protein 2 gamma))

Function TFAP2C gene expression (Li and Kellems, 2003). It plays a role in the development of the eyes, face, body wall, limbs, and neural tube (Hoffman et al., Implicated in 2007; Li and Cornell, 2007). Breast cancer Deletion of Tcfap2c during development resulted in a specific reduction of upper layer neurons in the Note occipital cortex (Pinto et al., 2009). TFAP2C plays a critical role in maintaining the Conditional ablation of Tcfap2c results in a delay in luminal subtype of breast cancer. TFAP2C directly skin development and abnormal expression of p63, binds to promoters and activates ESR1 along with K14, K1, filaggrin, repetin and secreted Ly6/Plaur luminal-associated genes (Woodfield et al., 2010). domain containing 1, key genes required for TFAP2C repressed CD44 expression in basal- epidermal development and differentiation derived breast cancer (Spanheimer et al., 2013a). (Guttormsen et al., 2008). Heterozygous Tfap2c- Regulation of Ret by TFAP2C occurs knockout mice were detected to have decreased independently of ESR1 expression in breast body size while homozygous mice died at 7-9 days carcinoma (Spanheimer et al., 2013b). TFAP2C of embryonic development due to failure of regulates the expression of GPX1, which influences proliferation of extraembryonic trophectodermal the redox state and sensitivity to oxidative stress cells (Werling and Schorle, 2002). TFAP2C is also induced by peroxides (Kulak et al., 2013). implicated in the regulation of the adenosine Prognosis deaminase (ADA) gene, a gene involved in purine Resistance to Tamoxifen treatment and reduction of metabolism found expressed at the maternal-fetal survival rate had correlation with TFAP2C interface (Werling and Schorle, 2002). overexpression (Guler et al., 2007). ERBB2- Homology negative/AP-2-positive expression patients had a better prognosis than patients with ERBB2- Mouse, Tfap2c (Mus musculus: NP_033361.2) positive/AP-2-positive tumors (Gee et al., 2009). (NCBI). In primary breast cancer specimens, high TFAP2C Predicted homology: chicken (Gallus gallus: and low CD44 expression were associated with XM_417497.4), zebrafish (Danio rerio: pCR after neoadjuvant chemotherapy and could be NM_001008576.1) (NCBI). predictive of tumors that have improved response to neoadjuvant chemotherapy (Spanheimer et al., Mutations 2013a). Germinal Elevated expression levels of TFAP2C in breast tumors were reported as predictors of poor 2 patients with deletions of chromosome 20q13.2- prognosis (Zhao et al., 2003) and advancing clinical q13.3 were reported to have feeding difficulties, grade (Sotiriou et al., 2006). microcephaly, facial dysmorphism with high forehead, broad nasal bridge, small chin and Seminomatous germ cell tumors malformed ears, mild psychomotor retardation, and Note hypotonia (Geneviève et al., 2005). Immunohistochemistry marker to the detection of Somatic germ cell tumors (Pauls et al., 2005). 39 mutations were detected after analysis of 8164 Melanoma samples (COSMIC: gene overview for TFAP2C) Note without direct links to certain diseases AP-2γ expression is lower in thick melanomas, it is pathogenesis. associated with unfavourable histo-pathological Deletion analyses of the promoter and parameters (increased vascularity, vascular invasion chloramphenicol acetyl transferase reporter gene and mitoses) (Osella-Abate et al., 2012). assays indicate that the sequence between -746 and -575 is important for its expression in mammary Pre-eclampsia carcinoma cell lines (Li et al., 2002). Note Combined mutation of the three putative Sp sites Elevated TFAP2C concentrations are associated reduced promoter activity by 80% in trophoblast with human placental defects such as pre-eclampsia and nontrophoblast cells, demonstrating the and intrauterine growth restriction (Kuckenberg et functional importance of these sites in regulating al., 2012).

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 348 TFAP2C (transcription factor AP-2 gamma (activating Bogachek MV, Weigel RJ enhancer binding protein 2 gamma))

TFAP2C target genes. Analysis was done by Ingenuity Systems. Red tone indicates genes repressed by TFAP2C and green indicates genes induced by TFAP2C. Insert: TFAP2C target genes RXR, RAR, and CRABP2 are involved in the retinoic acid signaling pathway (Woodfield et al., 2010).

Breakpoints Acad Sci U S A. 1995 Jan 31;92(3):744-7 Williamson JA, Bosher JM, Skinner A, Sheer D, Williams See figure above. T, Hurst HC. Chromosomal mapping of the human and mouse homologues of two new members of the AP-2 family of transcription factors. Genomics. 1996 Jul References 1;35(1):262-4 Williams T, Tjian R. Characterization of a dimerization McPherson LA, Baichwal VR, Weigel RJ. Identification of motif in AP-2 and its function in heterologous DNA-binding ERF-1 as a member of the AP2 transcription factor family. proteins. Science. 1991a Mar 1;251(4997):1067-71 Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4342-7 Williams T, Tjian R. Analysis of the DNA-binding and Eloranta JJ, Hurst HC. Transcription factor AP-2 interacts activation properties of the human transcription factor AP- with the SUMO-conjugating enzyme UBC9 and is 2. Genes Dev. 1991b Apr;5(4):670-82 sumolated in vivo. J Biol Chem. 2002 Aug 23;277(34):30798-804 Bosher JM, Williams T, Hurst HC. The developmentally regulated transcription factor AP-2 is involved in c-erbB-2 Li M, Wang Y, Yu Y, Nishizawa M, Nakajima T, Ito S, overexpression in human mammary carcinoma. Proc Natl Kannan P. The human transcription factor activation

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 349 TFAP2C (transcription factor AP-2 gamma (activating Bogachek MV, Weigel RJ enhancer binding protein 2 gamma))

protein-2 gamma (AP-2gamma): gene structure, promoter, Xingwang H, Rushi L, Jian Z, Shuanglin X. Identification of and expression in mammary carcinoma cell lines. Gene. target genes of transcription factor activator protein 2 2002 Nov 13;301(1-2):43-51 gamma in breast cancer cells. BMC Cancer. 2009 Aug 11;9:279 Werling U, Schorle H. Transcription factor gene AP-2 gamma essential for early murine development. Mol Cell Gee JM, Eloranta JJ, Ibbitt JC, Robertson JF, Ellis IO, Biol. 2002 May;22(9):3149-56 Williams T, Nicholson RI, Hurst HC. Overexpression of TFAP2C in invasive breast cancer correlates with a poorer Jäger R, Werling U, Rimpf S, Jacob A, Schorle H. response to anti-hormone therapy and reduced patient Transcription factor AP-2gamma stimulates proliferation survival. J Pathol. 2009 Jan;217(1):32-41 and apoptosis and impairs differentiation in a transgenic model. Mol Cancer Res. 2003 Oct;1(12):921-9 Pinto L, Drechsel D, Schmid MT, Ninkovic J et al.. AP2gamma regulates basal progenitor fate in a region- Li M, Kellems RE. Sp1 and Sp3 Are important regulators of and layer-specific manner in the developing cortex. Nat AP-2gamma gene transcription. Biol Reprod. 2003 Neurosci. 2009 Oct;12(10):1229-37 Oct;69(4):1220-30 Williams CM, Scibetta AG, Friedrich JK, Canosa M, Zhao C, Yasui K, Lee CJ, Kurioka H, Hosokawa Y, Oka T, Berlato C, Moss CH, Hurst HC. AP-2gamma promotes Inazawa J. Elevated expression levels of NCOA3, TOP1, proliferation in breast tumour cells by direct repression of and TFAP2C in breast tumors as predictors of poor the CDKN1A gene. EMBO J. 2009 Nov 18;28(22):3591- prognosis. Cancer. 2003 Jul 1;98(1):18-23 601 Aqeilan RI, Palamarchuk A, Weigel RJ, Herrero JJ, Woodfield GW, Hitchler MJ, Chen Y, Domann FE, Weigel Pekarsky Y, Croce CM. Physical and functional RJ. Interaction of TFAP2C with the estrogen receptor- interactions between the Wwox tumor suppressor protein alpha promoter is controlled by chromatin structure. Clin and the AP-2gamma transcription factor. Cancer Res. Cancer Res. 2009 Jun 1;15(11):3672-9 2004 Nov 15;64(22):8256-61 Woodfield GW, Chen Y, Bair TB, Domann FE, Weigel RJ. Delacroix L, Begon D, Chatel G, Jackers P, Winkler R. Identification of primary gene targets of TFAP2C in Distal ERBB2 promoter fragment displays specific hormone responsive breast carcinoma cells. Genes transcriptional and nuclear binding activities in ERBB2 Chromosomes Cancer. 2010 Oct;49(10):948-62 overexpressing breast cancer cells. DNA Cell Biol. 2005 Sep;24(9):582-94 Kuckenberg P, Kubaczka C, Schorle H. The role of transcription factor Tcfap2c/TFAP2C in trophectoderm Geneviève D, Sanlaville D, Faivre L, Kottler ML et al.. development. Reprod Biomed Online. 2012 Jul;25(1):12- Paternal deletion of the GNAS imprinted locus (including 20 Gnasxl) in two girls presenting with severe pre- and post- natal growth retardation and intractable feeding difficulties. Osella-Abate S, Novelli M, Quaglino P, Orso F, Ubezio B, Eur J Hum Genet. 2005 Sep;13(9):1033-9 Tomasini C, Berardengo E, Bernengo MG, Taverna D. Expression of AP-2α, AP-2γ and ESDN in primary Pauls K, Jäger R, Weber S, Wardelmann E, Koch A, melanomas: correlation with histopathological features and Büttner R, Schorle H. Transcription factor AP-2gamma, a potential prognostic value. J Dermatol Sci. 2012 novel marker of gonocytes and seminomatous germ cell Dec;68(3):202-4 tumors. Int J Cancer. 2005 Jun 20;115(3):470-7 Qiao Y, Zhu Y, Sheng N, Chen J, Tao R, Zhu Q, Zhang T, Sotiriou C, Wirapati P, Loi S, Harris A, Fox S et al.. Gene Qian C, Jing N. AP2 γ regulates neural and epidermal expression profiling in breast cancer: understanding the development downstream of the BMP pathway at early molecular basis of histologic grade to improve prognosis. J stages of ectodermal patterning. Cell Res. 2012 Natl Cancer Inst. 2006 Feb 15;98(4):262-72 Nov;22(11):1546-61 Guler G, Iliopoulos D, Guler N, Himmetoglu C, Hayran M, Kulak MV, Cyr AR, Woodfield GW, Bogachek M, Huebner K. Wwox and Ap2gamma expression levels Spanheimer PM, Li T, Price DH, Domann FE, Weigel RJ. predict tamoxifen response. Clin Cancer Res. 2007 Oct Transcriptional regulation of the GPX1 gene by TFAP2C 15;13(20):6115-21 and aberrant CpG methylation in human breast cancer. Hoffman TL, Javier AL, Campeau SA, Knight RD, Schilling Oncogene. 2013 Aug 22;32(34):4043-51 TF. Tfap2 transcription factors in zebrafish neural crest Spanheimer PM, Askeland RW, Kulak MV, Wu T, Weigel development and ectodermal evolution. J Exp Zool B Mol RJ. High TFAP2C/low CD44 expression is associated with Dev Evol. 2007 Sep 15;308(5):679-91 an increased rate of pathologic complete response Li W, Cornell RA. Redundant activities of Tfap2a and following neoadjuvant chemotherapy in breast cancer. J Tfap2c are required for neural crest induction and Surg Res. 2013a Sep;184(1):519-25 development of other non-neural ectoderm derivatives in Spanheimer PM, Woodfield GW, Cyr AR, Kulak MV, zebrafish embryos. Dev Biol. 2007 Apr 1;304(1):338-54 White-Baer LS, Bair TB, Weigel RJ. Expression of the RET Woodfield GW, Horan AD, Chen Y, Weigel RJ. TFAP2C proto-oncogene is regulated by TFAP2C in breast cancer controls hormone response in breast cancer cells through independent of the estrogen receptor. Ann Surg Oncol. multiple pathways of estrogen signaling. Cancer Res. 2007 2013b Jul;20(7):2204-12 Sep 15;67(18):8439-43 This article should be referenced as such: Guttormsen J, Koster MI, Stevens JR, Roop DR, Williams T, Winger QA. Disruption of epidermal specific gene Bogachek MV, Weigel RJ. TFAP2C (transcription factor expression and delayed skin development in AP-2 gamma AP-2 gamma (activating enhancer binding protein 2 mutant mice. Dev Biol. 2008 May 1;317(1):187-95 gamma)). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):346-350. Ailan H, Xiangwen X, Daolong R, Lu G, Xiaofeng D, Xi Q,

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Gene Section Review

USP1 (ubiquitin specific peptidase 1) Iraia García-Santisteban, Godefridus J Peters, Jose A Rodriguez, Elisa Giovannetti Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Leioa, Spain (IGS, JAR), Department of Medical Oncology, VU University Medical Center, Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands (GJP, EG)

Published in Atlas Database: October 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/USP1ID43072ch1p31.html DOI: 10.4267/2042/53649 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Description Ubiquitin specific peptidase 1 is located at Review on USP1, with data on DNA/RNA, on the chromosome 1 in the region p31.3. USP1 was first protein encoded and where the gene is implicated. cloned in 1998 as part of the Human Genome Identity Project (Fujiwara et al., 1998). Transcription Other names: UBP USP1 transcription is controlled by different HGNC (Hugo): USP1 mechanisms. On one hand, USP1 mRNA levels Location: 1p31.3 fluctuate during the cell cycle, reaching a peak in S Local order: Based on Mapviewer, genes flanking phase, and remaining low before and after it USP1 are: (Nijman et al., 2005). On the other hand, DNA damaging agents can - L1TD1 (LINE-1 type transposase domain repress USP1 transcription by a mechanism that containing 1); 1p31.3 involves p21 cyclin dependent kinase inhibitor - ANKRD38 (ankyrin repeat domain 38); 1p31.3 (Rego et al., 2012). - USP1 (ubiquitin specific peptidase 1); 1p31.3 Transcription produces 10 different mRNAs, 6 - DOCK7 (dedicator of cytokinesis 7); 1p31.3 alternatively spliced variants and 4 unspliced forms. - ANGPTL3 (angiopoietin-like 3); 1p31.1-p22.3. There are 5 probable alternative promotors, 2 non overlapping alternative last exons and 9 validated DNA/RNA alternative polyadenylation sites. Note The mRNAs appear to differ by truncation of the 5' Structural organization of USP1 gene: USP1 end, overlapping exons with different boundaries. gene is located on chromosome 1. 3 transcripts of Efficacy of translation may be reduced by the this gene, encoding the same protein product, have presence of a shorter translated product (uORF) been identified. initiating at an AUG upstream of the main open The gene contains 14 distinct gt-ag introns. reading frame.

Structural organization of USP1 protein. Cys and His boxes containing the catalytic residues (C90, H593, D751) are represented in green. The "degradation signal" (Degron) that mediates APC/C Cdh1 -mediated degradation of USP1 is shown in orange, also the location of the Serine 313 CDK phosphorylation site is highlighted. The diglycine motif (Gly-Gly) represented in purple constitutes the USP1 autocleavage site. Nuclear localization signals (NLSs) are illustrated in blue.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 351 USP1 (ubiquitin specific peptidase 1) García-Santisteban I, et al.

Pseudogene subjected to proteasomal degradation (Huang et al., 2006; Piatkov et al., 2012). No reported pseudogenes. Paralogs for USP1 gene include USP12, USP35, USP38, and USP46. Localisation The localization of USP1 is nuclear. USP1 bears Protein two nuclear localization signals (NLSs) which Description mediate the import of the USP1/UAF1 complex to the cell nucleus, where it exerts its function USP1 gene encodes a 785 amino acid protein with a (García-Santisteban et al., 2012b). USP1 also predicted molecular weight of 88,2 kDa (Fujiwara contains a nuclear export signal (NES, not indicated et al., 1998). USP1 belongs to the ubiquitin specific in the figure) that was shown to be functional in an protease (USP) family of human deubiquitinases export assay, but whose function in the context of (DUBs). Like other members of its family, it the full length protein needs to be evaluated harbours a highly conserved USP domain (García-Santisteban et al., 2012a). organization comprising a N-terminal Cys box and a C-terminal His box, which contain the catalytic Function residues (C90, H593 and D751) (Fujiwara et al., USP1, together with UAF1, plays an important role 1998; Villamil et al., 2012a; Békés et al., 2013). in the DNA damage response, mainly in the The enzymatic activity of USP1 alone is relatively Fanconi anemia (FA) pathway and in the process of low, but is enhanced upon binding to USP1 translesion synthesis (TLS). Deubiquitination of associated factor 1 (UAF1) (Cohn et al., 2007; FANCD2 and FANCI by the USP1/UAF1 complex Villamil et al., 2012a). The UAF1 binding region in is an essential step for the correct function of the USP1 is somewhat controversial, since two binding FA pathway (Nijman et al., 2005; Sims et al., motifs have been proposed based on different 2007). In addition, the USP1/UAF1 complex experimental approaches. Villamil and co-workers mediates the deubiqutination of Proliferating Cell proposed that the UAF1 binding region comprised Nuclear Antigen (PCNA), preventing the residues 235-408 (Villamil et al., 2012b), but recruitment of low fidelity DNA polymerases in the García-Santisteban et al. described that the binding absence of DNA damage (Huang et al., 2006). motif was between amino acid residues 420-520 In addition to its DNA damage-related functions, (García-Santisteban et al., 2012a). Further USP1 has also been reported to deubiquitinate and experimental evidence should clarify this stabilize three members of the family of inhibitors controversy. of DNA binding (ID) proteins (ID1, ID2 and ID3), Expression and thus contributing to preserve the undifferentiated state of osteosarcoma cells USP1 protein levels can be regulated through (Williams et al., 2011). different mechanisms that involve proteasome mediated degradation. On one hand, anaphase Homology Cdh1 Cdh1 promoting complex/cyclosome (APC/C ) The USP1 gene is conserved in chimpanzee, recognizes the 295-342 amino acid region (Degron) Rhesus monkey, dog, cow, mouse, rat, chicken, in USP1, mediating its degradation by the zebrafish, fruit fly, and mosquito. proteasome (Cotto-Rios et al., 2011a). The serine 313 residue located in this region is phosphorylated Mutations by cyclin dependent kinases (CDKs), which might prevent USP1 degradation in mitosis (Cotto-Rios et Note al., 2011b). On the other hand, UV damage causes A survey in the COSMIC mutation database USP1 autocleavage at an internal diglycine motif (accession date: 16 September 2013) revealed a (Gly-Gly) located in the C-terminal end of the total of 40 mutations that lead to different protein. The resulting USP1 fragments are modifications in different human tumors.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 352 USP1 (ubiquitin specific peptidase 1) García-Santisteban I, et al.

Cancer-associated mutations in USP1. Schematic representation of USP1 protein showing the position of cancer-associated USP1 mutations reported to date (September 2013) in the COSMIC mutation database. Missense amino acid substitutions are indicated in black, nonsense amino acid substitutions in red and frameshift insertion/deletions in blue. Synonymous amino acid substitutions have been omitted. The Table shows the detailed list of mutations, including the DNA modification (CDS Mutation), protein modification (AA Mutation), type of mutation and tissue.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 353 USP1 (ubiquitin specific peptidase 1) García-Santisteban I, et al.

Most of the modifications are missense mutations Disruption of the USP1 gene in mice results in whose functional consequences need to be genomic instability and FA phenotype, and also addressed. leads to defects in hematopoietic stem cell maintenance (Kim et al., 2009; Parmar et al., 2010). Implicated in Osteosarcoma To be noted Note Note A recent study showed that USP1 mRNA and This work was supported by the Basque Country protein levels were elevated in a subset of primary Government Department of Industry (grant number osteosarcoma tumors, and that increased USP1 ETORTEK BioGUNE2010 to JAR), the Spanish levels correlated with increased levels of its Government MICINN (Ministerio de Ciencia e substrate ID2. This observation is consistent with Innovacion) (grant number BFU2009-13245 to the finding that USP1 deubiquitinates and stabilizes JAR), the University of the Basque Country ID proteins, contributing to preserve the (UFI11/20), Department of Education of the undifferentiated state of osteosarcoma cells. Basque Country Government Fellowship (to IG-S), the Netherlands Organization for Scientific Cytogenetics Research, Veni grant (to EG) and CCA Foundation Comparative genomic hybridization (CGH) (grant number 2012-5-07 to EG and GJP). analyses found that the USP1 locus 1p31.3 was amplified in 26%-57% of osteosarcoma tumors (Ozaki et al., 2003; Stock et al., 2000). References Lung cancer Fujiwara T, Saito A, Suzuki M, Shinomiya H, Suzuki T, Takahashi E, Tanigami A, Ichiyama A, Chung CH, Note Nakamura Y, Tanaka K. Identification and chromosomal One study reported lower USP1 mRNA and protein assignment of USP1, a novel gene encoding a human levels in lung cancer cells and tissues (Zhiqiang et ubiquitin-specific protease. Genomics. 1998 Nov 15;54(1):155-8 al., 2012). However, most data support the view that USP1 is overexpressed in lung cancer. Thus, a Stock C, Kager L, Fink FM, Gadner H, Ambros PF. Chromosomal regions involved in the pathogenesis of survey in the Oncomine research edition database osteosarcomas. Genes Chromosomes Cancer. 2000 revealed that USP1 was overexpressed in 25% of Jul;28(3):329-36 the lung cancer microarray datasets available, while Ozaki T, Neumann T, Wai D, Schäfer KL, van Valen F, none of these studies reported significant Lindner N, Scheel C, Böcker W, Winkelmann W, downregulation of USP1 (García-Santisteban et al., Dockhorn-Dworniczak B, Horst J, Poremba C. 2013). In line with these data, Chromosomal alterations in osteosarcoma cell lines immunohistochemical analysis on a NSCLC tissue revealed by comparative genomic hybridization and multicolor karyotyping. Cancer Genet Cytogenet. 2003 Jan microarray revealed USP1 overexpression (Liu et 15;140(2):145-52 al., 2012). An association between USP1 Nijman SM, Huang TT, Dirac AM, Brummelkamp TR, overexpression with lung cancer was already Kerkhoven RM, D'Andrea AD, Bernards R. The demonstrated in a recent study on USP1 mRNA deubiquitinating enzyme USP1 regulates the Fanconi expression in NSCLC tissue and cell lines anemia pathway. Mol Cell. 2005 Feb 4;17(3):331-9 indicating that USP1 expression was higher in Huang TT, Nijman SM, Mirchandani KD, Galardy PJ, Cohn tumors and tumor-derived cells than in normal lung MA, Haas W, Gygi SP, Ploegh HL, Bernards R, D'Andrea tissue (García-Santisteban et al., 2013). AD. Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat Cell Biol. 2006 Apr;8(4):339-47 Fanconi anemia (FA) Cohn MA, Kowal P, Yang K, Haas W, Huang TT, Gygi SP, Note D'Andrea AD. A UAF1-containing multisubunit protein Fanconi anemia (FA) is a rare hereditary disorder complex regulates the Fanconi anemia pathway. Mol Cell. that results in congenital abnormalities, progressive 2007 Dec 14;28(5):786-97 bone marrow failure, DNA crosslinker Sims AE, Spiteri E, Sims RJ 3rd, Arita AG, Lach FP, hypersensitivity, genomic instability and increased Landers T, Wurm M, Freund M, Neveling K, Hanenberg H, Auerbach AD, Huang TT. FANCI is a second susceptibility to cancer (Kee and D'Andrea, 2012). monoubiquitinated member of the Fanconi anemia The disorder is the result of mutations in any of at pathway. Nat Struct Mol Biol. 2007 Jun;14(6):564-7 least 15 genes that regulate the DNA repair Kim JM, Parmar K, Huang M, Weinstock DM, Ruit CA, pathway that corrects interstrand crosslinks (ICLs). Kutok JL, D'Andrea AD. Inactivation of murine Usp1 USP1 cannot be considered a bona fide FA gene, results in genomic instability and a Fanconi anemia since mutations in USP1 have not been identified in phenotype. Dev Cell. 2009 Feb;16(2):314-20 FA patients yet. However, recent evicence supports Parmar K, Kim J, Sykes SM, Shimamura A, Stuckert P, the view that USP1 is crucial for the correct Zhu K, Hamilton A, Deloach MK, Kutok JL, Akashi K, regulation of the FA pathway. Gilliland DG, D'andrea A. Hematopoietic stem cell defects

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in mice with deficiency of Fancd2 or Usp1. Stem Cells. TT. The auto-generated fragment of the Usp1 2010 Jul;28(7):1186-95 deubiquitylase is a physiological substrate of the N-end rule pathway. Mol Cell. 2012 Dec 28;48(6):926-33 Cotto-Rios XM, Jones MJ, Busino L, Pagano M, Huang TT. APC/CCdh1-dependent proteolysis of USP1 regulates Rego MA, Harney JA, Mauro M, Shen M, Howlett NG. the response to UV-mediated DNA damage. J Cell Biol. Regulation of the activation of the Fanconi anemia 2011a Jul 25;194(2):177-86 pathway by the p21 cyclin-dependent kinase inhibitor. Oncogene. 2012 Jan 19;31(3):366-75 Cotto-Rios XM, Jones MJ, Huang TT. Insights into phosphorylation-dependent mechanisms regulating USP1 Villamil MA, Chen J, Liang Q, Zhuang Z. A noncanonical protein stability during the cell cycle. Cell Cycle. 2011b cysteine protease USP1 is activated through active site Dec 1;10(23):4009-16 modulation by USP1-associated factor 1. Biochemistry. 2012a Apr 3;51(13):2829-39 Williams SA, Maecker HL, French DM, Liu J, Gregg A, Silverstein LB, Cao TC, Carano RA, Dixit VM. USP1 Villamil MA, Liang Q, Chen J, Choi YS, Hou S, Lee KH, deubiquitinates ID proteins to preserve a mesenchymal Zhuang Z. Serine phosphorylation is critical for the stem cell program in osteosarcoma. Cell. 2011 Sep activation of ubiquitin-specific protease 1 and its interaction 16;146(6):918-30 with WD40-repeat protein UAF1. Biochemistry. 2012b Nov 13;51(45):9112-23 García-Santisteban I, Bañuelos S, Rodríguez JA. A global survey of CRM1-dependent nuclear export sequences in Zhiqiang Z, Qinghui Y, Yongqiang Z, Jian Z, Xin Z, Haiying the human deubiquitinase family. Biochem J. 2012a Jan M, Yuepeng G. USP1 regulates AKT phosphorylation by 1;441(1):209-17 modulating the stability of PHLPP1 in lung cancer cells. J Cancer Res Clin Oncol. 2012 Jul;138(7):1231-8 Garcia-Santisteban I, Zorroza K, Rodriguez JA. Two nuclear localization signals in USP1 mediate nuclear Bekes M, Huang T.. Ubiquitin-specific peptidase 1. import of the USP1/UAF1 complex. PLoS One. Handbook of proteolytic enzymes. Volume 1. 3rd edition. 2012b;7(6):e38570 Edited by Rawlings ND, Salvesen G.; 2013: 2079-2085. Kee Y, D'Andrea AD. Molecular pathogenesis and clinical Garcia-Santisteban I, Peters GJ, Giovannetti E, Rodriguez management of Fanconi anemia. J Clin Invest. 2012 Nov JA.. USP1 deubiquitinase: cellular functions, regulatory 1;122(11):3799-806 mechanisms and emerging potential as target in cancer therapy. Mol Cancer. 2013 Aug 10;12:91. doi: Liu Y, Luo X, Hu H, Wang R, Sun Y, Zeng R, Chen H. 10.1186/1476-4598-12-91. (REVIEW) Integrative proteomics and tissue microarray profiling indicate the association between overexpressed serum This article should be referenced as such: proteins and non-small cell lung cancer. PLoS One. 2012;7(12):e51748 García-Santisteban I, Peters GJ, Rodriguez JA, Giovannetti E. USP1 (ubiquitin specific peptidase 1). Atlas Piatkov KI, Colnaghi L, Békés M, Varshavsky A, Huang Genet Cytogenet Oncol Haematol. 2014; 18(5):351-355.

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Leukaemia Section Short Communication t(3;11)(q12;p15) NUP98/LNP1 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: October 2013 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0311q12p15ID1518.html DOI: 10.4267/2042/53650 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract of six cases. +19 was found in one T-ALL. Review on t(3;11)(q12;p15) NUP98/LNP1, with Genes involved and data on clinics, and the genes implicated. proteins Clinics and pathology Note NUP98 was found fused to LNP1 in cases with Disease molecular studies (Romana et al., 2006; Gorello et Myelodysplastic syndrome (MDS), acute myeloid al., 2008). leukemia (AML), and T-cell acute lymphoblastic leukemia (T-ALL) LNP1 Location Phenotype/cell stem origin 3q12.2 Six cases are available: one case of MDS, two cases Note of AML not otherwise specified, one M2-AML, Also named NP3 or LOC348801. and two T-ALL cases, one being a case of early T- cell precursor leukaemia (Romana et al., 2006; DNA/RNA Chen et al., 2007; Gorello et al., 2008; Coustan- Four exons, the first exon is non-coding. Smith et al., 2009; Lugthart et al., 2010). Protein Epidemiology Protein of unknown function. 178 amino acids, 21 kDa. There was 4 male and 2 female patients. Ages were: 3, 28, and 30 years in myeloid cases, and 16 and 36 NUP98 years in T-ALLs. Location Prognosis 11p15.4 Data on prognosis is very scarce: two AML cases Protein died 11 and 23 months after diagnosis, and the early Component of nuclear pore complex. T-cell precursor leukaemia phenotype, in this study NUP98 is found in the nucleoplasmic and of 17 cases with various karyotypes, was said to cytoplasmic sides of the nuclear pore complex, and bear a poor prognosis, but no individual data is functions as nuclear import and nuclear export available (Coustan-Smith et al., 2009). mRNA factor. NUP98 has a role in the regulation of gene Cytogenetics expression via EP300. NUP98 appears to be involved in mitotic spindle Cytogenetics morphological formation and cell cycle progression (review in The t(3;11)(q12;p15) was the sole anomaly in four Iwamoto et al., 2010).

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 356 t(3;11)(q12;p15) NUP98/LNP1 Huret JL

karyotypes confer a poor survival in adult acute myeloid Result of the chromosomal leukemia with unfavorable cytogenetic abnormalities. anomaly Cancer Genet Cytogenet. 2007 Apr 15;174(2):138-46 Gorello P, Brandimarte L, La Starza R, Pierini V, Bury L, Hybrid gene Rosati R, Martelli MF, Vandenberghe P, Wlodarska I, Mecucci C. t(3;11)(q12;p15)/NUP98-LOC348801 fusion Description transcript in acute myeloid leukemia. Haematologica. 2008 Nucleotide 1718 (exon 13) of NUP98 was fused in- Sep;93(9):1398-401 frame with nucleotide 1248 (exon 2) of LNP1. The Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, reciprocal LNP1-NUP98 fusion transcript was also Raimondi SC, Pei D, Cheng C, Su X, Rubnitz JE, Basso present (Gorello et al., 2008). G, Biondi A, Pui CH, Downing JR, Campana D. Early T- cell precursor leukaemia: a subtype of very high-risk acute Fusion protein lymphoblastic leukaemia. Lancet Oncol. 2009 Feb;10(2):147-56 Description Iwamoto M, Asakawa H, Hiraoka Y, Haraguchi T. The protein fuses the NUP98 FG repeat motifs and Nucleoporin Nup98: a gatekeeper in the eukaryotic GLEBS-like motif to the entire LNP1, at the start of kingdoms. Genes Cells. 2010 Jun;15(7):661-9 LNP1 exon 2 (Gorello et al., 2008). Lugthart S, Gröschel S, Beverloo HB, Kayser S, Valk PJ, van Zelderen-Bhola SL, Jan Ossenkoppele G, Vellenga E, References van den Berg-de Ruiter E, Schanz U, Verhoef G, Vandenberghe P, Ferrant A, Köhne CH, Pfreundschuh M, Romana SP, Radford-Weiss I, Ben Abdelali R, Schluth C, Horst HA, Koller E, von Lilienfeld-Toal M, Bentz M, Ganser Petit A, Dastugue N, Talmant P, Bilhou-Nabera C, A, Schlegelberger B, Jotterand M, Krauter J, Pabst T, Mugneret F, Lafage-Pochitaloff M, Mozziconacci MJ, Theobald M, Schlenk RF, Delwel R, Döhner K, Löwenberg Andrieu J, Lai JL, Terre C, Rack K, Cornillet-Lefebvre P, B, Döhner H. Clinical, molecular, and prognostic Luquet I, Nadal N, Nguyen-Khac F, Perot C, Van den significance of WHO type Akker J, Fert-Ferrer S, Cabrol C, Charrin C, Tigaud I, inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q Poirel H, Vekemans M, Bernard OA, Berger R. NUP98 abnormalities in acute myeloid leukemia. J Clin Oncol. rearrangements in hematopoietic malignancies: a study of 2010 Aug 20;28(24):3890-8 the Groupe Francophone de Cytogénétique Hématologique. Leukemia. 2006 Apr;20(4):696-706 This article should be referenced as such: Chen CC, Yang CF, Lee KD, You JY, Yu YB, Ho CH, Huret JL. t(3;11)(q12;p15) NUP98/LNP1. Atlas Genet Tzeng CH, Chau WK, Hsu HC, Gau JP. Complex Cytogenet Oncol Haematol. 2014; 18(5):356-357.

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Leukaemia Section Short Communication t(7;8)(p12;q24) /MYC Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: October 2013 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0708p12q24ID2140.html DOI: 10.4267/2042/53651 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

genes. IKZF1 is expressed during early embryonic Abstract hematopoiesis, including hematopoietic stem cells, Review on t(7;8)(p12;q24) /MYC, with data on lymphoid precursors, erythroid precursors, and clinics, and the genes implicated. myeloid precursors. It is also expressed in developing striatal neurons. Clinics and pathology In the adult, IKZF1 expression is mainly restricted to lymphopoietic tissues and peripheral blood Disease leukocytes (review in John and Ward, 2011). Diffuse large B-cell lymphoma (DLBCL) MYC Epidemiology Location One case to date, a female patient aged 80 years 8q24.2 (Bertrand et al., 2007). Protein Prognosis DNA binding protein. The patient died 6 months after diagnosis. Binds DNA as a heterodimer with MAX. Involved in various cellular processes including cell Cytogenetics growth, proliferation, cell adhesion, apoptosis, angiogenesis, and stem cell behaviour modulation. Cytogenetics morphological A complex karyotype was found, with an i(6)(p10), References a +20, and other abnormalities. Bertrand P, Bastard C, Maingonnat C, Jardin F, Maisonneuve C, Courel MN, Ruminy P, Picquenot JM, Tilly Genes involved and H. Mapping of MYC breakpoints in 8q24 rearrangements involving non-immunoglobulin partners in B-cell proteins lymphomas. Leukemia. 2007 Mar;21(3):515-23 Note John LB, Ward AC. The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity. Mol Immunol. Breakpoints occurred close to MYC in 8q24 and 2011 May;48(9-10):1272-8 100 kb from COBL and 1Mb from IKZF1 in 7p12. Schwintzer L, Koch N, Ahuja R, Grimm J, Kessels MM, - COBL is an actin nucleator which uses its WH2 Qualmann B. The functions of the actin nucleator Cobl in domains for binding actin, to promote actin cellular morphogenesis critically depend on syndapin I. filament formation. Role in neuromorphogenesis EMBO J. 2011 Jul 1;30(15):3147-59 (dendrite formation and dendritic arborisation) (Schwintzer et al., 2011). This article should be referenced as such: - IKZF1 is a zinc finger transcription factor Huret JL. t(7;8)(p12;q24) /MYC. Atlas Genet Cytogenet involved in both activation and repression of target Oncol Haematol. 2014; 18(5):358.

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Leukaemia Section Short Communication t(2;3)(p21;q26) THADA/MECOM Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: November 2013 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0203p21q26ID1665.html DOI: 10.4267/2042/53652 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Cytogenetics Review on t(2;3)(p21;q26) THADA/MECOM, with Cytogenetics morphological data on clinics, and the genes implicated. The t(2;3)(p21;q26) was the sole anomaly. Identity Genes involved and Note proteins This translocation is found in a subset of cases described in the card t(2;3)(p15-23;q26-27). THADA Other subsets involve other genes, such as BCL11A Location in the t(2;3)(p16;q26) BCL11A/MECOM. 2p21 Clinics and pathology Protein THADA is assumed to be involved it in the Disease TRAIL-induced apoptosis. Truncated THADA Acute myeloid leukemia (AML) have been found in thyroid adenomas; it would compete with normal THADA, thereby disturbing Epidemiology normal apoptosis of follicular cells (Rippe et al., One case to date, a 59-year old male patient with a 2003; Kloth et al., 2011). M4-AML (Trubia et al., 2006). MECOM Prognosis Location Clinical outcome in cases with the t(2;3)(p16;q26) 3q26 BCL11A/MECOM and the case with the Note t(2;3)(p21;q26) THADA/MECOM (plotted MECOM is also known as EVI1 or PRDM3; together) was severe: "One patient is alive with MECOM symbol means: "MDS1 and EVI1 active disease at 12 months, five patients died after complex locus". 4-14 months" (Trubia et al., 2006). Protein Genetics "EVI1" contains two domains of seven and three zinc finger motifs, respectively, a repression Note domain between the two sets of zinc fingers, and an MECOM was overexpressed. acidic domain at its C-term.

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 359 t(2;3)(p21;q26) THADA/MECOM Huret JL

Sequence specific DNA binding protein. Interacts with transcriptional coactivators, References corepressors, and other sequence specific Rippe V, Drieschner N, Meiboom M, Murua Escobar H, transcription factors. MECOM ("MDS1-EVI1") Bonk U, Belge G, Bullerdiek J. Identification of a gene rearranged by 2p21 aberrations in thyroid adenomas. also contains a PR domain from "MDS1" in N-term Oncogene. 2003 Sep 4;22(38):6111-4 (Wieser, 2008). Trubia M, Albano F, Cavazzini F, Cambrin GR et al.. Characterization of a recurrent translocation t(2;3)(p15- Result of the chromosomal 22;q26) occurring in acute myeloid leukaemia. Leukemia. anomaly 2006 Jan;20(1):48-54 Wieser R.. MECOM (Ecotropic Viral Integration Site 1 (EVI1) and Myelodysplastic Syndrome 1 (MDS1)-EVI1). Hybrid gene Atlas Genet Cytogenet Oncol Haematol. 2008;12(4):306- Description 310. http://documents.irevues.inist.fr/bitstream/handle/2042/385 Regulatory sequences were transferred 51/12-2007-EVI103q26ID19.pdf?sequence=2 telomerically to MECOM. Kloth L, Belge G, Burchardt K, Loeschke S, Wosniok W, Fusion protein Fu X, Nimzyk R, Mohamed SA, Drieschner N, Rippe V, Bullerdiek J.. Decrease in thyroid adenoma associated Description (THADA) expression is a marker of dedifferentiation of The t(2;3) brings about the juxtaposition at 3q26 of thyroid tissue. BMC Clin Pathol. 2011 Nov 4;11:13. doi: the MECOM locus with regulatory elements 10.1186/1472-6890-11-13. normally located in proximity of the 2p This article should be referenced as such: breakpoints, with consequent EVI1 overexpression, Huret JL. t(2;3)(p21;q26) THADA/MECOM. Atlas Genet without the formation of a fusion protein. Cytogenet Oncol Haematol. 2014; 18(5):359-360.

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Deep Insight Section

Adiponectin and cancer Maria Dalamaga, Vassiliki Koumaki Department of Clinical Biochemistry, University of Athens, School of Medicine, Attikon General University Hospital, Rimini 1, 12462 Athens, Chaidari, Greece (MD), Department of Microbiology, University of Athens, School of Medicine, University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece (VK)

Published in Atlas Database: November 2013 Online updated version : http://AtlasGeneticsOncology.org/Deep/AdiponectinandCancerID20128.html DOI: 10.4267/2042/53653 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Deep insight on adiponectin and cancer.

Obesity and cancer Adiponectin biology, physiology Obesity has increased worldwide, becoming a and pathophysiology major global health issue with epidemic Adiponectin is mainly produced by white adipose proportions. Obesity is implicated in many diseases tissue (Ziemke and Mantzoros, 2010; Maeda et al., such as cardiovascular disease, type 2 diabetes 2012), although other tissues express lower mellitus and various cancers (Hubert et al., 1983; quantities of adiponectin. Adiponectin is Mokdad et al., 2003; Ogden et al., 2007; Renehan alternatively called AdipoQ (Hu et al., 1996), et al., 2008; Dalamaga et al., 2012; Dalamaga et al., Acrp30 (adipocyte complement-related protein of 2013b) such as colon cancer, postmenopausal 30 kDa) (Scherer et al., 1995), apM1 (gene product breast cancer, endometrial cancer, renal cell cancer, of the adipose most abundant gene transcript-1) esophageal adenocarcinoma, non-Hodgkin's (Maeda et al., 2012), and GBP28 (gelatin-binding lymphoma, leukemia, multiple myeloma (Pischon protein-28) (Nakano et al., 1996), and was first et al., 2008; Lichtman, 2010; Dalamaga et al., described in the mid-1990s. 2009a; Dalamaga et al., 2010), thyroid cancer, The adiponectin gene is located on chromosome pancreatic cancer (Dalamaga et al., 2009b), 3q27 and consists of three exons and two introns gallbladder cancer, high-grade prostate cancer and (Takahashi et al., 2000). Some polymorphisms of ovarian cancer (Renehan et al., 2008; Larsson et al., the adiponectin gene have been shown to present 2007; Wiseman, 2008; Hsing et al., 2007; functional consequences of the adiponectin protein Dalamaga et al., 2012). and have been associated with clinical The main mechanisms associating obesity to manifestations (Dalamaga et al., 2012). cancers are: i) abnormalities of the insulin-like Adiponectin is a 244-amino acid protein growth factor-I (IGF-I) system; ii) encompassing four structural domains: an amino- hyperinsulinemia and insulin resistance; iii) terminal signal peptide followed by a variable obesity-driven chronic low-grade systemic domain, a collagen-like region of 22 Gly-X-Y inflammation; iv) the influence of obesity in sex repeats, and a carboxyl-terminal globular domain hormones biosynthesis; and v) variations in the that binds to the adiponectin receptors and levels of adipokines (Park et al., 2011; van resembles tumor necrosis factor-α (TNF-α) Kruijsdijk et al., 2009). (Dalamaga et al., 2012).

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 361 Adiponectin and cancer Dalamaga M, Koumaki V

Adiponectin is firstly synthesized as a single Adiponectin plays also an important role in lipid subunit that forms trimers, hexamers, and metabolism (Barb et al., 2007; Ziemke and multimers before secretion. The monomeric form of Mantzoros, 2010) by redirecting fatty acids to the adiponectin is thought to be present only in the muscles to undergo oxidation, decreasing the liver adipocyte (Chandran et al., 2003), whereas uptake of fatty acids and the total triglyceride adiponectin is mainly circulating as a trimer. content resulting in increased insulin sensitivity in Adiponectin can be found into five different liver and skeletal muscle. Particularly in the liver, configurations with different biological effects: the these actions are considered to be achieved by globular adiponectin (gAPN), full-length HMW adiponectin (Hada et al., 2007). Adiponectin adiponectin (fAPN), low-molecular-weight presents anti-atherogenic actions by direct adiponectin, medium molecular-weight inhibition of atherosclerosis and plaque formation. adiponectin, and high-molecular-weight Adiponectin presents also central actions by adiponectin (HMW) (Dalamaga et al., 2012). modulating food intake and energy expenditure Adiponectin binds to two main receptors, (Dalamaga et al., 2012). adiponectin receptor 1 and 2 (AdipoR1 and Circulating adiponectin levels are generally AdipoR2) encoded by genes located on measured in the range of 2 to 20 µg/mL. Depending chromosomes 1p36.13-q41 and 12p13.31, on the assay methodology, race and gender, median respectively (Yamauchi et al., 2003). AdipoR1 is adiponectin levels in healthy individuals with a expressed ubiquitously but most abundantly in body mass index (BMI) between 20 and 25 kg/m 2 skeletal muscle, whereas AdipoR2 is predominantly are approximately 8 µg/mL for men and 12.5 expressed in the liver. Although both receptors are µg/mL for women (Dalamaga et al., 2012; Fabian, expressed in almost every tissue, including 2012). Circulating adiponectin levels are regulated pancreatic β-cells, one or the other receptor usually by factors like genetic background, anthropometric prevails (Dalamaga et al., 2012). A plethora of characteristics, hormonal profile, inflammation, cancer cell lines express adiponectin receptors, nutritional habits, and pharmacologic parameters. In suggesting that adiponectin may exhibit direct obesity, serum adiponectin is decreased, in contrast effects on these cells and limit their proliferation at to other hormones secreted by the adipose tissue, least in vitro (Kim et al., 2010). The two main and presents, generally, a negative correlation with receptors are integral membrane proteins with BMI, waist and hip circumference, waist-to-hip seven transmembrane domains with an internal N- ratio, and visceral fat (Barb et al., 2007; Ziemke terminal collagenous domain and an external C- and Mantzoros, 2010). terminal globular structure. AdipoR1 has high Hypoadiponectinemia related to genetic and affinity for gAPN whereas AdipoR2 mainly environmental factors, such as diet and obesity, recognizes fAPN (Kadowaki and Yamauchi, 2005). may be implicated in the pathogenesis of insulin T-cadherin has also been proposed as an resistance (Weyer et al., 2001), metabolic adiponectin receptor, acting as a co-receptor by syndrome, type 2 diabetes (Weyer et al., 2001), competing with AdipoR1/R2 and binding to the gestational diabetes (Mazaki-Tovi et al., 2009), hexameric and HMW forms of adiponectin; though hypertension and cardiovascular disease (Trujillo its pathophysiological importance is not yet and Scherer, 2005). Low adiponectin levels are the elucidated in humans (Hug et al., 2004). The two common pathodenominator of the constellation of classical adiponectin receptors, AdipoR1 and risk factors that synthesize the metabolic syndrome AdipoR2, are structurally very related and share such as hypertension, dyslipidemia, obesity, 67% identity in their protein sequence. They are hyperglycemia, hyperinsulinemia and insulin also highly conserved sharing 95% homology resistance (Dalamaga et al., 2012). between humans and mice (Dalamaga et al., 2012). Adiponectin and carcinogenesis Adiposity is considered to downregulate the expression of AdipoR1/R2, which results to a mechanisms decrease in adiponectin sensitivity, leading to A growing body of evidence suggests that insulin resistance (Ouchi et al., 2000). On the other adiponectin presents anti-neoplastic effects via two hand, physical exercise upregulates adiponectin mechanisms. First, adiponectin can act directly on receptors in muscles and adipose tissue, and tumor cells by enhancing receptor-mediated increases the levels of circulating adiponectin signaling pathways. Secondly, adiponectin may act (Blüher et al., 2006). indirectly by regulating inflammatory responses, Adiponectin exerts diverse effects on different influencing cancer angiogenesis and regulating tissues and organs, and the various isoforms present insulin sensitivity at the target tissue site (Dalamaga various biological effects on different target tissues et al., 2012). (Ziemke and Mantzoros, 2010). Adiponectin is In vitro and in vivo studies have shown the considered to be a protective hormone, exhibiting expression of AdipoR1 and AdipoR2 in various insulin-sensitizing, anti-inflammatory, anti- cancer cell types, suggesting that adiponectin can atherogenic and cardioprotective properties. exhibit direct receptor-mediated effect. Adiponectin

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has shown to restrain proliferation of most obesity- such as sex steroids and leptin, underscoring the related cancer types with some conflicting complex mechanisms that regulate carcinogenesis published data. For example, in the case of liver in vivo (Dalamaga et al., 2012). carcinoma, esophageal adenocarcinoma, gastric, Animal experiments have been conducted in order endometrial and prostate carcinoma, adiponectin to further evaluate the in vitro adiponectin findings. presented clear anti-carcinogenic effects, whereas it Animal models testing the role of adiponectin in had no effect on melanoma cell proliferation carcinogenesis have elucidated the anti-tumorigenic (Dalamaga et al., 2012). However, inhibition of action of adiponectin, particularly in obesity- proliferation or no effect on proliferation of associated cancer types. The diet-mediated colorectal cancer cell lines was noted after influences have also been tested in animal models treatment with adiponectin (Williams et al., 2008). and have contributed to the knowledge of the role Also, in vitro studies on breast cancer cell lines of adiponectin in vivo . Importantly, adiponectin have been conflicting pointing towards cell line presents the strongest effect under the high-fat diet dependent effects (Dalamaga et al., 2012). Potential condition, which is characterized by insulin reasons for these discrepancies may be biological resistance and a pro-inflammatory state. Generally, variations between the several lines of the inhibition of tumor growth has been shown for respective cells used in various laboratories, colon, gastric, liver, breast and lung cancer as well differences in culture conditions, glucose as melanoma (Dalamaga et al., 2012). Finally, the availability medium, incubation time or adiponectin role of adiponectin in tumor angiogenesis remains dosage, the specific isoform of adiponectin used, to be defined as both pro-angiogenic (Ouchi et al., etc. 2004) and anti-angiogenic activities (Bråkenhielm The signaling pathways linking adiponectin to et al., 2004) have been described with a prevailing inhibition of tumorigenesis involve several pro-angiogenic function (Dalamaga et al., 2012). intracellular signaling pathways, including 5' AMP- Adiponectin and cancer: activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), phosphatidylinositol epidemiologic evidence 3-kinase (PI3K)/v-Akt murine thymoma viral Epidemiological evidence has linked adiponectin to oncogene homolog (Akt), mitogen-activated protein the risk of obesity-associated cancers, including but kinase (MAPK), signal transducer and activator of not limited to breast, endometrial, prostate, gastric, transcription 3 (STAT 3), nuclear factor-κB (NF κB) colon, pancreatic, and hematologic malignancies. and the sphingolipid metabolic pathway. Moreover, many studies have reported adiponectin Furthermore, inhibition of β-catenin, activation of receptors and their expression in specific cancer c-AMP/protein kinase A and reduction of reactive tissues. Few epidemiologic studies have related oxygen species (ROS) may also contribute to the specific gene polymorphisms of adiponectin and response of tumor cells to adiponectin (Dalamaga et adiponectin receptors with cancer risk presenting al., 2012). Nevertheless, most of the effects of variable associations (Dalamaga et al., 2012). adiponectin on cancer cells are mediated through Hypoadiponectinemia has been proposed as a AMPK. Collectively, the adiponectin anti- biological link between obesity, insulin resistance neoplastic effects result in decreased protein and and colorectal cancer as well as colorectal fatty acid synthesis, reduced cellular growth, adenoma. Two meta-analyses and a large, proliferation and DNA-mutagenesis as well as prospective study in the context of the Health enhanced cell cycle arrest and apoptosis (Dalamaga Professionals Study examining the association et al., 2012). The interplay between the mentioned between circulating adiponectin and the risk of CC pathways adds further complexity to the and adenoma have found significantly lower adiponectin signaling network. Interestingly, recent adiponectin levels than healthy controls and an evidence has indicated that adiponectin can elevated risk for colorectal cancer associated with stimulate ceramidase activity independently of hypoadiponectinemia (Wei et al., 2005; Xu et al., AMPK via the classical adiponectin receptors 2011; An et al., 2012). Determining serum (Holland et al., 2011), contributing to increased adiponectin levels and assessing the expression of amounts of prosurvival sphingosine 1 phosphate adiponectin receptors in colorectal cancer tissue (S1P). Elevated S1P is associated with enhanced could be useful in predicting the risk of colorectal cell survival and higher local pro-angiogenic cancer, establishing the prognosis and recurrence of activity as observed in mammary tumor mouse colorectal cancer. models (Landskroner-Eiger et al., 2009). Hypoadiponectinemia has also been found in Adiponectin can also present receptor-independent, patients with gastric cancer, especially upper gastric anti-proliferative actions through controlling the cancer, esophageal adenocarcinoma and esophageal bioavailability of certain growth and inflammatory squamous cell carcinoma in comparison to healthy factors related to carcinogenesis. Finally, in vitro controls (Ishikawa et al., 2005; Yildirim et al., studies have shown interactions between 2009). In particular, lower plasma adiponectin adiponectin and other hormonal signaling pathways levels were inversely correlated with tumor size,

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depth of invasion and tumor TNM stage, women younger than 65 years, independently from underscoring a potential role for adiponectin in BMI, leptin, the IGF system and other known risk gastric cancer progression (Ishikawa et al., 2005). factors (Petridou et al., 2003). Interestingly, a Evidence for the relationship between pancreatic combination of obesity and hypoadiponectinemia adenocarcinoma and adiponectin levels is constitutes a greater risk for endometrial cancer conflicting and depends mainly on the study design occurrence. In particular, among obese and peri-/ (retrospective versus prospective). In general, postmenopausal women, lower pre-diagnostic circulating adiponectin levels have been reported circulating adiponectin levels may predispose to a decreased in prospective studies (Bao et al., 2013) higher risk of endometrial cancer independently and increased in retrospective case-control studies from BMI, measures of central obesity and other (Dalamaga et al., 2009a; Dalamaga et al., 2009b). obesity-related biological risk factors such as Elevated adiponectin levels seen in retrospective circulating levels of C-peptide, a biomarker studies for pancreatic cancer may be a reflecting pancreatic insulin production, compensatory response to inflammation, insulin endogenous sex steroid hormones, and IGF binding resistance and the disease-induced weight loss due proteins (Cust et al., 2007). to cancer cachexia, a metabolic state characterized Although the relationship between adiponectin by adipose and muscle tissue loss (Dalamaga et al., concentrations and prostate cancer has not been 2009b). Moreover, cachectic patients may exhibit consistently shown, there is growing evidence that glucose intolerance and insulin resistance due to hypoadiponectinemia is not only associated with alterations in fat metabolism, hypoleptinemia, a prostate cancer risk (Dalamaga et al., 2012) but also pro-inflammatory state and an increased activity of with the histologic grade and disease stage the Cori cycle (Dalamaga, 2013). (Michalakis et al., 2007). Indeed, in a 25-year The majority of epidemiologic evidence has linked prospective study, men with elevated pre-diagnostic lower total or HMW adiponectin levels to an adiponectin levels presented lower risk for increased risk for breast cancer independently of developing high-grade or metastatic prostate cancer classical risk factors, including leptin and the IGF-I (Li et al., 2010). system in both premenopausal and postmenopausal Finally, circulating adiponectin levels have been women (Mantzoros et al., 2004; Dalamaga et al., related mainly to the risk of hematologic 2011; Dalamaga et al., 2012). Macis et al. identified malignancies of the "myeloid" cell line (Dalamaga hypoadiponectinemia in premenopausal women as et al., 2012) such as childhood acute myeloblastic a risk biomarker for progression from intraepithelial leukemia, myelodysplastic syndromes (Dalamaga et neoplasia to invasive breast cancer independently of al., 2007; Dalamaga et al., 2008; Dalamaga et al., age, BMI, and treatment group (Macis et al., 2012). 2013a), and myeloproliferative disorders including Because adipocytes constitute the predominant chronic myelogenous leukemia (Avcu et al., 2006). breast stromal element, adiponectin may exert a Interestingly, lower serum adiponectin and free major paracrine and autocrine influence in leptin, and elevated fetuin-A levels, may mediate mammary epithelium. Since AdipoR1/R2 are effects of excess body weight on insulin resistance expressed in breast cancer tissue samples and cell and risk for myelodysplastic syndromes (Dalamaga lines, adiponectin could act not only through et al., 2013a). These findings are in accordance with altering the hormonal milieu but directly through a previous hypothesis showing that adiponectin suppression of breast cancer cell proliferation. In induces apoptosis and inhibits the proliferation of addition, some studies have pointed out that breast myeloid cell lineage predominanltly (Yokota et al., tumors arising in women with low adiponectin 2000). Controversial data exist in the literature in levels may present a more aggressive phenotype relation to circulating adiponectin levels as a characterized by a higher histologic grade, a large biomarker of hematologic malignancies from size of tumor and estrogen-receptor negativity "lymphoid" origin. A decrease, no change and even (Dalamaga et al., 2012). Hypoadiponectinemia was an elevation in adiponectinemia have been reported also associated with lymph node metastases and (Dalamaga et al., 2012). In addition, no prospective increased mortality in breast cancer survivors after epidemiologic studies have been performed adjustment for parameters, including obesity and examining the association of pre-diagnostic insulin resistance (Duggan et al., 2011). Finally, adiponectin levels and non-Hodgkin lymphomas some studies focusing on adiponectin genetic due to the rarity of these malignancies in the variants (ADIPOQ) and adiponectin receptor genes general population. Lower levels of adiponectin (ADIPOR1) and breast cancer risk have reported were associated with a greater risk for multiple associations of ADIPOQ single nucleotide myeloma adjusting for age, gender, BMI, serum polymorphisms (SNPs) and ADIPOR1 SNP with leptin and resistin (Dalamaga et al., 2009a) in breast cancer risk. However, other studies did not accordance with a recent research by Fowler et al., find such associations (Dalamaga et al., 2012). which reported a significant percent decrease in Hypoadiponectinemia was associated with an circulating HMW adiponectin concentrations in elevated risk of endometrial cancer, particularly in patients with monoclonal gammopathy of

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undetermined significance that either progress or do increased adiponectin levels, and a lower risk of not progress to multiple myeloma from age-, developing insulin resistance, diabetes type 2, gender-, and BMI-matched controls (Fowler et al., cardiovascular disease and malignancies. 2011). This is in accordance with the finding that adiponectin can induce apoptosis of myeloma cells References through an activation of AMPK, and that myeloma Hubert HB, Feinleib M, McNamara PM, Castelli WP. cell apoptosis is reduced in myeloma-bearing Obesity as an independent risk factor for cardiovascular adiponectin-deficient mice (Fowler et al., 2011). disease: a 26-year follow-up of participants in the Augmenting adiponectin via an apolipoprotein Framingham Heart Study. Circulation. 1983 peptide mimetic, L-4F, increased apoptosis of May;67(5):968-77 myeloma cells in vivo and prevented myeloma Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. bone disease (Fowler et al., 2011). A novel serum protein similar to C1q, produced exclusively Therefore, adiponectin could not only represent a in adipocytes. J Biol Chem. 1995 Nov 10;270(45):26746-9 biomarker for cancer development in obesity, but Hu E, Liang P, Spiegelman BM. AdipoQ is a novel could also act as a molecular mediator relating adipose-specific gene dysregulated in obesity. J Biol adipose tissue with carcinogenesis. The Chem. 1996 May 3;271(18):10697-703 mechanisms underlying the actions of adiponectin Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M. and its potential diagnostic, prognostic and/or Isolation and characterization of GBP28, a novel gelatin- binding protein purified from human plasma. J Biochem. therapeutic utility need further investigation 1996 Oct;120(4):803-12 (Dalamaga et al., 2012). Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Future perspectives Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, The action of adiponectin in ameliorating insulin Matsuzawa Y. Adiponectin, an adipocyte-derived plasma sensitivity synergistically with its anti-proliferative protein, inhibits endothelial NF-kappaB signaling through a and pro-apoptotic properties has rendered this cAMP-dependent pathway. Circulation. 2000 Sep adipokine a promising potential diagnostic and 12;102(11):1296-301 prognostic biomarker, and a novel therapeutic tool Takahashi M, Arita Y, Yamagata K, Matsukawa Y, in the pharmacologic armamentarium for cancer Okutomi K, Horie M, Shimomura I, Hotta K, Kuriyama H, Kihara S, Nakamura T, Yamashita S, Funahashi T, treatment. In the future, based on circulating Matsuzawa Y. Genomic structure and mutations in adiponectin determinations and specific adipose-specific gene, adiponectin. Int J Obes Relat Metab combinations of adiponectin pathway SNPs, a high- Disord. 2000 Jul;24(7):861-8 risk population for developing cancer could be Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama identified and benefit from adiponectin replacement A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama therapy. Y, Matsuzawa Y. Adiponectin, a new member of the family Research efforts could be directed towards of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of identifying ways to augment endogenous macrophages. Blood. 2000 Sep 1;96(5):1723-32 adiponectin levels in order to moderate the obesity- Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, cancer relationship. Adiponectin-mimetics, agonists Pratley RE, Tataranni PA. Hypoadiponectinemia in obesity of AdipoR1/R2 and strategies to increase and type 2 diabetes: close association with insulin adiponectin receptors and to modulate their resistance and hyperinsulinemia. J Clin Endocrinol Metab. sensitivity to adiponectin could provide novel 2001 May;86(5):1930-5 therapeutic approaches for insulin resistance, Chandran M, Phillips SA, Ciaraldi T, Henry RR. diabetes type 2 and obesity-associated cancers. Adiponectin: more than just another fat cell hormone? Pharmacologic agents such as full and selective Diabetes Care. 2003 Aug;26(8):2442-50 PPAR-γ agonists increasing circulating adiponectin Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, levels or stimulating adiponectin signaling are at Bales VS, Marks JS. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2003 Jan the forefront of future therapeutic modalities for 1;289(1):76-9 obesity-linked cancers. Nonetheless, further basic research, in vivo animal studies, observational Petridou E, Mantzoros C, Dessypris N, Koukoulomatis P, Addy C, Voulgaris Z, Chrousos G, Trichopoulos D. Plasma human studies, and prospective and longitudinal adiponectin concentrations in relation to endometrial studies are required in order to clearly determine cancer: a case-control study in Greece. J Clin Endocrinol the mechanisms underlying the actions of Metab. 2003 Mar;88(3):993-7 adiponectin in cancer. Yamauchi T, Kamon J, Ito Y, Tsuchida A et al.. Cloning of At present, lifestyle amelioration remains the most adiponectin receptors that mediate antidiabetic metabolic important component in preventing obesity-related effects. Nature. 2003 Jun 12;423(6941):762-9 cancer. Bråkenhielm E, Veitonmäki N, Cao R, Kihara S, Physical exercise, reduction of body-weight, a Matsuzawa Y, Zhivotovsky B, Funahashi T, Cao Y. Mediterranean-based diet with consumption of Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell fruits, nuts, coffee and/or moderate amounts of apoptosis. Proc Natl Acad Sci U S A. 2004 Feb alcohol present a well-established association with 24;101(8):2476-81

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Hug C, Wang J, Ahmad NS, Bogan JS, Tsao TS, Lodish Michalakis K, Williams CJ, Mitsiades N, Blakeman J, HF. T-cadherin is a receptor for hexameric and high- Balafouta-Tselenis S, Giannopoulos A, Mantzoros CS. molecular-weight forms of Acrp30/adiponectin. Proc Natl Serum adiponectin concentrations and tissue expression Acad Sci U S A. 2004 Jul 13;101(28):10308-13 of adiponectin receptors are reduced in patients with prostate cancer: a case control study. Cancer Epidemiol Mantzoros C, Petridou E, Dessypris N, Chavelas C, Biomarkers Prev. 2007 Feb;16(2):308-13 Dalamaga M, Alexe DM, Papadiamantis Y, Markopoulos C, Spanos E, Chrousos G, Trichopoulos D. Adiponectin Ogden CL, Yanovski SZ, Carroll MD, Flegal KM. The and breast cancer risk. J Clin Endocrinol Metab. 2004 epidemiology of obesity. Gastroenterology. 2007 Mar;89(3):1102-7 May;132(6):2087-102 Ouchi N, Kobayashi H, Kihara S, Kumada M, Sato K, Dalamaga M, Karmaniolas K, Nikolaidou A, Chamberland Inoue T, Funahashi T, Walsh K. 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Associations of insulin Dalamaga M, Karmaniolas K, Papadavid E, Pelekanos N, resistance and adiponectin with mortality in women with Sotiropoulos G, Lekka A.. Hyperresistinemia is associated breast cancer. J Clin Oncol. 2011 Jan 1;29(1):32-9 with postmenopausal breast cancer. Menopause. 2013b Aug;20(8):845-51. doi: 10.1097/GME.0b013e31827f06dc. Fowler JA, Lwin ST, Drake MT, Edwards JR, Kyle RA, Mundy GR, Edwards CM. Host-derived adiponectin is This article should be referenced as such: tumor-suppressive and a novel therapeutic target for multiple myeloma and the associated bone disease. Blood. Dalamaga M, Koumaki V. Adiponectin and cancer. Atlas 2011 Nov 24;118(22):5872-82 Genet Cytogenet Oncol Haematol. 2014; 18(5):361-367. Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, Davis KE, Bikman BT, Halberg N, Rutkowski JM,

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 367 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Manuscripts submitted to the Atlas must be submitted solely to the Atlas. Iconography is most welcome: there is no space restriction. The Atlas publishes "cards", "deep insights", "case reports", and "educational items". Cards are structured review articles. Detailed instructions for these structured reviews can be found at: http://AtlasGeneticsOncology.org/Forms/Gene_Form.html for reviews on genes, http://AtlasGeneticsOncology.org/Forms/Leukaemia_Form.html for reviews on leukaemias, http://AtlasGeneticsOncology.org/Forms/SolidTumour_Form.html for reviews on solid tumours, http://AtlasGeneticsOncology.org/Forms/CancerProne_Form.html for reviews on cancer-prone diseases. According to the length of the paper, cards are divided, into "reviews" (texts exceeding 2000 words), "mini reviews" (between), and "short communications" (texts below 400 words). The latter category may not be accepted for indexing by bibliographic databases. Deep Insights are written as traditional papers, made of paragraphs with headings, at the author's convenience. No length restriction. Case Reports in haematological malignancies are dedicated to recurrent -but rare- chromosomes abnormalities in leukaemias/lymphomas. Cases of interest shall be: 1- recurrent (i.e. the chromosome anomaly has already been described in at least 1 case), 2- rare (previously described in less than 20 cases), 3- with well documented clinics and laboratory findings, and 4- with iconography of chromosomes. It is mandatory to use the specific "Submission form for Case reports": see http://AtlasGeneticsOncology.org/Reports/Case_Report_Submission.html. Educational Items must be didactic, give full information and be accompanied with iconography. Translations into French, German, Italian, and Spanish are welcome.

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Rules, Copyright Notice and Disclaimer Conflicts of Interest: Authors must state explicitly whether potential conflicts do or do not exist. Reviewers must disclose to editors any conflicts of interest that could bias their opinions of the manuscript. The editor and the editorial board members must disclose any potential conflict. Privacy and Confidentiality – Iconography: Patients have a right to privacy. Identifying details should be omitted. If complete anonymity is difficult to achieve, informed consent should be obtained. Property: As "cards" are to evolve with further improvements and updates from various contributors, the property of the cards belongs to the editor, and modifications will be made without authorization from the previous contributor (who may, nonetheless, be asked for refereeing); contributors are listed in an edit history manner. Authors keep the rights to use further the content of their papers published in the Atlas, provided that the source is cited. Copyright: The information in the Atlas of Genetics and Cytogenetics in Oncology and Haematology is issued for general distribution. All rights are reserved. The information presented is protected under international conventions and under national laws on copyright and neighbouring rights. Commercial use is totally forbidden. Information extracted from the Atlas may be reviewed, reproduced or translated for research or private study but not for sale or for use in conjunction with commercial purposes. Any use of information from the Atlas should be accompanied by an acknowledgment of the Atlas as the source, citing the uniform resource locator (URL) of the article and/or the article reference, according to the Vancouver convention. Reference to any specific commercial products, process, or service by trade name, trademark, manufacturer, or otherwise, does not necessarily constitute or imply its endorsement, recommendation, or favouring. The views and opinions of contributors and authors expressed herein do not necessarily state or reflect those of the Atlas editorial staff or of the web site holder, and shall not be used for advertising or product endorsement purposes. The Atlas does not make any warranty, express or implied, including the warranties of merchantability and fitness for a particular purpose, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information, and shall not be liable whatsoever for any damages incurred as a result of its use. In particular, information presented in the Atlas is only for research purpose, and shall not be used for diagnosis or treatment purposes. No responsibility is assumed for any injury and/or damage to persons or property for any use or operation of any methods products, instructions or ideas contained in the material herein. See also: "Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication - Updated October 2004": http://www.icmje.org.

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