Number 10 October 2015

VolumeVolume 19 1 - -Number Number 10 1 MayOctober - September 2015 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematologyis a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It is made for and by: clinicians and researchers in cytogenetics, molecular biology, oncology, haematology, and pathology. One main scope of the Atlas is to conjugate the scientific information provided by cytogenetics/molecular genetics to the clinical setting (diagnostics, prognostics and therapeutic design), another is to provide an encyclopedic knowledge in cancer genetics. The Atlas deals with cancer research and genomics. It is at the crossroads of research, virtual medical university (university and post-university e-learning), and telemedicine. It contributes to "meta-medicine", this mediation, using information technology, between the increasing amount of knowledge and the individual, having to use the information. Towards a personalized medicine of cancer.

It presents structured review articles ("cards") on: 1- Genes, 2- Leukemias, 3- Solid tumors, 4- Cancer-prone diseases, and also 5- "Deep insights": more traditional review articles on the above subjects and on surrounding topics. It also present 6- Case reports in hematology and 7- Educational items in the various related topics for students in Medicine and in Sciences. The Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles.

See also: http://documents.irevues.inist.fr/bitstream/handle/2042/56067/Scope.pdf

Editorial correspondance

Jean-Loup Huret, MD, PhD, Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France phone +33 5 49 44 45 46 [email protected] or [email protected] .

Editor, Editorial Board and Publisher See:http://documents.irevues.inist.fr/bitstream/handle/2042/48485/Editor-editorial-board-and-publisher.pdf

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008. The Atlas is hosted by INIST-CNRS (http://www.inist.fr) Staff: Vanessa Le Berre Philippe Dessen is the Database Directorof the on-line version (Gustave Roussy Institute – Villejuif – France).

Publisher Contact:INIST-CNRS Mailing Address:Catherine Morel, 2,Allée du Parc de Brabois, CS 10130, 54519 Vandoeuvre-lès-Nancy France. Email Address:[email protected] Articles of the ATLAS are free in PDF format, and metadata are available on the web in Dublin Core XML format and freely harvestable.A Digital object identifier (DOI®), recorded at the International Agency CrossRefhttp://www.crossref.org/ is assigned to each article. http://AtlasGeneticsOncology.org

The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS. Atlas of Genetics and Cytogenetics in Oncology and Haematology

OPEN ACCESS JOURNAL INIST-CNRS Editor -in-Chief Jean-Loup Huret (Poitiers, France)

Board Members SreeparnaBanerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Alessandro Beghini Department of Health Sciences, University of Milan, Italy; [email protected] Judith Bovée 2300 RC Leiden, The Netherlands; [email protected] Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy; Antonio Cuneo [email protected] Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; Paola Dal Cin [email protected] IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, François Desangles Dewoitine C212, 91223 Bretigny-sur-Orge, France; [email protected] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, Enric Domingo OX37BN, UK [email protected] AyseElifErson- Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Bensan Ad Geurts van Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Kessel Sciences, 6500 HB Nijmegen, The Netherlands; [email protected] Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Oskar A. Haas Children's Cancer Research Institute Vienna, Vienna, Austria. [email protected] Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; Anne Hagemeijer [email protected] Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, NylaHeerema USA; [email protected] Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; SakariKnuutila [email protected] Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; Lidia Larizza l.larizza@auxologico Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell RoderickMcLeod Cultures, Braunschweig, Germany; [email protected] Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; Cristina Mecucci [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Fredrik Mertens [email protected] Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; miller.konstantin@mh- Konstantin Miller hannover.de Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Felix Mitelman [email protected] HossainMossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; [email protected] Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Stefan Nagel Cultures, Braunschweig, Germany; [email protected] Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; Florence Pedeutour [email protected] Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Susana Raimondi Memphis, Tennessee 38105-3678, USA; [email protected] Clelia Tiziana Department of Biology, University of Bari, Bari, Italy; [email protected] Storlazzi CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; Sabine Strehl [email protected] Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; Nancy Uhrhammer [email protected] Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected] Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) Roberta Vanni - Italy; [email protected] Service d'Histologie-Embryologie-Cytogénétique, Unité de Cytogénétique Onco-Hématologique, Hôpital Franck Viguié Universitaire Necker-Enfants Malades, 75015 Paris, France; [email protected]

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’InformationScientifique 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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Volume 19, Number 10, October 2015

Table of contents

Gene Section

TNFRSF17 (tumor necrosis factor receptor superfamily, member 17) 603 Abigail Gillespie, Eric Sanchez, George Tang, Haiming Chen, James Berenson FBLN2 (fibulin 2) 605 Santiago Cal, Alvaro J Obaya MCM3 (minichromosome maintenance complex component 3) 611 Kaifee Arman, Esra Bozgeyik, Yusuf Ziya Igci NTSR1 (neurotensin receptor 1 (high affinity)) 617 Sofiane Saada, Pierre Marget, Amazigh Abacci, Anne-Laure Fauchais, Marie-Odile Jauberteau, Daniel Petit, Fabrice Lalloue PDCD5 (programmed cell death 5) 621 Yingyu Chen, Ge Li ZFX (zinc finger protein, X-linked) 625 Modjtaba Emadi-Baygi

Leukaemia Section t(1;2)(q12;q37) in acute leukemias 628 Shen Yueyang , Gillan Tanya, Héléne Bruyère

Solid Tumour Section

Pseudomyogenic hemangioendothelioma: t(7;19)(q22;q13) SERPINE1/FOSB 630 Charles Walther, Fredrik Mertens

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Short Communication

TNFRSF17 (tumor necrosis factor receptor superfamily, member 17) Abigail Gillespie, Eric Sanchez, George Tang, Haiming Chen, James Berenson Institute for Myeloma & Bone Cancer Research, 9201 W. Sunset Blvd., Ste. 300, West Hollywood, CA 90069, USA

Published in Atlas Database: October 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/TNFRSF17ID42616ch16p13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62477/10-2014-TNFRSF17ID42616ch16p13.pdf DOI: 10.4267/2042/62477

Abstract Protein B Cell Maturation Antigen (BCMA) is a Description transmembrane signaling protein preferentially 184 aa; a glycoprotein with a single transmembrane expressed on plasma cells. Its ligands include B- domain; N-terminally glycosylated at asparagine 42 Cell Activating Factor (BAFF) and A Proliferation regulates its function (Huang et al., 2013). Inducing Ligand (APRIL). BCMA is involved in BCMA is a signaling protein that activates the NF- JNK and NF-kB activation pathways that induce B- kB. cell development and autoimmune responses. BCMA contains one cysteine rich domain and a BCMA has been implicated in autoimmune DXL motif, comprised of (Phe/Tyr/Trp)-Asp-Xaa- disorders as well as B-lymphocyte malignancies. Leu-(Val/Thr)-(Arg/Gly), to facilitate ligand Keywords binding with BAFF or APRIL (Hymowitz et al., BCMA, multiple myeloma, immunity, JNK, NF-kB 2005). Identity Expression Preferentially expressed in lymph node tissue, B Other names: BCM, BCMA, CD269, lymphoblast, NK cells, and dendritic cells. TNFRSF13A Localisation HGNC (Hugo): TNFRSF17 Plasma membrane. Location: 16p13.13 Function DNA/RNA BCMA mediates the development and survival of B cell lymphocytes that maintain humoral immunity. Description Spans 3.8 kb; 3 exons, 2 introns. Homology TNFRSF17 is conserved in P. Troglodytes, M. Transcription mulatta, C. lupus, B. taurus, M. musculus, and R. 961 nt mRNA. norvegicus.

Atlas Genet Cytogenet Oncol Haematol. 2015; 19(10) 603 TNFRSF17 (tumor necrosis factor receptor superfamily, Gillespie A, et al. member 17)

Mutations 22 single nucleotide polymorphisms (SNP) have been reported. Implicated in Multiple myeloma Disease Multiple myeloma is a fatal malignancy that involves the abnormal proliferation and accumulation of plasma cells characterized by their Partial R-Banded karyotype. The karyotype shows a resistance to apoptosis. Sanchez et al. not only (4;16) (q26;p13.1) chromosomal translocation that led to showed increased expression of BCMA in patients' the identification of BCMA by Laâbi et al. (Laâbi et al., plasma cells, but that patients with multiple 1992). myeloma have a high concentration of BCMA Acute monocytic leukemia protein circulating in their blood. Furthermore, the t(8;16)(p11;p13) translocation has been noted in group found that higher levels of circulating BCMA cases of acute monocytic leukemia (Laâbi et al., are associated with a worse prognosis. 1992). Prognosis Follicular lymphoma Poor. Translocation (16;18)(p13;q21.3) has been reported Acute myelomonocytic leukemia in follicular lymphoma (Mahmoodi et al., 2004). (AMML) with eosinophilia Disease References AMML is a malignancy involving myeloid Laâbi Y, Gras MP, Carbonnel F, Brouet JC, Berger R, precursors of the bone marrow. Although this Larsen CJ, Tsapis A. A new gene, BCM, on chromosome condition is rare, it is a common type of pediatric 16 is fused to the interleukin 2 gene by a t(4;16)(q26;p13) translocation in a malignant T cell lymphoma. EMBO J. acute myeloid leukemia. In about 50% of the cases 1992 Nov;11(11):3897-904 of AMML, increased numbers of abnormal eosinophils are observed in the bone marrow Mahmoodi M, Tanev SS, Punnett HH, Crilley P, Hou JS. Translocation (16;18)(p13;q21.3) in follicular lymphoma. (eosinophilia). AMML patients with eosinophilia Cancer Genet Cytogenet. 2004 Oct 15;154(2):160-2 who carry a pericentric inversion at 16(p13q22) tend to have a better prognosis. Hymowitz SG, Patel DR, Wallweber HJ, Runyon S, Yan M, Yin J, Shriver SK, Gordon NC, Pan B, Skelton NJ, Kelley Prognosis RF, Starovasnik MA. Structures of APRIL-receptor 61% 5 year survival rate; AMML patients who complexes: like BCMA, TACI employs only a single cysteine-rich domain for high affinity ligand binding. J Biol carry the pericentric inversion have a higher rate of Chem. 2005 Feb 25;280(8):7218-27 complete remission than those without the inversion (Chang et al., 2006). Chang ST, Hsieh YC, Lee LP, Tzeng CC, Chuang SS. Acute myelomonocytic leukemia with abnormal Cytogenetics eosinophils: a case report with multi-modality diagnostic Pericentric inversion at 16(p13q22) in 3-5% of work-up. Chang Gung Med J. 2006 Sep-Oct;29(5):532-7 AMML cases. Huang HW, Chen CH, Lin CH, Wong CH, Lin KI. B-cell maturation antigen is modified by a single N-glycan chain T cell lymphoma that modulates ligand binding and surface retention. Proc Note Natl Acad Sci U S A. 2013 Jul 2;110(27):10928-33 (4;16)(q26;p13.1) chromosome translocation, This article should be referenced as such: which led to the discovery of BCMA, was noted by Gillespie A, Sanchez E, Tang G, Chen H, Berenson J. Laâbi et al. in a single case of T cell lymphoma. TNFRSF17 (tumor necrosis factor receptor superfamily, This translocation resulted in a IL-2/BCMA member 17). Atlas Genet Cytogenet Oncol Haematol. composite gene. 2015; 19(10):603-604.

Atlas Genet Cytogenet Oncol Haematol. 2015; 19(10) 604 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Review

FBLN2 (fibulin 2) Santiago Cal, Alvaro J Obaya Departamento de Bioquimica y Biologia Molecular, Instituto Universitario de Oncologia (IUOPA), Universidad de Oviedo, 33006, Asturias, Spain (SC); Departamento de Biologia Funcional, Instituto Universitario de Oncologia (IUOPA), Universidad de Oviedo, 33006, Asturias, Spain (AJO) Published in Atlas Database: October 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/FBLN2ID52662ch3p25.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62478/10-2014-FBLN2ID52662ch3p25.pdf DOI: 10.4267/2042/62478

(NC_000003.12) is encoded in 19 exons in Abstract chromosome 3, spans approximately 89.3 Kb of genomic DNA in the telomere-to-centromere Fibulin-2 is an extracellular matrix glycoprotein orientation. with an important function in maintaining elastic The translation initiation codon is located to exon 3, properties in different tissues. Fibulin-2 belongs to and the stop codon to exon 19. a protein family with seven members characterized by sharing a globular domain at the carboxy- Transcription terminus, which is called "fibulin-like", "FC Northern blot analysis of mRNA from various domain" or domain III. Together with fibulin-1, human tissues reveals an abundant 4.5-kb transcript fibulin-2 forms the so called subgroup 1 in the in heart, placenta, and ovary tissue (Zhang et al., fibulin family which contains three anaphylatoxin 1994). modules in their sequence. Fibulin-2 does not only form part of elastic fibers but is also present in Protein basement membranes and other connective tissue structures. Besides its structural function, The open reading frame encodes a 1231 amino acid alterations in fibulin-2 expression have also been protein, with an estimated molecular weight of related to several pathological processes. Thus, 131,9 kDa. fibulin-2 has been shown to be implicated in blood Fibulin-2 shares a structural multidomain complex pressure regulation, vascular injury protection or architecture with the rest of the members of the with a protective role in some heart malfunctioning. fibulin family, specially with fibulin-1. Also, fibulin-2 participation has been described in This organization includes a signal peptide, a cancer showing both oncogenic or tumor- cystein rich domain, a cystein free domain, three suppressor properties. anaphylotoxyn domains, an EGF-like (Epidermal Keywords Growth Factor) domain following the first out of a total of ten cbEGF (calcium-binding Epidermal Extracellular matrix, elastic fibers. Growht Factor) domains and finally, at the carboxy- terminus the fibulin-like domain, characteristic of Identity the fibulin family (Figure 1) (Timpl et al., 2003; de HGNC (Hugo): FBLN2 Vega et al., 2009; Obaya et al., 2012). Location : 3p25.1 An alternative splicing has been described for fibulin-2 mRNA by which exon 10 is removed DNA/RNA resulting in a short fibulin-2 (FBLN2S) of 1184 amino which lacks the third EFG-like domain in According to NCBI (National Center for comparison to the long fibulin-2 (FBLN2L) (Zhang Biotechnology Information) fibulin-2 et al., 1994; Grassel et al., 1999; Law et al., 2012).

Atlas Genet Cytogenet Oncol Haematol. 2015; 19(10) 605 FBLN2 (fibulin 2) Cal S and Obaya AJ

Figure 1. Fibulin-2 domain organization. EGF : Epidermal Growth Factor.

It has been described that fibulin-2 forms anti- structures (Zhang et al., 1995; Ducros et al., 2007; paralel homodimers stabilized by a single disulfide Kobayashi et al., 2007). bond throug a cysteine residue located in the second anaphylotoxin domain. As seen by electron Localisation microscopy, fibulin-2 homodimerization produces a Secreted, extracellular matrix. set of star-like particles consisting in two-, three- or Function four-arm structures as well as some larger aggregates. Thus, the complexity of fibulin-2 Fibulin-2 as well as other members of the fibulin structure allows different combinations and family play essential role for the correct assembly possibilities to interact with other extracellular of elastic fibers in connective tissues (Kielty et al., matrix proteins (Pan et al., 1993; Sasaki et al., 2002). 1997). In particular, fibulin-2 is localized in the interface between the two main components of elastic fibers, Expression microfibrils and the elastin core (Reinhardt et al., Northern blot analysis of mRNA from various 1996; Kobayashhi et al., 2007). In its structural human tissues reveals the presence of fibulin-2 function, fibulin-2 is able to interact with several transcript in heart, placenta and ovary tissue (Zhang other extracellular components to maintain specific et al., 1994). Fibulin-2 expression is restricted to connective tissues properties. Thus, fibulin-2 is able certain tissues and partially overlaps with that of to interact with troposlatin-2 (Sasaki et al., 1999), fibulin-1. Both proteins are localized in basement aggrecan and versican (Olin et al., 2001), membranes, elastic fibers, and other connective fibronectin and nidogen-1 (Sasaki et al., 1995). All tissue structures (Pan et al., 1993; Roark et al., those bindings partners overlap with those of 1995; Miosge et al., 1996; Reinhardt et al., 1996; fibulin-1 but, fibulin-2 is also able to specifically Zhang et al., 1996). Both proteins can be detected interact with fibrillin-1 and perlecan (Reinhardt et in early stages of embryonic development although al., 1996; Hopf et al., 2001). fibulin-2 synthesis is delayed with respect to Fibulin-2 is also suggested to regulate steroid fibulin-1. However, both are at relatively high hormone action since it is able to interact with sex levels at the onset of organogenesis in mouse and hormone globulin (SHBG) (Ng et al., 2006). humans (Miosge, 1996; Zhang et al., 1996). Mutations in SHGB alter its binding capacities to Fibulin-2 is expressed during the epithelial to fibulin-2 and sex hormones suggesting participation mesenchymal transformation in the endocardial in human diseases (Wu and Hammond, 2014). In cushion matrix, aortic arch vessels and coronary relation with steroid hormones, progesterone, vessels during embryonic heart development dexamethasone, estradiol and glucocorticoids are (Zhang et al., 1995; Tsuda et al., 2001). Fibulin-1 able to regulate fibulin-2 expression levels in and fibulin-2 are also expressed and deposited in different tissues and contexts (Talts et al., 1995; Gu several, although different neuronal structures. et al., 2001; Okada et al., 2003; Eyster et al., 2014 ; Specifically, fibulin-2 was detected primarily Olijnyk et al., 2014). within the neuropithelium, spinal ganglia and peripheral nerves (Zhang et al., 1996). Furthermore, Homology fibulin-2 has also been detected during skin wound The FBLN2 gene is conserved in chimpanzee healing, in the developing cartilage (perichondrium) (Refseq: NC_006490.3), dog (Refseq: or deposited in the organization of corneal NC_006602.3), cow (Refseq: AC_000179.1),

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mouse (Refseq: NC_000072.6), rat (Refseq: al., 2012). Fibulin-2/ADAMTS-12 interaction has NC_005103.4), chicken (Refseq: NC_006099.3), been shown to inhibit the migration, invasion and and zebrafish (Refseq: NC_007122.5). tumorigenicity properties of cancer breast cell lines after exogenous expression of ADAMTS-12 Implicated in (Fontanil et al., 2014). Various cancers Lung adenocarcinoma Fibulin-2 was early related to cancer in a study Based on the previous study of Ramaswamy et al. aimed to look for genes differently expressed comparing primary a metastatic tumors in the between adenocarcinoma metastases of multiple search of a gene metastatic signature (Ramaswamy tumor types and the unmatched primary et al., 2003), a proteomic screen of highly and adenocarcinomas (breast, prostate, lung, colon, poorly metastatic tumor cell lines derived from uterus and ovary) (Ramaswamy et al., 2003). mice that develop lung adenocarcinoma revealed that fibulin-2 was preferentially expressed in highly Nasopharyngeal carcinoma metastatic cells (Schliekelman et al., 2011). A more Genome-wide Human Mapping Array analysis profound and functional study revealed that fibulin- showed that the chromosome 3p25 region, where 2 shows an oncogenic potential in lung FBLN2 maps, is often deleted in esophageal adenocarcinoma (Baird et al., 2013). Fibulin-2 is squamous cell carcinoma patients (Chattopadhyay found expressed in metastatic-derived cell lines and et al., 2010). More recently, fibulin-2 RNA tumor growth depends on the endogenously downregulation has been described in 100% of expressed fibulin-2 since they are able to grow nasopharingeal carcinoma cell lines as well as equally in Fbln2-null and wild-type mice. 46.7% of biopsies tested. Deletion and promoter Furthermore, fibulin-2 requires the presence of hypermethylation events contribute to the silencing collagen in the extracellular matrix in order to of FBLN2 expression (Law et al., 2012). Functional promote tumorigenic properties of these cells lines analysis of fibulin-2 role as a tumor suppressor (Baird et al., 2013). gene showed angio-inhibitory and tumor- Pancreatic cancer suppressive properties that are linked to a short Expression of MUC4, a transmembrane type I isoform of FBLN2, FBLN2S, in nasopharingeal glycoprotein, is elevated in pancreatic cancer. It is carcinoma (Law et al., 2012). Interestingly, also known that MUC4 is able to interact through FBLN2-associated anti-angiogenic activity is its nidogen-like domain with fibulin-2 and authors concomitant with a downregulation of two pro- suggest that this association contributes to the angiogenic factors such as VEGF and matrix- MUC4-mediated metastasis of pancreatic tumor metalloprotease-2 (MMP-2). cells (Senapati et al., 2012). Breast cancer Kaposí's sarcoma Fibulin-2 was suggested to be a putative biomarker Infection of dermal microvascular endothelial cells of breast cancer attending to the proteomic analysis (DMVEC) with Kaposi's sarcoma-associated performed in a breast cancer mouse model herpesvirus (KSHV) reduced fibulin-2 protein and (Whiteaker et al., 2007). A role of fibulin-2 as a RNA. Furthermore, a decrease in the expression of tumor suppressor gene in breast cancer came after fibronectin and tropoelastin, binding partners of the observation of its down-regulation in several fibulin-2, was also detected in infected cells cancer cell lines (Yi et al., 2007). Exogenous (Alcendor et al., 2011). Since downregulataion of expression of fibulin-2 in breast cancer cell lines other fibulins is observed, authors suggest that was able to reduce cell motility as well as invasion dysregulation of fibulin family members such as capacities, some of the tumor properties of those fibulin-2, fibulin-3, fibulin-5, fibulin 1C, and cells (Yi et al., 2007). One of the mechanisms to fibulin 1D likely contribute to KSHV-induced reduce FBLN2 gene expression is throuh promoter pathogenesis in Kaposi's sarcoma (Alcendor et al., hypermethylation as it has been described in breast 2011). cancer cell lines (60%), primary breast tumors (34%) and matched tumor/normal pairs (32%) Various diseases biopsies (Hill et al., 2010). Fibulin-2 might exert its Fibulin-2 participation in disease has been tumor suppressor function by interaction with other somehow elusive due to functional redundacy with proteins of the extracellular matrix as is the case of other members of the fibulin family. Thus, fibulin-1 ADAMTS-12 (Fontanil et al., 2014). ADAMTS-12 staining is highly detected in the absence of fibulin- is a secreted metalloprotease (Cal et al., 2001; Cal 2 in the viable, fertile and free of anatomic and Obaya, 2014) and different studies have abnormalities fibulin-2 knock-out mice (Sicot et al., suggested a role for this metalloprotease in tissue 2008; Olijnyk et al.,2014). However, several studies remodeling and cell migration or adhesion (Noel et support fibulin-2 functions in disease and cancer. In

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the case of cancer, fibulin-2 shows a dual function, control blood pressure and it has been described the showing either suppresor gene or oncogenic existence of some polymorphisms of FBLN2 activities (Obaya et al., 2012). associated with reduced levels of systolic blood pressure and decreased risk of hypertension (Vallvé Skin damage et al., 2012). In normal skin, regulation of skin elastogenesis depends on the association between fibulin-2 and References fibulin-5 with fibrillin-1 matrix (Lemaire et al., Alcendor DJ, Knobel S, Desai P, Zhu WQ, Hayward GS. 2004). Fibulin-2 is not only known to participate in KSHV regulation of fibulin-2 in Kaposi's sarcoma: the elastic structure of the skin but also participates implications for tumorigenesis. Am J Pathol. 2011 in skin wound healing where it shows an increased Sep;179(3):1443-54 expression with mRNA levels returning to normal Baird BN, Schliekelman MJ, Ahn YH, Chen Y, Roybal JD, after skin repair (Fässler el al., 1996). Fibulin-2 Gill BJ, Mishra DK, Erez B, O'Reilly M, Yang Y, Patel M, deposition is also high in a mice model of chronic Liu X, Thilaganathan N, Larina IV, Dickinson ME, West JL, contact dermatitis as well as in models of solar Gibbons DL, Liu DD, Kim MP, Hicks JM, Wistuba II, Hanash SM, Kurie JM. Fibulin-2 is a driver of malignant elastosis which suggests a protective role of fibulin- progression in lung adenocarcinoma. PLoS One. 2 in skin formation and maintenance (Kusubata et 2013;8(6):e67054 al., 1999; Hunzelmann et al., 2001). Furthermore, Cal S, Arguelles JM, Fernandez PL, López-Otín C. fibulin-2 reduction in fbln2 null mice or due to the Identification, characterization, and intracellular processing lack of integrin α3β1-laminin interaction of ADAM-TS12, a novel human disintegrin with a complex contributes to loss of the integrity of basement structural organization involving multiple thrombospondin-1 membrane and skin blistering (Sicot et al., 2008; repeats. J Biol Chem. 2001 May 25;276(21):17932-40 Longmate el al., 2014). In fact, the latest occurs Cal S, Obaya AJ.. ADAMTS12 (ADAM Metallopeptidase since fibulin-2 is one of the genes regulated by With Thrombospondin Type 1 Motif, 12) Atlas Genet Cytogenet Oncol Haematol. 2014;18(2):78-81. integrin α3β1 in inmortalized keratinocytes and seems to be one of the mediators in the invasive Chapman SL, Sicot FX, Davis EC, Huang J, Sasaki T, Chu capacities exerted by integrin α3β1 (Missan et al., ML, Yanagisawa H.. Fibulin-2 and fibulin-5 cooperatively function to form the internal elastic lamina and protect from 2014). vascular injury. Arterioscler Thromb Vasc Biol. 2010 Jan;30(1):68-74. doi: 10.1161/ATVBAHA.109.196725. Cardiaovascular pathologies Epub 2009 Nov 5. Fibulin-2 has been detected in the endocardial Chattopadhyay I, Singh A, Phukan R, Purkayastha J, cushion tissue, endocardium and the basement Kataki A, Mahanta J, Saxena S, Kapur S.. Genome-wide membrane zones and adventitia of blood vessels of analysis of chromosomal alterations in patients with esophageal squamous cell carcinoma exposed to tobacco developing human and mouse embryo (Zhang et al., and betel quid from high-risk area in India. Mutat Res. 1995; Miosge et al., 1996). Fibulin-2 is also up- 2010 Feb;696(2):130-8. doi: regulated in transformed cells that migrate into the 10.1016/j.mrgentox.2010.01.001. Epub 2010 Jan 18. extracellular matrix of cardiac valves and aortic Ducros E, Berthaut A, Mirshahi P, Lemarchand S, Soria J, arch vessels and authors suggest that fibulin-2 is Legeais JM, Mirshahi M.. Expression of extracellular matrix also required for the correct formation of coronary proteins fibulin-1 and fibulin-2 by human corneal arteries and veins in postnatal life (Tsuda et al., fibroblasts. Curr Eye Res. 2007 Jun;32(6):481-90. 2001). However, although mice lacking fibulin-2 do Eyster KM, Appt S, Chalpe A, Mark-Kappeler CJ, Register not show any obvious phenotypic anomalies (Sicot TC, Clarkson TB.. Effects of estradiol on transcriptional profiles in atherosclerotic iliac arteries in ovariectomized et al., 2008), loss of fibulin-2 significantly cynomolgus macaques. Menopause. 2014 Feb;21(2):143- improved the survival rate after experimental 52. doi: 10.1097/GME.0b013e31829367c0. myocardial infarction through attenuating Fassler R, Sasaki T, Timpl R, Chu ML, Werner S.. progressive ventricular dysfunction accompanied Differential regulation of fibulin, tenascin-C, and nidogen by reduced activation of the TGFβ-dependent expression during wound healing of normal and pathway (Tsuda et al., 2012). The modulation of glucocorticoid-treated mice. Exp Cell Res. 1996 Jan this signalling pathway by fibulin-2 in heart 10;222(1):111-6. homeostasis has also been described in an Fontanil T, Rua S, Llamazares M, Moncada-Pazos A, angiotensin II-induced heart hypertrophy model Quiros PM, Garcia-Suarez O, Vega JA, Sasaki T, (Zhang et al., 2014). In both cases, fibulin-2 Mohamedi Y, Esteban MM, Obaya AJ, Cal S.. Interaction between the ADAMTS-12 metalloprotease and fibulin-2 deficiency results in a better outcome of the induces tumor-suppressive effects in breast cancer cells. pathologies. Oncotarget. 2014 Mar 15;5(5):1253-64. Fibulin-2 is required, in cooperation with fibulin-5, Grassel S, Sicot FX, Gotta S, Chu ML.. Mouse fibulin-2 in the maintenance of vessel integrity as well as in gene. Complete exon-intron organization and promoter vessel recovery after injury (Chapman et al., 2010). characterization. Eur J Biochem. 1999 Jul;263(2):471-7. In this regard, participation of fibulin-2 in artery Gu YC, Talts JF, Gullberg D, Timpl R, Ekblom M.. integrity and stiffnes is also important in order to Glucocorticoids down-regulate the extracellular matrix

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proteins fibronectin, fibulin-1 and fibulin-2 in bone marrow C.. New and paradoxical roles of matrix metalloproteinases stroma. Eur J Haematol. 2001 Sep;67(3):176-84. in the tumor microenvironment. Front Pharmacol. 2012 Jul 17;3:140. doi: 10.3389/fphar.2012.00140. eCollection Hill VK, Hesson LB, Dansranjavin T, Dallol A, Bieche I, 2012. Vacher S, Tommasi S, Dobbins T, Gentle D, Euhus D, Lewis C, Dammann R, Ward RL, Minna J, Maher ER, Obaya AJ, Rua S, Moncada-Pazos A, Cal S.. The dual role Pfeifer GP, Latif F.. Identification of 5 novel genes of fibulins in tumorigenesis. Cancer Lett. 2012 Dec methylated in breast and other epithelial cancers. Mol 28;325(2):132-8. doi: 10.1016/j.canlet.2012.06.019. Epub Cancer. 2010 Mar 5;9:51. doi: 10.1186/1476-4598-9-51. 2012 Jul 7. Hopf M, Gohring W, Mann K, Timpl R.. Mapping of binding Okada H, Nakajima T, Yoshimura T, Yasuda K, Kanzaki sites for nidogens, fibulin-2, fibronectin and heparin to H.. Microarray analysis of genes controlled by different IG modules of perlecan. J Mol Biol. 2001 Aug progesterone in human endometrial stromal cells in vitro. 17;311(3):529-41. Gynecol Endocrinol. 2003 Aug;17(4):271-80. Hunzelmann N, Nischt R, Brenneisen P, Eickert A, Krieg Olijnyk D, Ibrahim AM, Ferrier RK, Tsuda T, Chu ML, T.. Increased deposition of fibulin-2 in solar elastosis and Gusterson BA, Stein T, Morris JS.. Fibulin-2 is involved in its colocalization with elastic fibres. Br J Dermatol. 2001 early extracellular matrix development of the outgrowing Aug;145(2):217-22. mouse mammary epithelium. Cell Mol Life Sci. 2014 Oct;71(19):3811-28. doi: 10.1007/s00018-014-1577-4. Kielty CM, Sherratt MJ, Shuttleworth CA.. Elastic fibres. J Epub 2014 Feb 13. Cell Sci. 2002 Jul 15;115(Pt 14):2817-28. (REVIEW) Olin AI, Morgelin M, Sasaki T, Timpl R, Heinegard D, Kobayashi N, Kostka G, Garbe JH, Keene DR, Bachinger Aspberg A.. The proteoglycans aggrecan and Versican HP, Hanisch FG, Markova D, Tsuda T, Timpl R, Chu ML, form networks with fibulin-2 through their lectin domain Sasaki T.. A comparative analysis of the fibulin protein binding. J Biol Chem. 2001 Jan 12;276(2):1253-61. family. Biochemical characterization, binding interactions, and tissue localization. J Biol Chem. 2007 Apr Pan TC, Sasaki T, Zhang RZ, Fassler R, Timpl R, Chu 20;282(16):11805-16. Epub 2007 Feb 26. ML.. Structure and expression of fibulin-2, a novel extracellular matrix protein with multiple EGF-like repeats Kusubata M, Hirota A, Ebihara T, Kuwaba K, Matsubara Y, and consensus motifs for calcium binding. J Cell Biol. 1993 Sasaki T, Kusakabe M, Tsukada T, Irie S, Koyama Y.. Dec;123(5):1269-77. Spatiotemporal changes of fibronectin, tenascin-C, fibulin- 1, and fibulin-2 in the skin during the development of Ramaswamy S, Ross KN, Lander ES, Golub TR.. A chronic contact dermatitis. J Invest Dermatol. 1999 molecular signature of metastasis in primary solid tumors. Dec;113(6):906-12. Nat Genet. 2003 Jan;33(1):49-54. Epub 2002 Dec 9. Law EW, Cheung AK, Kashuba VI, Pavlova TV, Reinhardt DP, Sasaki T, Dzamba BJ, Keene DR, Chu ML, Zabarovsky ER, Lung HL, Cheng Y, Chua D, Lai-Wan Gohring W, Timpl R, Sakai LY.. Fibrillin-1 and fibulin-2 Kwong D, Tsao SW, Sasaki T, Stanbridge EJ, Lung ML.. interact and are colocalized in some tissues. J Biol Chem. Anti-angiogenic and tumor-suppressive roles of candidate 1996 Aug 9;271(32):19489-96. tumor-suppressor gene, Fibulin-2, in nasopharyngeal carcinoma. Oncogene. 2012 Feb 9;31(6):728-38. doi: Roark EF, Keene DR, Haudenschild CC, Godyna S, Little 10.1038/onc.2011.272. Epub 2011 Jul 11. CD, Argraves WS.. The association of human fibulin-1 with elastic fibers: an immunohistological, ultrastructural, and Lemaire R, Korn JH, Schiemann WP, Lafyatis R.. Fibulin-2 RNA study. J Histochem Cytochem. 1995 Apr;43(4):401- and fibulin-5 alterations in tsk mice associated with 11. disorganized hypodermal elastic fibers and skin tethering. J Invest Dermatol. 2004 Dec;123(6):1063-9. Sasaki T, Gohring W, Miosge N, Abrams WR, Rosenbloom J, Timpl R.. Tropoelastin binding to fibulins, nidogen-2 and Longmate WM, Monichan R, Chu ML, Tsuda T, Mahoney other extracellular matrix proteins. FEBS Lett. 1999 Oct MG, DiPersio CM.. Reduced fibulin-2 contributes to loss of 29;460(2):280-4. basement membrane integrity and skin blistering in mice lacking integrin α3β1 in the epidermis. J Invest Dermatol. Sasaki T, Mann K, Wiedemann H, Gohring W, Lustig A, 2014 Jun;134(6):1609-17. doi: 10.1038/jid.2014.10. Epub Engel J, Chu ML, Timpl R.. Dimer model for the 2014 Jan 3. microfibrillar protein fibulin-2 and identification of the connecting disulfide bridge. EMBO J. 1997 Jun Miosge N, Gotz W, Sasaki T, Chu ML, Timpl R, Herken R.. 2;16(11):3035-43. The extracellular matrix proteins fibulin-1 and fibulin-2 in the early human embryo. Histochem J. 1996 Schliekelman MJ, Gibbons DL, Faca VM, Creighton CJ, Feb;28(2):109-16. Rizvi ZH, Zhang Q, Wong CH, Wang H, Ungewiss C, Ahn YH, Shin DH, Kurie JM, Hanash SM.. Targets of the tumor Missan DS, Chittur SV, DiPersio CM.. Regulation of fibulin- suppressor miR-200 in regulation of the epithelial- 2 gene expression by integrin α3β1 contributes to the mesenchymal transition in cancer. Cancer Res. 2011 Dec invasive phenotype of transformed keratinocytes. J Invest 15;71(24):7670-82. doi: 10.1158/0008-5472.CAN-11-0964. Dermatol. 2014 Sep;134(9):2418-27. doi: Epub 2011 Oct 10. 10.1038/jid.2014.166. Epub 2014 Apr 2. Senapati S, Gnanapragassam VS, Moniaux N, Momi N, Ng KM, Catalano MG, Pinos T, Selva DM, Avvakumov GV, Batra SK.. Role of MUC4-NIDO domain in the MUC4- Munell F, Hammond GL.. Evidence that fibulin family mediated metastasis of pancreatic cancer cells. members contribute to the steroid-dependent Oncogene. 2012 Jul 12;31(28):3346-56. doi: extravascular sequestration of sex hormone-binding 10.1038/onc.2011.505. Epub 2011 Nov 21. globulin. J Biol Chem. 2006 Jun 9;281(23):15853-61. Epub 2006 Apr 6. Sicot FX, Tsuda T, Markova D, Klement JF, Arita M, Zhang RZ, Pan TC, et al. Fibulin-2 is dispensable for mouse Noel A, Gutierrez-Fernandez A, Sounni NE, Behrendt N, development and elastic fiber formation. Mol Cell Biol. Maquoi E, Lund IK, Cal S, Hoyer-Hansen G, Lopez-Otin 2008 Feb;28(3):1061-7. Epub 2007 Dec 10.

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Talts JF, Weller A, Timpl R, Ekblom M, Ekblom P.. Jul;28(7):1026-38. doi: 10.1210/me.2014-1058. Epub 2014 Regulation of mesenchymal extracellular matrix protein Jun 3. synthesis by transforming growth factor-beta and glucocorticoids in tumor stroma. J Cell Sci. 1995 Jun;108 ( Yi CH, Smith DJ, West WW, Hollingsworth MA.. Loss of Pt 6):2153-62. fibulin-2 expression is associated with breast cancer progression. Am J Pathol. 2007 May;170(5):1535-45. Timpl R, Sasaki T, Kostka G, Chu ML.. Fibulins: a versatile family of extracellular matrix proteins. Nat Rev Mol Cell Zhang H, Wu J, Dong H, Khan SA, Chu ML, Tsuda T.. Biol. 2003 Jun;4(6):479-89. (REVIEW) Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth Tsuda T, Wang H, Timpl R, Chu ML.. Fibulin-2 expression factor-β signalling. Clin Sci (Lond). 2014 Feb;126(4):275- marks transformed mesenchymal cells in developing 88. doi: 10.1042/CS20120636. cardiac valves, aortic arch vessels, and coronary vessels. Dev Dyn. 2001 Sep;222(1):89-100. Zhang HY, Chu ML, Pan TC, Sasaki T, Timpl R, Ekblom P.. Extracellular matrix protein fibulin-2 is expressed in the Tsuda T, Wu J, Gao E, Joyce J, Markova D, Dong H, Liu embryonic endocardial cushion tissue and is a prominent Y, Zhang H, Zou Y, Gao F, Miller T, Koch W, Ma X, Chu component of valves in adult heart. Dev Biol. 1995 ML.. Loss of fibulin-2 protects against progressive Jan;167(1):18-26. ventricular dysfunction after myocardial infarction. J Mol Cell Cardiol. 2012 Jan;52(1):273-82. doi: Zhang HY, Timpl R, Sasaki T, Chu ML, Ekblom P.. Fibulin- 10.1016/j.yjmcc.2011.11.001. Epub 2011 Nov 9. 1 and fibulin-2 expression during organogenesis in the developing mouse embryo. Dev Dyn. 1996 Vallve JC, Serra N, Zalba G, Fortuno A, Beloqui O, Ferre Mar;205(3):348-64. R, Ribalta J, Masana L.. Two variants in the fibulin2 gene are associated with lower systolic blood pressure and Zhang RZ, Pan TC, Zhang ZY, Mattei MG, Timpl R, Chu decreased risk of hypertension. PLoS One. ML.. Fibulin-2 (FBLN2): human cDNA sequence, mRNA 2012;7(8):e43051. doi: 10.1371/journal.pone.0043051. expression, and mapping of the gene on human and Epub 2012 Aug 13. mouse chromosomes. Genomics. 1994 Jul 15;22(2):425- 30. Whiteaker JR, Zhang H, Zhao L, Wang P, Kelly-Spratt KS, Ivey RG, Piening BD, Feng LC, Kasarda E, Gurley KE, de Vega S, Iwamoto T, Yamada Y.. Fibulins: multiple roles Eng JK, Chodosh LA, Kemp CJ, McIntosh MW, Paulovich in matrix structures and tissue functions. Cell Mol Life Sci. AG.. Integrated pipeline for mass spectrometry-based 2009 Jun;66(11-12):1890-902. doi: 10.1007/s00018-009- discovery and confirmation of biomarkers demonstrated in 8632-6. (REVIEW) a mouse model of breast cancer. J Proteome Res. 2007 Oct;6(10):3962-75. Epub 2007 Aug 21. This article should be referenced as such: Wu TS, Hammond GL.. Naturally occurring mutants inform Cal S, Obaya AJ. FBLN2 (fibulin 2). Atlas Genet Cytogenet SHBG structure and function. Mol Endocrinol. 2014 Oncol Haematol. 2015; 19(10):605-610.

Atlas Genet Cytogenet Oncol Haematol. 2015; 19(10) 610 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Review

MCM3 (minichromosome maintenance complex component 3) Kaifee Arman, Esra Bozgeyik, Yusuf Ziya Igci University of Gaziantep, Faculty of Medicine, Department of Medical Biology, Gaziantep, Turkey

Published in Atlas Database: October 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/MCM3ID41319ch6p12.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62479/10-2014-MCM3ID41319ch6p12.pdf DOI: 10.4267/2042/62479 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

carcinoma (PTC) (Igci et al., 2014). The expression Abstract level of MCM3 is also increased in cell lines overexpressing E2F, suggesting that MCM3 is also Review on MCM3, with data on DNA/RNA, on the target of E2F (Leone et al., 1998; Bruemmer et al., protein encoded and where the gene is implicated. 2003). Identity Pseudogene There is no known pseudogene for MCM3. Other names: HCC5, P1-MCM3, P1.h, RLFB HGNC (Hugo): MCM3 Protein Location: 6p12.2 Description DNA/RNA The protein encoded by MCM3 gene is known to be a well conserved mini-chromosome maintenance Description protein (MCM) which is needed for triggering the The human MCM3 gene is located on the minus eukaryotic genome replication. strand and spans 20868 bps of genomic region It acts as DNA replication licensing factor. (52264014-52284881). This gene has 7 transcripts The well known other synonym for this protein is (splice variants). It has 853 amino acids and its size DNA polymerase alpha holoenzyme-associated is about 91 kDa. It contains a nuclear localization protein P1 due to its indispensable role in DNA signal and possess an ATPase/helicase region at the replication and cell proliferation and also centre. It has a total of 17 exons and extends a bit participates in the control of genome duplication more than 20 KB of genomic DNA. (Hofmann et during cell cycle. The MCM3 protein is composed al., 2000) (Fig. 1). of 808 amino acid residues, having molecular mass of approximately 91 kDa and a basal isoelectric Transcription point of 5.53.The MCM3 protein is subunit of the There are two transcript variants encoding different protein complex (MCM 2-7) i.e the isoforms known for MCM3. These are transcript minichromosome maintenance (MCM) complex. It variant 1 (accession number NM_002388.4) and contains active ATPase sites which supplement to transcript variant 2 (NM_001270472.1). The the helicase activity needed during DNA transcript variant 2 lacks an alternate exon replication. MCM3 protein contains 8 nucleotide compared to transcript variant 1. MCM3 gene has length region that binds nucleotide phosphates. been observed to be expressed highly in different (Fig. 2). cancer cell lines as compared to normal tissues (Ha MCM3AP (Minichromosome Maintenance-3 et al., 2004). Higher mRNA expression of MCM3 Associated Protein) interacts and acetylates MCM3 was also shown to be linked with papillary thyroid protein inhibiting cell cycle progression.

Atlas Genet Cytogenet Oncol Haematol. 2015; 19(10) 611 MCM3 (minichromosome maintenance complex component Arman K, et al. 3)

Figure 1. MCM3 gene location, the representation of two major splice variants, and the depiction of major motifs.

There is an interaction between MCM3 and "arginine finger". Infact all other MCMs also MCM3AP which is required for nuclear contain these sequences. localization and chromatin binding of MCM3AP The MCM3 also possesses a zinc finger residing (Takei et al., 2002). The acetylase activity of prior to the MCM box that somewhat matches a MCM3AP is known to inhibit only initiation of classic zinc finger region, but has been stated that DNA replication and does not inhibit its elongation the residues are capable of chelating zinc (Fletcher (Takei et al., 2002). MCM3 are known to have et al., 2003). distinguishable nuclear localization sequences Biochemical analysis also revealed that the zinc (NLS), indicating that these MCMs help in motif aids in formation of complex assembly as providing nuclear targeting to different other well as ATPase activity (Poplawski et al., 2001; members of the MCM family (Kimura et al., 1996; Fletcher et al., 2003). Members of the AAA+ Forsburg, 2004). ATPases are well known to function as molecular Like other MCM proteins, MCM3 is a member of chaperons. The AAA+ proteins possess several the AAA+ class of ATPases. It contains binding distinct characteristics. The formation of active site for ATP, Walker A motif, Walker B motif and ATPase sites in the MCM2-7 ring takes place via arginine motif. AAA+ ATPases usually form ATP- interacting surfaces of two adjacent subunits. This dependent complexes usually heterohexamers. The interaction occurs in such a way that the conserved structure of MCM3 includes the MCM box arginine finger motif resides in trans relative to the spanning about 200 residues. This peculiar MCM Walker A box (ATP-binding site) of the of the box has two ATPase consensus domains or motifs. adjacent subunit. One of them is the Walker A domain which includes the active site with P-loop. In Walker A Expression consensus, glycine is replaced by alanine or serine Despite an increase in transcription for some MCM along with many other conserved residues, genes during the G1/S phase in dividing cells, eventually forming the MCM-specific region MCM3 protein levels remain constant during the GDPxx(S/A)KS (Forsburg, 2004). Other is the cell cycle (Forsburg et al., 1997; Diffley and Labib, classic Walker B which is hydrophobic in nature 2002). MCM3 protein is found to have nuclear that is primarily responsible for the hydrolysis of expression in all in proliferating cells. There is high ATP rather than binding. Like all the MCM expression of MCM3 proteins in trophoblastic cells proteins, the Walker B motif of MCM3 possess the of placenta, hematopoietic cells of bone marrow. conserved sequence IDEFDKM that distinguishes But it has not been detected in decidual cells of the MCM family. There is also presence of a short placenta, brain, liver, kidney, ovary, spleen, lung, motif, SRFD that is present about 70 residues skeletal muscles, smooth muscles and heart following the Walker B element, constitutes an muscles.

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Figure 2. MCM3 protein sequence showing AAA region (blue coloured), ATP binding site (blue colour underlined), Walker A motif (highlighted with yellow color), Walker B motif (highlighted with grey color), SRFD arginine finger motif (red).

This DNA replication licensing factor is also the peripheral subunits of the complex that is expressed at lower intensity in many other cell known to negatively regulate the active MCM core types, including squamous epithelial cells of subunits (MCM4, MCM6 and MCM7). It is known oesophagus, glandular cells of appendix and breast, to interact directly with MCM5/CDC46. The well urothelial cells of the urinary bladder, respiratory known MCM3 acetylating protein, MCM3AP (a epithelial cells of nasopharynx. chromatin-associated acetyltransferase) binds and Localisation acetylates MCM3 further inhibiting the initiation of DNA replication including cell cycle progression. The MCM3 protein is localized to the nucleus. It has been shown that there is a functional Function interaction between two important moieties i.e the glucocorticoid receptor and GANP (germinal MCM3 protein is extremely conserved mini- center-associated protein)/MCM3AP. GANP and chromosome maintenance proteins (MCM) in MCM3AP are known to bind to the MCM3 protein eukaryotes and is ubiquitously expressed. MCM3 is which is involved in triggering of DNA replication one of the members of MCM family with (Osman et al., 2006). It is shown that cyclin E/Cdk2 chromatin-binding proteins. MCM3 by acting as an phosphorylates MCM3 at a particular site i.e indispensable factor permits a single round of Thr722, regulating the loading of MCM3 onto replication of DNA per cell cycle. It is responsible chromatin and thus controls S phase checkpoint (Li for the initiation of eukaryotic genome replication et al., 2011). Mcm3, Mcm2 and Mcm4 show cell and cell proliferation and monitors the cell cycle cycle specific phosphorylation that relates to control of genome duplication. MCM3 gene chromatin binding. They are shown to be encodes P1 protein which has a role in the DNA hypophosphorylated and chromatin-bound in G1 replication process. which eventually gets phosphorylated by Cdk MCM3 protein is part of the protein complex activity at G1/S and later in the cell cycle (Fujita et consisting of MCM2-7. It participates in the al., 1998). Phosphorylation of Mcm proteins is also formation of the heterohexameric MCM complex, needed for pre-RC assembly and activation which which is loaded onto the chromatin at sites of DNA is dependent on Cdk activity and Cdc7-Dbf4 kinase replication, leading to the formation of pre- is also required (Sato et al., 1997; Weinreich and replication complex (pre-RC). The proteins that Stillman, 1999; Masai et al., 2000). In summary, compose the MCM complex also serve as DNA the molecular function of MCM3 includes DNA helicases that unwind the DNA double helix at the helicase activity, DNA binding, protein binding and replication forks apart from the initiation of ATP binding while the biological processes of replication. Furthermore, MCM3 actively MCM3 includes DNA replication initiation, DNA participates in cell cycle regulation. The MCM3 is strand elongation, mitotic cell cycle, DNA responsible for genome stability, as it limits the replication, DNA duplex unwinding, G1/S replication to only once per cell cycle. transition during mitotic cell cycle. MCMs have a direct role in transcription. There are several evidences suggesting that the MCM Homology proteins do associate with specific transcription The gene encoding the human P1 protein (MCM3) factors. Mcm3-Mcm5 complex forms a heterodimer has 60% homology to the yeast MCM3 associating with STAT1a (a transcription factor) (minichromosome maintenance deficiency) during biochemical purification (Zhang et al., 1998; replication control gene of S. cerevisiae (Thommes DaFonseca et al., 2001). Infact MCM5 mediates et al., 1992). In another study it has been observed this association. MCM3, MCM2 and MCM5 form that MCM3 shares three central regions of high

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sequence similarity i.e about 75% as well as highly immunohistochemical analysis and Western blot hydrophilic carboxy-terminal region with the analysis (Lee et al., 2010). A comparative study of Mcm3 replication protein of the yeast (Schulte et MCM3 protein expression levels was also done in al., 1995). MCM3 is also homologous to other follicular variant of papillary thyroid carcinoma MCM complex components (MCM2, MCM5, (FVPTC), classic variant of papillary thyroid MCM6, MCM7) and can form several kind of carcinoma (CVPTC), and multi-nodular goitre heteromeric complexes. Mutants defective in (MNG) tissues. MCM3 protein expression was MCM2 or MCM3 are extremely similar in higher in FVPTC and CVPTC as compared to phenotype. They both possess an autonomously MNG (Igci et al., 2011; Igci et al., 2014). This replicating sequence (ARS)-specific shows that MCM3 might be used as a suitable minichromosome maintenance defect, however marker in order to distinguish FVPTC and CVPTC their ARS specificities are not identical. MCM3 from MNG. resembles MCM2 as they both contain NLS (Nuclear localization sequences) and are involved Brain malignancies in translocating the complex from the cytoplasm to MCM3 shows a restricted immune response by the nucleus (Gozuacik et al., 2003). cancer in patients with brain malignancies. It is a strong predictor of survival in patients with Mutations anaplastic astrocytoma (Soling et al., 2005). MCM3 has been shown to have higher expression in human A nuclear localization signal of human MCM3 has astrocytic tumors and highlights a cancer-restricted been clarified and being established that humoral immune response in patients with brain mutagenesis on the nuclear localization signal of tumors and brain metastases but not in healthy MCM3 affects the binding of newly isolated controls. MCM3 expression in diffuse astrocytoma MCM3-assosiated protein, Map80 (Takei and is found to be significantly associated with age, Tsujimoto, 1998). In Saccharomyces cerevisiae, histologic grade, time to recurrence (Soling et al., two mutant alleles i.e mcm3-1 and mcm3-10 that 2005). are defective at different steps of the replication initiation process have been characterized (Lei et Endometrial carcinogenesis al., 2002). Both Mcm3-10 and Mcm3-1 have The expression of MCM3 in endometrial defectiveness with regard to the recruitment of the carcinomas was shown to be significantly lower MCM2-7 complex to replication origins. Mcm3-10 than the normal proliferative endometrium. The affects a step before, and Mcm3-1 affects a step expression of MCM3 also differs according to the after the recruitment of the MCM2-7 complex to phases. It is significantly higher in the proliferative replication origins. Mcm3-1 has a G246E mutation phase than in the secretory phase. The above that lessens the efficiency of replication initiation observations show that the expression of MCM3 (Yan et al., 1993). reflects cell proliferation in normal and hyperplastic endometria (Kato et al., 2003). The replication- Implicated in licensing system may be aberrant in endometrial Uterine cervical cancer carcinomas as there is an inconsistency between the expression of MCMs and cell proliferation in It has been shown that MCM3 is ubiquitously endometrial carcinomas. expressed in cancer cells by immunohistochemical studies of surgical materials from human uterine. Salivary gland tumors Moreover, cancerous cells has higher MCM3 MCM3 was significantly higher in mucoepidermoid expression than in normal proliferating cells of the carcinomas (MEC) and adenoid cystic carcinomas uterine cervix and dysplastic cells, making it a (ADCC) with respect to pleomorphic adenomas useful marker to differentiate these cells (Ishimi et (PA). A high sensitivity and specificity for MCM3 al., 2003). These results indicate that the malignant was obtained to differentiate benign and malignant transformation of cells is directly related to the tumors (Ashkavandi et al., 2013). higher expression of MCM3 protein. Other malignancies Papillary thyroid carcinoma Minichromosome maintenance 3 (MCM3) gene Papillary thyroid carcinoma (PTC) is known to be was highly expressed in a lot of human cancers, like the most common histological type among the other lymphoma, leukemia, carcinomas of the uterine types which accounts for up to 80 % of the total cervix, stomach, breast, kidney and lung, malignant thyroid cancer cases (Fagin and Mitsiades, 2008). It melanoma as well as benign and malignant has been shown that the MCM3 protein expression melanocytic skin lesions (Ha et al., 2004; levels were overexpressed in papillary thyroid as Gambichler et al., 2009). MCM3 protein was also compared to normal thyroid tissues through found to be upraised in several human cancer

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tissues analysed by western blot and LF. Genomic structure of the gene for the human P1 immunohistochemical analyses (Ha et al., 2004). protein (MCM3) and its exclusion as a candidate for autosomal recessive polycystic kidney disease. Eur J Hum To be noted Genet. 2000 Mar;8(3):163-6 Igci YZ, Arslan A, Akarsu E, Erkilic S, Igci M, Oztuzcu S, Acknowledgments: Kaifee Arman is recipient of Cengiz B, Gogebakan B, Cakmak EA, Demiryurek AT. Differential expression of a set of genes in follicular and Graduate Scholarship from TUBITAK under the classic variants of papillary thyroid carcinoma. Endocr program 2215-Graduate Scholarship Program for Pathol. 2011 Jun;22(2):86-96 International Students. Igci YZ, Erkilic S, Igci M, Arslan A. MCM3 protein expression in follicular and classical variants of papillary References thyroid carcinoma. Pathol Oncol Res. 2014 Jan;20(1):87- 91 Ashkavandi ZJ, Najvani AD, Tadbir AA, Pardis S, Ranjbar MA, Ashraf MJ. MCM3 as a novel diagnostic marker in Ishimi Y, Okayasu I, Kato C, Kwon HJ, Kimura H, Yamada benign and malignant salivary gland tumors. Asian Pac J K, Song SY. Enhanced expression of Mcm proteins in Cancer Prev. 2013;14(6):3479-82 cancer cells derived from uterine cervix. Eur J Biochem. 2003 Mar;270(6):1089-101 Bruemmer D, Yin F, Liu J, Kiyono T, Fleck E, Van Herle AJ, Law RE. Rapamycin inhibits E2F-dependent Kato K, Toki T, Shimizu M, Shiozawa T, Fujii S, Nikaido T, expression of minichromosome maintenance proteins in Konishi I. Expression of replication-licensing factors MCM2 vascular smooth muscle cells. Biochem Biophys Res and MCM3 in normal, hyperplastic, and carcinomatous Commun. 2003 Mar 28;303(1):251-8 endometrium: correlation with expression of Ki-67 and estrogen and progesterone receptors. Int J Gynecol DaFonseca CJ, Shu F, Zhang JJ. Identification of two Pathol. 2003 Oct;22(4):334-40 residues in MCM5 critical for the assembly of MCM complexes and Stat1-mediated transcription activation in Kimura H, Ohtomo T, Yamaguchi M, Ishii A, Sugimoto K. response to IFN-gamma. Proc Natl Acad Sci U S A. 2001 Mouse MCM proteins: complex formation and Mar 13;98(6):3034-9 transportation to the nucleus. Genes Cells. 1996 Nov;1(11):977-93 Diffley JF, Labib K. The chromosome replication cycle. J Cell Sci. 2002 Mar 1;115(Pt 5):869-72 Lee YS, Ha SA, Kim HJ, Shin SM, Kim HK, Kim S, Kang CS, Lee KY, Hong OK, Lee SH, Kwon HS, Cha BY, Kim Fagin JA, Mitsiades N. Molecular pathology of thyroid JW. Minichromosome maintenance protein 3 is a cancer: diagnostic and clinical implications. Best Pract Res candidate proliferation marker in papillary thyroid Clin Endocrinol Metab. 2008 Dec;22(6):955-69 carcinoma. Exp Mol Pathol. 2010 Feb;88(1):138-42 Fletcher RJ, Bishop BE, Leon RP, Sclafani RA, Ogata CM, Lei M, Cheng IH, Roberts LA, McAlear MA, Tye BK. Two Chen XS. The structure and function of MCM from mcm3 mutations affect different steps in the initiation of archaeal M. Thermoautotrophicum. Nat Struct Biol. 2003 DNA replication. J Biol Chem. 2002 Aug Mar;10(3):160-7 23;277(34):30824-31 Forsburg SL, Sherman DA, Ottilie S, Yasuda JR, Hodson Leone G, DeGregori J, Yan Z, Jakoi L, Ishida S, Williams JA. Mutational analysis of Cdc19p, a RS, Nevins JR. E2F3 activity is regulated during the cell Schizosaccharomyces pombe MCM protein. Genetics. cycle and is required for the induction of S phase. Genes 1997 Nov;147(3):1025-41 Dev. 1998 Jul 15;12(14):2120-30 Forsburg SL. Eukaryotic MCM proteins: beyond replication Li J, Deng M, Wei Q, Liu T, Tong X, Ye X. Phosphorylation initiation. Microbiol Mol Biol Rev. 2004 Mar;68(1):109-31 of MCM3 protein by cyclin E/cyclin-dependent kinase 2 (Cdk2) regulates its function in cell cycle. J Biol Chem. Fujita M, Yamada C, Tsurumi T, Hanaoka F, Matsuzawa 2011 Nov 18;286(46):39776-85 K, Inagaki M. Cell cycle- and chromatin binding state- dependent phosphorylation of human MCM Masai H, Matsui E, You Z, Ishimi Y, Tamai K, Arai K. heterohexameric complexes. A role for cdc2 kinase. J Biol Human Cdc7-related kinase complex. In vitro Chem. 1998 Jul 3;273(27):17095-101 phosphorylation of MCM by concerted actions of Cdks and Cdc7 and that of a criticial threonine residue of Cdc7 bY Gambichler T, Shtern M, Rotterdam S, Bechara FG, Cdks. J Biol Chem. 2000 Sep 15;275(37):29042-52 Stücker M, Altmeyer P, Kreuter A. Minichromosome maintenance proteins are useful adjuncts to differentiate Osman W, Laine S, Zilliacus J. Functional interaction between benign and malignant melanocytic skin lesions. J between the glucocorticoid receptor and GANP/MCM3AP. Am Acad Dermatol. 2009 May;60(5):808-13 Biochem Biophys Res Commun. 2006 Oct 6;348(4):1239- 44 Gozuacik D, Chami M, Lagorce D, Faivre J, Murakami Y, Poch O, Biermann E, Knippers R, Bréchot C, Paterlini- Poplawski A, Grabowski B, Long SE, Kelman Z. The zinc Bréchot P. Identification and functional characterization of finger domain of the archaeal minichromosome a new member of the human Mcm protein family: hMcm8. maintenance protein is required for helicase activity. J Biol Nucleic Acids Res. 2003 Jan 15;31(2):570-9 Chem. 2001 Dec 28;276(52):49371-7 Ha SA, Shin SM, Namkoong H, Lee H, Cho GW, Hur SY, Sato N, Arai K, Masai H. Human and Xenopus cDNAs Kim TE, Kim JW. Cancer-associated expression of encoding budding yeast Cdc7-related kinases: in vitro minichromosome maintenance 3 gene in several human phosphorylation of MCM subunits by a putative human cancers and its involvement in tumorigenesis. Clin Cancer homologue of Cdc7. EMBO J. 1997 Jul 16;16(14):4340-51 Res. 2004 Dec 15;10(24):8386-95 Schulte D, Burkhart R, Musahl C, Hu B, Schlatterer C, Hofmann Y, Becker J, Wright F, Avner ED, Mrug M, Guay- Hameister H, Knippers R. Expression, phosphorylation and Woodford LM, Somlo S, Zerres K, Germino GG, Onuchic nuclear localization of the human P1 protein, a homologue

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of the yeast Mcm 3 replication protein. J Cell Sci. 1995 11;20(5):1069-74 Apr;108 ( Pt 4):1381-9 Weinreich M, Stillman B. Cdc7p-Dbf4p kinase binds to Söling A, Sackewitz M, Volkmar M, Schaarschmidt D, chromatin during S phase and is regulated by both the Jacob R, Holzhausen HJ, Rainov NG. Minichromosome APC and the RAD53 checkpoint pathway. EMBO J. 1999 maintenance protein 3 elicits a cancer-restricted immune Oct 1;18(19):5334-46 response in patients with brain malignancies and is a strong independent predictor of survival in patients with Yan H, Merchant AM, Tye BK. Cell cycle-regulated nuclear anaplastic astrocytoma. Clin Cancer Res. 2005 Jan localization of MCM2 and MCM3, which are required for 1;11(1):249-58 the initiation of DNA synthesis at chromosomal replication origins in yeast. Genes Dev. 1993 Nov;7(11):2149-60 Takei Y, Assenberg M, Tsujimoto G, Laskey R. The MCM3 acetylase MCM3AP inhibits initiation, but not elongation, of Zhang JJ, Zhao Y, Chait BT, Lathem WW, Ritzi M, DNA replication via interaction with MCM3. J Biol Chem. Knippers R, Darnell JE Jr. Ser727-dependent recruitment 2002 Nov 8;277(45):43121-5 of MCM5 by Stat1alpha in IFN-gamma-induced transcriptional activation. EMBO J. 1998 Dec Takei Y, Tsujimoto G. Identification of a novel MCM3- 1;17(23):6963-71 associated protein that facilitates MCM3 nuclear localization. J Biol Chem. 1998 Aug 28;273(35):22177-80 This article should be referenced as such: Thömmes P, Fett R, Schray B, Burkhart R, Barnes M, Arman K, Bozgeyik E, Igci YZ. MCM3 (minichromosome Kennedy C, Brown NC, Knippers R. Properties of the maintenance complex component 3). Atlas Genet nuclear P1 protein, a mammalian homologue of the yeast Cytogenet Oncol Haematol. 2015; 19(10):611-616. Mcm3 replication protein. Nucleic Acids Res. 1992 Mar

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NTSR1 (neurotensin receptor 1 (high affinity)) Sofiane Saada, Pierre Marget, Amazigh Abacci, Anne-Laure Fauchais, Marie-Odile Jauberteau, Daniel Petit, Fabrice Lalloue Universite de Limoges, Equipe Accueil 3842 Homeostasie Cellulaire et Pathologies Limoges France (SS, PM, AA, ALF, MOJ, FL); Universite de Limoges, UMR INRA 1061 Unite de Genetique Moleculaire Animale, Limoges France (DP) Published in Atlas Database: October 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/NTSR1ID44217ch20q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62480/10-2014-NTSR1ID44217ch20q13.pdf DOI: 10.4267/2042/62480

Abstract Transcription Two transcripts are identified, a 4132 bp coding for Review on NTSR1, with data on DNA/RNA, on the a protein of 418 aa. The second contains 2950 bp protein encoded and where the gene is implicated. but without yet identified coding protein. Identity Protein Other names: NTR Description HGNC (Hugo): NTSR1 NTSR1 (418 aa in human) belongs to the GPCR Location: 20q13.33 family containing 7 TM domains. Its structure Note contains 4 extracellular and intracellular loops, the Neurotensin receptor 1 is the high affinity receptor N terminal amino acid extracellular part located in for neurotensin, a 13 amino acid peptide with extra cellular region. neurotransmitter and hormone functions. Four glycosylation sites (extracellular) are reported Neurotensin binds 3 known receptors. Two of them as essential for the functions. The binding of belong to the superfamily of G-protein coupled neurotensin is depending on 6 aa of the 4th receptors (GPCR): NTSR1 the high affinity extracellular loop of the protein (Vincent et al., receptor for neurotensin and NTSR2 its low affinity 1999). receptor, both belonging to GPCR class A (Mazella et al., 1996). The third receptor is NTR3 or sortilin, Expression a member of VPS10 family (Petersen et al., 1997; In central nervous system, NTSR1 is expressed in Mazella et al., 1998). substantia nigra, ventral tegmental area, amygdal NTSR1 through neurotensin binding is implicated nucleus, striatum and entorrhinal and prefrontal in several functions, the modulation of cortices (Kanba at al., 1986; Nicot et al., 1994). dopaminergic systems, analgesia, and inhibition of In extra cerebral region, NTSR1 was detected in food uptake, hypothermia, hypotension, intestinal small intestine (Seybold et al., 1990; Mendez et al., motility and digestive secretions. 1997), fundus of stomach (Huidobro-Toro et al., 1985), pancreas (Wang et al., 2000), fetal liver DNA/RNA (Ehrenfried et al., 1994), colon (Mendez et al., 1997) uterine tissue (Rodriguez et al., 2010) and Description prostate (Swift et al., 2010). The length of NTSR1 gene is 53.93 Kb, including 4 NTSR1 expression in human cells was reported in exons and 3 introns. prostatic cells (Swift et al., 2010), colonic epithelial

Atlas Genet Cytogenet Oncol Haematol. 2015; 19(10) 617 NTSR1 (neurotensin receptor 1 (high affinity)) Saada S, et al

cells (Martin et al., 2002), lymphocytes (Evers et unknown, as genes clearly encoding neurotensin al., 1994) including T (Magazin et al., 2004) and B receptors are doubtfully present in more basal lymphocytes (Saada et al., 2012). vertebrates such as lampreys and hagfishes. Localisation Unlike its paralogue gene, NTSR1 was subject to positive selection in mammals, as numerous genes In the cell membrane: Activation of NTSR1 involved in chemosensory perception (Kosiol et al., through neurotensin binding needs some post 2008). translational events including glycosylation and palmitoylation to downstream heterotrimeric G Implicated in protein subunits effectors. This lipidation allows its localization within cell membrane microdomains Breast cancer and enhances the interaction with Gαq /11 which NTSR1 is associated with the tumor grade and is a mainly reside within structured microdomains. This candidate risk factor involved in ductal breast NTSR-1-mediated MAPK signaling and cellular cancer progression (Dupouy et al., 2009). Its proliferation was demonstrated in breast cancer functions in oncogenesis depend on EGFR, HER2 cells (Heakal et al., 2011). and HER3 expression in breast cancer cells Endocytosis: After activation by neurotensin, (Dupouy et al., 2014). NTSR1 is desensitized through its internalization in endosomal vesicles in association with β-arrestin. Lung cancer This event requires phosphorylation depending on NTSR1 is overexpressed in lung cancer (Alifano et the C terminal region of NTSR1. Intracellular al., 2010b). trafficking leads to NTSR1 degradation in Its activation enhances HER2, HER3 and EGFR lysosomes (Mazella and Vincent, 2006). expression in lung cancer (Younes et al., 2014). Function Pharmacological NTSR1 inhibitor (SR48692) inhibits EGFR activation (Moody et al., 2014). NTSR1 is activated by neurotensin binding through autocrine or paracrine mechanism. Several Malignant pleural mesothelioma signalizations were described depending on cell In malignant pleural mesothelioma, neurotensin and lines. NTSR1 are significantly overexpressed in patients Indeed, neurotensin induces Erk phosphorylation (Alifano et al., 2010a). colonic HT29 cells through PLC activation leading Head and neck squamous cell to Inositol phosphate formation (Massa et al., 2011). carcinomas The recruitment of G protein was described through NTSR1 contributed to cancer cell invasion and NTSR1 activation in microdomains (Heakal et al., migration and is highly expressed in patients with 2011). metastasis (Shimizu et al., 2008). In other cell types, cell proliferation, migration and Prostatic cancer invasion are depending on a transactivation of EGFR by NTSR1 (Amorino et al., 2007; Moody et NTSR1 is overexpressed in malignant prostatic al., 2014 ) or act through the increase of expression tumors and malignant cell lines (Swift et al., 2010). and activation of EGFR, HER2, HER3 (Younes et Pancreatic cancer al., 2014; Dupouy et al., 2014). An increase of NTSR1 expression is detected in Homology human ductal pancreatic adenocarcinoma (Reubi et al., 1998; Wang et al., 2000) as well as in PANC-1 The NTSR1 gene is conserved in Rhesus monkey, cell line (Wang et al., 2011). dog, cow, mouse, rat, chicken, zebrafish, and frog. 81 organisms have orthologs with human gene Colorectal cancer NTSR1. NTSR1 is associated with human cell proliferation Conservation during evolution: (Massa et al., 2011), promotes tumor development NTSR1 gene is retrieved in jaw vertebrates in mouse colon cancer model (Bugni et al., 2012) (Gnathostomes) from the australian ghostshark, and is overexpressed in colorectal cancer (Callorhinchus milii) to man, including most progression (Gui et al., 2008). vertebrate groups (Teleosts, Coelacanth, the NTSR1 activates miR-21 and miR-155, via Akt and Amphibian Rana catesbeiana (Hwang et al., 2009), NFkB, to down-regulate PTEN and SOCS1 and reptiles (python and lizard), birds and mammals. promote growth of tumors in mice. The duplication giving rise to NTSR1 and NTSR2 NTR1, miR-21, and miR-155 levels are increased occurred probably in early vertebrates via the in human colon tumor samples and correlate with genome doubling (R2) events but details are tumor stage (Bakirtzi et al., 2011).

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Glioblastoma receptors on human lymphocytes. Surgery. 1994 Aug;116(2):134-9; discussion 139-40 Neurotensin through NTSR1 activation is Ferraro L, Beggiato S, Borroto-Escuela DO, Ravani L, implicated in maintaining glioblastoma stem, O'Connor WT, Tomasini MC, Borelli AC, Agnati LF, depending on IL-8 and Stat3 pathways (Zhou et al., Antonelli T, Tanganelli S, Fuxe K. Neurotensin NTS1- 2014). dopamine D2 receptor-receptor interactions in putative receptor heteromers: relevance for Parkinson's disease Melanoma and schizophrenia. Curr Protein Pept Sci. 2014;15(7):681- SR48692 through NTSR1 inhibition decreases 90 melanoma cell proliferation and induces melanoma Gromova P, Rubin BP, Thys A, Erneux C, Vanderwinden cell apoptosis (Zhang et al., 2014). JM. Neurotensin receptor 1 is expressed in gastrointestinal stromal tumors but not in interstitial cells of Cajal. PLoS Neurodegenerative and psychiatric One. 2011 Feb 18;6(2):e14710 diseases Gui X, Guzman G, Dobner PR, Kadkol SS. Increased neurotensin receptor-1 expression during progression of Schizophrenia and Parkinson disease (Ferraro et al., colonic adenocarcinoma. Peptides. 2008 Sep;29(9):1609- 2014) and addiction (Ma et al., 2013). 15 Inflammation Hagihara A, Miyamoto K, Furuta J, Hiraoka N, Wakazono K, Seki S, Fukushima S, Tsao MS, Sugimura T, Ushijima NTSR1 is overexpressed in colonic epithelial cells T. Identification of 27 5' CpG islands aberrantly methylated during inflammatory bowel diseases (Castagliuolo and 13 genes silenced in human pancreatic cancers. et al., 1999; Gui et al., 2013) Oncogene. 2004 Nov 11;23(53):8705-10 Heakal Y, Woll MP, Fox T, Seaton K, Levenson R, Kester References M. Neurotensin receptor-1 inducible palmitoylation is required for efficient receptor-mediated mitogenic-signaling Alifano M, Loi M, Camilleri-Broet S, Dupouy S, Régnard within structured membrane microdomains. Cancer Biol JF, Forgez P. Neurotensin expression and outcome of Ther. 2011 Sep 1;12(5):427-35 malignant pleural mesothelioma. Biochimie. 2010 Feb;92(2):164-70 Huidobro-Toro JP, Kullak A. Excitatory neurotensin receptors on the smooth muscle of the rat fundus: possible Alifano M, Souazé F, Dupouy S, Camilleri-Broët S, Younes implications in gastric motility. Br J Pharmacol. 1985 M, Ahmed-Zaïd SM, Takahashi T, Cancellieri A, Damiani Apr;84(4):897-910 S, Boaron M, Broët P, Miller LD, Gespach C, Regnard JF, Forgez P. Neurotensin receptor 1 determines the outcome Hwang JI, Kim DK, Kwon HB, Vaudry H, Seong JY. of non-small cell lung cancer. Clin Cancer Res. 2010 Sep Phylogenetic history, pharmacological features, and signal 1;16(17):4401-10 transduction of neurotensin receptors in vertebrates. Ann N Y Acad Sci. 2009 Apr;1163:169-78 Amorino GP, Deeble PD, Parsons SJ. Neurotensin stimulates mitogenesis of prostate cancer cells through a Kanba KS, Kanba S, Okazaki H, Richelson E. Binding of novel c-Src/Stat5b pathway. 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J Mol Neurosci. 2013 tumor development in a sporadic but not an inflammation- Oct;51(2):408-15 associated mouse model of colon cancer. Int J Cancer. Magazin M, Poszepczynska-Guigné E, Bagot M, Boumsell 2012 Apr 15;130(8):1798-805 L, Pruvost C, Chalon P, Culouscou JM, Ferrara P, Castagliuolo I, Wang CC, Valenick L, Pasha A, Nikulasson Bensussan A. Sezary syndrome cells unlike normal S, Carraway RE, Pothoulakis C. Neurotensin is a circulating T lymphocytes fail to migrate following proinflammatory neuropeptide in colonic inflammation. J engagement of NT1 receptor. J Invest Dermatol. 2004 Clin Invest. 1999 Mar;103(6):843-9 Jan;122(1):111-8 Dupouy S, Viardot-Foucault V, Alifano M, Souazé F, Plu- Martin S, Navarro V, Vincent JP, Mazella J. Neurotensin Bureau G, Chaouat M, Lavaur A, Hugol D, Gespach C, receptor-1 and -3 complex modulates the cellular signaling Gompel A, Forgez P. The neurotensin receptor-1 pathway of neurotensin in the HT29 cell line. 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PDCD5 (programmed cell death 5) Yingyu Chen, Ge Li Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Science Center, Beijing, 100191, China

Published in Atlas Database: October 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/PDCD5ID41676ch19q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62481/10-2014-PDCD5ID41676ch19q13.pdf DOI: 10.4267/2042/62481 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract DNA/RNA Programmed Cell Death 5 (PDCD5) was originally identified as an apoptosis-accelerating molecule Description that was widely expressed and well-conserved in The PDCD5 gene, with 6286 bases in length, the process of evolution. consists of 6 exons and 5 intervening introns. It has significant homology to the corresponding proteins of species ranging from yeast to mice gene. Transcription PDCD5 can accelerate apoptosis in different type of The PDCD5 gene encodes a 604 bp mRNA cells in response to different stimuli, and can also transcript. Transcription site is located 75 bp induce different types of cell death, including upstream the first ATG of the PDCD5 ORF. The paraptosis-like cell death. In cells undergoing translation start site is located in exon 1. apoptosis, PDCD5 rapidly translocates from the Pseudogene cytoplasm to the nucleus before phosphatidylserine is externalized and genomic DNA undergoes Pseudogenes have been identified on chromosomes fragmentation. 12p12.3 and 5q13.2. PDCD5 interacts with TIP60 and TP53 and plays Protein an important positive role in TIP60-P53 signaling pathway. Description PDCD5 also participates in immune regulation PDCD5 protein is composed of 125 amino acids, through regulating the level of FOXP3 protein and with a calculated molecular mass of 14.285 kDa. In percentage of regulatory T cells. the protein sequence exist six phosphorylation sites, Dysfunction of PDCD5 was associated in many including a cAMP and cGMP depended protein diseases including different tumors, rheumatoid kinase phosphorylation site (Ser100), 4 PKC arthritis and presbycusis, etc. phosphorylation sites (Ser51, Ser84, Thr103, Keywords Thr108), and a casein kinase 2 (CK2) Programmed Cell Death 5 (PDCD5), Apoptosis, phosphorylation site (Ser118) (Saivi et al., 2009). Tumor, Immnuoregulation. Five of the phosphorylation sites are located in the C-terminal region. Identity Expression Other names: TFAR19 PDCD5 is widely expressed in different organs and HGNC (Hugo): PDCD5 different stages. Decreased expression of PDCD5 has been detected in various human tumors, such as Location: 19q13.11 lung cancer, gastric cancer, chronic myelogenous Local order: Orientation: Plus Strand.

Atlas Genet Cytogenet Oncol Haematol. 2015; 19(10) 621 PDCD5 (programmed cell death 5) Chen Y, Li G

leukemia, prostate cancer, chondrosarcoma and epithelial ovarian carcinomas.

The DNA sequence of PDCD5.

The abnormal expression of PDCD5 is also Somatic involved in some autoimmune diseases and inflammatory processes, such as lupus nephritis, The promoter with -27G/-11A is associated with osteoarthritis, rheumatoid arthritis, hepatitis, sepsis reduced PDCD5 promoter activity and increased and bronchial asthma. In the patients with susceptibility to chronic myelogenous leukemia rheumatoid arthritis, the levels of PDCD5 in serum (Ma et al., 2005). and synovial fluid are inversely associated with the A C/G polymorphism (rs1862214) located 35 kb expression of inflammatory cytokines IL-17 and upstream of the PDCD5 gene was associated with TNF- α and disease activity. lung cancer susceptibility (Spinola et al., 2006). Localisation PDCD5 protein has been reported to be localized Implicated in mainly in the cytoplasm and nucleus, and translocated to the nucleus during apoptosis (Chen Various cancers et al., 2006). Note Function Reduced PDCD5 expression has been found in a few types of human tumors and is also associated PDCD5 can promote apoptosis in different cell with the high progression and poor prognosis. types in response to various stimuli. PDCD5 Decreased expression of PDCD5 has been reported interacts with the histone acetyltransferase TIP60 in various human tumors, such as gastric cancer and the transcription factor TP53 to promote (Gao et al., 2012), brain tumors (Li et al., 2008), apoptosis (Xu et al., 2009; Xu et al., 2012). PDCD5 bone tumor (Chen et al., 2010a), ovarian can also interact with other molecules such as NF- carcinomas (Zhang et al., 2011), leukemia (Ruan et kB p65 and CCT in which participate in the al., 2006), renal tumor (Tan et al., 2006), lung regulation of cell apoptosis. It also associates with cancer (Spinola et al., 2006), prostate cancer (Du et TAJ/TROY-induced paraptosis-like cell death al., 2009), hepatocellular cancer (Fu et al., 2013), (Wang et al., 2004), focal cerebral ischemic laryngeal cancer (Xu et al., 2013), oral squamous reperfusion injury (Jiang et al., 2014), virus cell carcinoma (Zhao et al., 2013) and cervical infections (Li et al., 2014) and cardiac remodeling cancer (Liu et al., 2013). (An et al., 2012). PDCD5 negatively regulates PDCD5 expression predicts a favorable outcome in autoimmunity by enhancing the level of FOXP3 patients with hepatocellular carcinoma, epithelial protein, upregulating FOXP3+ regulatory T cells ovarian carcinomas, chondrosarcoma. and suppressing Th17 and Th1 responses (Xiao et PDCD5 may make significance to inhibit tumor al., 2013). malignant transformation and progress. Homology Recombinant human PDCD5 (rhPDCD5) has been PDCD5 gene is highly-conserved among species shown to enter a variety of cells by clathrin- (from yeast to human). independent endocytosis and exert biological activities. Mutations RhPDCD5 could enhance cell death of tumor cells and enhance the sensitivity to chemotherapeutic, Germinal such as cisplatin (Chen et al., 2010b; Shi et al., No data. 2010; Wang et al., 2013c).

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PDCD5 (programmed cell death 5) Chen Y, Li G

Rheumatoid arthritis PDCD5 is associated with high-grade astrocytic gliomas. Oncol Rep. 2008 Sep;20(3):573-9. PDCD5 is associated with rheumatoid arthritis and Li K, Zhou Z, Wang YO, Liu J, Zhao HB, Yang J, Wang osteoarthritis, which can regulate the apoptosis of SQ.. Pretreatment of mice with oligonucleotide prop5 synoviocytes and chondrocytes (Wang et al., 2007). protects them from influenza virus infections. Viruses. The levels of PDCD5 in serum, synovial fluid and 2014 Feb 6;6(2):573-81. doi: 10.3390/v6020573. cartilage are higher in RA and OA than healthy Liu H, Wang Y, Zhang Y, Song Q, Di C, Chen G, Tang J, control, which are negatively correlated with IL-17 Ma D.. TFAR19, a novel apoptosis-related gene cloned or TNF-α levels (Wang et al., 2013a). The from human leukemia cell line TF-1, could enhance expression of PDCD5 may be down regulated by apoptosis of some tumor cells induced by growth factor withdrawal. Biochem Biophys Res Commun. 1999 Jan Insulin-like growth factor 1 (Yi et al., 2013). 8;254(1):203-10. Recombinant human PDCD5 has an anti- Ma X, Ruan G, Wang Y, Li Q, Zhu P, Qin YZ, Li JL, Liu inflammatory effect in collagen-induced arthritis YR, Ma D, Zhao H.. Two single-nucleotide polymorphisms (CIA) rats (Xiao et al., 2014). with linkage disequilibrium in the human programmed cell death 5 gene 5' regulatory region affect promoter activity References and the susceptibility of chronic myelogenous leukemia in Chinese population. Clin Cancer Res. 2005 Dec 15;11(24 An L, Zhao X, Wu J, Jia J, Zou Y, Guo X, He L, Zhu H.. Pt 1):8592-9. Involvement of autophagy in cardiac remodeling in Salvi M, Xu D, Chen Y, Cabrelle A, Sarno S, Pinna LA.. transgenic mice with cardiac specific over-expression of Programmed cell death protein 5 (PDCD5) is human programmed cell death 5. PLoS One. phosphorylated by CK2 in vitro and in 293T cells. Biochem 2012;7(1):e30097. doi: 10.1371/journal.pone.0030097. Biophys Res Commun. 2009 Sep 25;387(3):606-10. doi: Epub 2012 Jan 11. 10.1016/j.bbrc.2009.07.067. Epub 2009 Jul 17. Chen C, Zhou H, Xu L, Xu D, Wang Y, Zhang Y, Liu X, Liu Shi L, Song Q, Zhang Y, Lou Y, Wang Y, Tian L, Zheng Y, Z, Ma D, Ma Q, Chen Y.. Recombinant human PDCD5 Ma D, Ke X, Wang Y.. Potent antitumor activities of sensitizes chondrosarcomas to cisplatin chemotherapy in recombinant human PDCD5 protein in combination with vitro and in vivo. Apoptosis. 2010b Jul;15(7):805-13. doi: chemotherapy drugs in K562 cells. Biochem Biophys Res 10.1007/s10495-010-0489-5. Commun. 2010 May 28;396(2):224-30. doi: Chen CH, Jiang Z, Yan JH, Yang L, Wang K, Chen YY, 10.1016/j.bbrc.2010.04.068. Epub 2010 Apr 14. Han JY, Zhang JH, Zhou CM.. The involvement of Spinola M, Meyer P, Kammerer S, Falvella FS, Boettger programmed cell death 5 (PDCD5) in the regulation of MB, Hoyal CR, Pignatiello C, Fischer R, Roth RB, apoptosis in cerebral ischemia/reperfusion injury. CNS Pastorino U, Haeussinger K, Nelson MR, Dierkesmann R, Neurosci Ther. 2013 Aug;19(8):566-76. doi: Dragani TA, Braun A.. Association of the PDCD5 locus 10.1111/cns.12114. Epub 2013 May 3. with lung cancer risk and prognosis in smokers. J Clin Chen Y, Sun R, Han W, Zhang Y, Song Q, Di C, Ma D.. Oncol. 2006 Apr 10;24(11):1672-8. Epub 2006 Mar 20. Nuclear translocation of PDCD5 (TFAR19): an early signal Tracy CM, Gray AJ, Cuellar J, Shaw TS, Howlett AC, for apoptosis? FEBS Lett. 2001 Dec 7;509(2):191-6. Taylor RM, Prince JT, Ahn NG, Valpuesta JM, Willardson Du YJ, Xiong L, Lou Y, Tan WL, Zheng SB.. Reduced BM.. Programmed cell death protein 5 interacts with the expression of programmed cell death 5 protein in tissue of cytosolic chaperonin containing tailless complex human prostate cancer. Chin Med Sci J. 2009 polypeptide 1 (CCT) to regulate β-tubulin folding. J Biol Dec;24(4):241-5. Chem. 2014 Feb 14;289(7):4490-502. doi: 10.1074/jbc.M113.542159. Epub 2013 Dec 27. Essers PB, Klasson TD, Pereboom TC, Mans DA, Nicastro M, Boldt K, Giles RH, Macinnes AW.. The von Hippel- Wang J, Guan Z, Ge Z.. Plasma and synovial fluid Lindau tumor suppressor regulates programmed cell death programmed cell death 5 (PDCD5) levels are inversely 5-mediated degradation of Mdm2. Oncogene. 2014 Jan associated with TNF-α and disease activity in patients with 27. doi: 10.1038/onc.2013.598. [Epub ahead of print] rheumatoid arthritis. Biomarkers. 2013a Mar;18(2):155-9. doi: 10.3109/1354750X.2012.759277. Epub 2013 Jan 18. Fu DZ, Cheng Y, He H, Liu HY, Liu YF.. PDCD5 expression predicts a favorable outcome in patients with Wang JF, Guan ZP, Zhang SL, Pei Z, Chen YY, Pan H.. hepatocellular carcinoma. Int J Oncol. 2013 Programmed cell death 5 correlates with disease activity Sep;43(3):821-30. doi: 10.3892/ijo.2013.1993. Epub 2013 and interleukin-17 in serum and synovial fluid of Jun 26. rheumatoid arthritis patients. Chin Med J (Engl). 2013b Jan;126(2):296-9. Gao F, Ding L, Zhao M, Qu Z, Huang S, Zhang L.. The clinical significance of reduced programmed cell death 5 Wang L, Wang C, Su B, Song Q, Zhang Y, Luo Y, Li Q, expression in human gastrointestinal stromal tumors. Tan W, Ma D, Wang L.. Recombinant human PDCD5 Oncol Rep. 2012 Dec;28(6):2195-9. doi: protein enhances chemosensitivity of breast cancer in vitro 10.3892/or.2012.2023. Epub 2012 Sep 11. and in vivo. Biochem Cell Biol. 2013c Dec;91(6):526-31. doi: 10.1139/bcb-2013-0052. Epub 2013 Sep 13. Jiang Z, Chen CH, Chen YY, Han JY, Riley J, Zhou CM.. Autophagic effect of programmed cell death 5 (PDCD5) Wang N, Lu HS, Guan ZP, Sun TZ, Chen YY, Ruan GR, after focal cerebral ischemic reperfusion injury in rats. Chen ZK, Jiang J, Bai CJ.. Involvement of PDCD5 in the Neurosci Lett. 2014 Apr 30;566:298-303. doi: regulation of apoptosis in fibroblast-like synoviocytes of 10.1016/j.neulet.2014.02.066. Epub 2014 Mar 12. rheumatoid arthritis. Apoptosis. 2007 Aug;12(8):1433-41. Li H, Wang Q, Gao F, Zhu F, Wang X, Zhou C, Liu C, Wang Y, Li X, Wang L, Ding P, Zhang Y, Han W, Ma D.. Chen Y, Ma C, Sun W, Zhang L.. Reduced expression of An alternative form of paraptosis-like cell death, triggered

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PDCD5 (programmed cell death 5) Chen Y, Li G

by TAJ/TROY and enhanced by PDCD5 overexpression. J PDCD5 interacts with p53 and functions as a positive Cell Sci. 2004 Mar 15;117(Pt 8):1525-32. regulator in the p53 pathway. Apoptosis. 2012 Nov;17(11):1235-45. doi: 10.1007/s10495-012-0754-x. Xiao J, Li G, Hu J, Qu L, Ma D, Chen Y.. Anti-Inflammatory Effects of Recombinant Human PDCD5 (rhPDCD5) in a Xu S, Sui G, Yuan L, Zou Z.. Expression of programmed Rat Collagen-Induced Model of Arthritis. Inflammation. cell death 5 protein inhibits progression of lung carcinoma 2014 Sep 2. [Epub ahead of print] in vitro and in vivo via the mitochondrial apoptotic pathway. Mol Med Rep. 2014 Oct;10(4):2059-64. doi: Xiao J, Liu C, Li G, Peng S, Hu J, Qu L, Lv P, Zhang Y, Ma 10.3892/mmr.2014.2454. Epub 2014 Aug 5. D, Chen Y.. PDCD5 negatively regulates autoimmunity by upregulating FOXP3(+) regulatory T cells and suppressing Yi C, Ma C, Xie Z, Zhang G, Song W, Zhou X, Cao Y.. Th17 and Th1 responses. J Autoimmun. 2013 Dec;47:34- Down-regulation of programmed cell death 5 by insulin-like 44. doi: 10.1016/j.jaut.2013.08.002. Epub 2013 Sep 5. growth factor 1 in osteoarthritis chondrocytes. Int Orthop. 2013 May;37(5):937-43. doi: 10.1007/s00264-012-1744-x. Xu F, Wu K, Zhao M, Qin Y, Xia M.. Expression and Epub 2013 Jan 16. clinical significance of the programmed cell death 5 gene and protein in laryngeal squamous cell carcinoma. J Int Zhang X, Wang X, Song X, Wei Z, Zhou C, Zhu F, Wang Med Res. 2013 Dec;41(6):1838-47. doi: Q, Ma C, Zhang L.. Clinical and prognostic significance of 10.1177/0300060513498021. lost or decreased PDCD5 expression in human epithelial ovarian carcinomas. Oncol Rep. 2011 Feb;25(2):353-8. Xu L, Chen Y, Song Q, Xu D, Wang Y, Ma D.. PDCD5 doi: 10.3892/or.2010.1103. Epub 2010 Dec 13. interacts with Tip60 and functions as a cooperator in acetyltransferase activity and DNA damage-induced This article should be referenced as such: apoptosis. Neoplasia. 2009 Apr;11(4):345-54. Chen Y, Li G. PDCD5 (programmed cell death 5). Atlas Xu L, Hu J, Zhao Y, Hu J, Xiao J, Wang Y, Ma D, Chen Y.. Genet Cytogenet Oncol Haematol. 2015; 19(10):621-624.

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Gene Section Review

ZFX (zinc finger protein, X-linked) Modjtaba Emadi-Baygi Dept of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran Published in Atlas Database: October 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/ZFXID43623chXp22.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62482/10-2014-ZFXID43623chXp22.pdf DOI: 10.4267/2042/62482

Identity Pseudogene Other names: ZNF926 Pseudogenes were not exactly identified. HGNC (Hugo): ZFX Protein Location : Xp22.11 Description DNA/RNA The ZFX isoform I, the longest isoform, contains 805 amino acids (130 kDa). Isoforms II (91 kDa) Note and III contain 576 and 432 amino acids, Differential splicing of a single ZFX transcript respectively. Isoform II binds to the AGGGCCCCA results in five variants. Variants 1, 2 and 3 result in and AGGCCCCGA sequences located at HLA-A11 isoform I, variant 4 results in isoform II and variant promoter (L'Haridon et al.,1996) and in 5 results in isoform III. accompanying with isoform I could play a role as Description co-activators in HIV-1 LTR induction (Nikpour et al., 2012). Isoforms I and II contain three domains: ZFX gene is a human X- chromosome gene that acidic domain (transcription activation region), escapes X inactivation (Schneider-Gadicke et nuclear localization signal (NLS) and 13 zinc finger al.,1989a) and is composed of 10 exons, ranging in domains, that differ in the length of their N- size from 57 to 6062 nt. terminal (acidic) domain resulting in qualitatively Exons 1 to 5 in isoform 2 and exons 1 to 6 in and quantitatively different regulatory properties isoform 1 comprise the 5' UTR and encodes N- (Schneider-Gadicke et al., 1989b). terminal acidic domain. Exon 10 contains 3' UTR and AATAAA Expression polyadenylation signal and encodes C-terminal zinc ZFX gene escapes X inactivation in humans - finger domain for isoforms 1 and 2 (Schneider- (Schneider-Gadicke et al., 1989a) and is expressed Gadicke et al.,1989a). in a wide range of human tissues (Schneider- Transcription Gadicke et al.,1989b). Transcription initiation sites were not exactly Localisation identified, but there is same ORF with the first It was shown that ZFX isoform I is concentrated in ATG codon at nucleotide 1 in cDNAs (Schneider- the nucleus of glioma cell line, while ZFX isoform Gadicke et al.,1989b). II is found in the cytoplasm (Zhu et al., 2013).

Structure of the human ZFX gene. Exon positions (green) and sizes (nt-nucleotides) are labelled.

Atlas Genet Cytogenet Oncol Haematol. 2015; 19(10) 625 ZFX (zinc finger protein, X-linked) Emadi-Baygi M.

Structure of the human ZFX isoforms. Acidic domain (orange), nuclear localisation signal (blue) and zinc finger domain (green) are labelled.

Function in U251 cells using semi- quantitative PCR. They showed that expression of ZFX is significantly ZFX gene is differentially expressed in tissues and higher in glioma tissues compared to non glioma may have separate functions in gonadal and somatic tissues using real-time RT-PCR. In the same vein, tissues (Lau and Chan, 1989). It may play a role as Knocking down of ZFX gene expression in U251 a sex determination factor in mammals (Zhu et al., cells results in disturbed cell proliferation and 2013). ZFX acts as a transcriptional regulator in increased apoptosis and arrested cells in S phase self renewal and differentiation mechanisms in (Zhou et al., 2011). human embryonic and hematopoietic stem cells (Galan-Caridad et al., 2007; Harel et al., 2012). Gastric cancer tissues and cells ZFX has an important role in cell cycle progression ZFX gene expression was examined by quantitative and cell growth control (Jiang et al., 2012b). real-time RT-PCR in 30 paired gastric tissue Homology samples. Result shows that ZFX gene has differential expression in gastric tissues. There is a In mammals, ZFX gene is highly conserved statistically significant association between the (Ashworth et al., 1990; Lau and Chan, 1989; ZFX expression and different tumour types and Palmer et al., 1990). Zinc finger protein X linked is grades (Nikpour et al., 2012). Furthermore, ZFX one of the members of ZFY family comprised of silencing inhibits gastric cancer cell growth in both three members: ZFX, ZFY and ZFA (Palmer et al., in vitro and in vivo via modulating extracellular 1990). signal-regulated kinase/mitogen-activated protein Mutations kinase (ERK-MAPK) pathway (Wu et al., 2013). Non - small cell lung cancer (NSCLC) A novel Xp22.11 deletion causing a syndrome of ZFX overexpresses in NSCLC and its expression is craniosynostosis and periventricular nodular correlated with lymph node metastasis. Knocking heterotopias affecting all or part of three annotated down of ZFX gene by short hairpin RNA genes, ZFX, PDK3, and PCYT1B has recently been interference (shRNA) in NSCLC cell line reduces reported in a male subject (van Kogelenberg et al., cell viability and colony formation and causes cell 2011). Furthermore, Zfx mutation results in small cycle arrest (Jiang et al., 2012b). animal size and reduced germ cell number in male and female mice (Luoh et al., 1997). Moreover, Laryngeal squamous cell carcinoma molecular cytogenetic analysis of a male infant with (LSCC) severe mental retardation and autism shows that ZFX expression up-regulates in LSCC tissues there is a duplication in Xp in this subject (Rao et compared to the non- tumoral tissues. Knock-down al., 1994). of ZFX by shRNA results in suppression of proliferation and colony-forming potential of Implicated in infected Hep-2 human LSCC cells and induces Glioma cell and cell lines enhancing of cell apoptosis. Furthermore, high expression of ZFX associates with LSCC In human glioma cell lines, knocking down of ZFX progression and its decreased expression associates expression by lentivirus-mediated RNA with declined tumor cell growth (Fang et al., 2012). interference (RNAi) shows that ZFX plays an important role in glioma cell proliferation, survival Osteosarcoma cells and growth potential in both subcutaneous and Inhibition of ZFX expression by siRNA results in intracranial models in mice (Zhu et al., 2013). decreased proliferation, colony formation and Furthermore, Zhou et al. detected ZFX expression invasion of Saos-2 cells. Silencing of ZFX gene

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ZFX (zinc finger protein, X-linked) Emadi-Baygi M

expression causes cell cycle arrest in which greater Jiang R, Wang JC, Sun M, Zhang XY, Wu H. Zinc finger X- portion of the cells existed in G1 phase and minor chromosomal protein (ZFX) promotes solid agar colony growth of osteosarcoma cells. Oncol Res. portion in S and G2/M phases (Jiang et al., 2013; 2012;20(12):565-70 Jiang et al., 2012a). L'Haridon M, Paul P, Xerri JG, Dastot H, Dolliger C, Prostate cancer Schmid M, de Angelis N, Grollet L, Sigaux F, Degos L, Gazin C. Transcriptional regulation of the MHC class I Prostate cancer tissues show higher expression of HLA-A11 promoter by the zinc finger protein ZFX. Nucleic ZFX than that observed in normal adjacent tissues Acids Res. 1996 May 15;24(10):1928-35 and BPH tissues. Furthermore, silencing the Lau YF, Chan KM. The putative testis-determining factor expression of ZFX in the prostate cancer cells and related genes are expressed as discrete-sized effectively abolishes the cellular proliferation and transcripts in adult gonadal and somatic tissues. Am J colony-formation ability, and results in G1 phase Hum Genet. 1989 Dec;45(6):942-52 cell cycle arrest. Moreover, inhibition of ZFX Luoh SW, Bain PA, Polakiewicz RD, Goodheart ML, induces apoptosis by activating caspase-1, caspase- Gardner H, Jaenisch R, Page DC. Zfx mutation results in 3 and caspase-9. (Jiang et al., 2012c). small animal size and reduced germ cell number in male and female mice. Development. 1997 Jun;124(11):2275-84 Childhood B lineage acute Nikpour P, Emadi-Baygi M, Mohammad-Hashem F, lymphoblastic leukemia Maracy MR, Haghjooy-Javanmard S. Differential expression of ZFX gene in gastric cancer. J Biosci. 2012 ZFX protein expresses in human leukemia cell lines Mar;37(1):85-90 REH, HL-60, NB(4) and K562. Furthermore, ZFX mRNA expression increases in the newly- Palmer MS, Berta P, Sinclair AH, Pym B, Goodfellow PN. Comparison of human ZFY and ZFX transcripts. Proc Natl diagnosed ALL group while in the ALL complete Acad Sci U S A. 1990 Mar;87(5):1681-5 remission group was significantly reduces. Rao PN, Klinepeter K, Stewart W, Hayworth R, Grubs R, Moreover, ZFX mRNA level is significantly higher Pettenati MJ. Molecular cytogenetic analysis of a in Children with a poor prognosis than those with a duplication Xp in a male: further delineation of a possible good prognosis at diagnosis (Wang et al., 2013). sex influencing region on the X chromosome. Hum Genet. 1994 Aug;94(2):149-53 References Schneider-Gädicke A, Beer-Romero P, Brown LG, Nussbaum R, Page DC. ZFX has a gene structure similar Ashworth A, Skene B, Swift S, Lovell-Badge R. Zfa is an to ZFY, the putative human sex determinant, and escapes expressed retroposon derived from an alternative X inactivation. Cell. 1989 Jun 30;57(7):1247-58 transcript of the Zfx gene. EMBO J. 1990 May;9(5):1529- 34 Wang Z, Liang HH, Li BS, Huang XH, Zhang J, Wang X, Ding LX, Jiang H. [Expression of zinc finger protein X- Fang J, Yu Z, Lian M, Ma H, Tai J, Zhang L, Han D. linked in childhood B lineage acute lymphoblastic Knockdown of zinc finger protein, X-linked (ZFX) inhibits leukemia]. Zhongguo Dang Dai Er Ke Za Zhi. 2013 cell proliferation and induces apoptosis in human laryngeal Jul;15(7):509-13 squamous cell carcinoma. Mol Cell Biochem. 2012 Jan;360(1-2):301-7 Wu S, Lao XY, Sun TT, Ren LL, Kong X, Wang JL, Wang YC, Du W, Yu YN, Weng YR, Hong J, Fang JY. Galan-Caridad JM, Harel S, Arenzana TL, Hou ZE, Knockdown of ZFX inhibits gastric cancer cell growth in Doetsch FK, Mirny LA, Reizis B. Zfx controls the self- vitro and in vivo via downregulating the ERK-MAPK renewal of embryonic and hematopoietic stem cells. Cell. pathway. Cancer Lett. 2013 Sep 1;337(2):293-300 2007 Apr 20;129(2):345-57 Zhou Y, Su Z, Huang Y, Sun T, Chen S, Wu T, Chen G, Harel S, Tu EY, Weisberg S, Esquilin M, Chambers SM, Xie X, Li B, Du Z. The Zfx gene is expressed in human Liu B, Carson CT, Studer L, Reizis B, Tomishima MJ. ZFX gliomas and is important in the proliferation and apoptosis controls the self-renewal of human embryonic stem cells. of the human malignant glioma cell line U251. J Exp Clin PLoS One. 2012;7(8):e42302 Cancer Res. 2011 Dec 20;30:114 Jiang H, Zhang L, Liu J, Chen Z, Na R, Ding G, Zhang H, Zhu Z, Li K, Xu D, Liu Y, Tang H, Xie Q, Xie L, Liu J, Wang Ding Q. Knockdown of zinc finger protein X-linked inhibits H, Gong Y, Hu Z, Zheng J. ZFX regulates glioma cell prostate cancer cell proliferation and induces apoptosis by proliferation and survival in vitro and in vivo. J Neurooncol. activating caspase-3 and caspase-9. Cancer Gene Ther. 2013 Mar;112(1):17-25 2012 Oct;19(10):684-9 van Kogelenberg M, Lerone M, De Toni T, Divizia MT, de Jiang M, Xu S, Yue W, Zhao X, Zhang L, Zhang C, Wang Brouwer AP, Veltman JA, van Bokhoven H, Robertson SP. Y. The role of ZFX in non-small cell lung cancer A novel Xp22.11 deletion causing a syndrome of development. Oncol Res. 2012;20(4):171-8 craniosynostosis and periventricular nodular heterotopia. Am J Med Genet A. 2011 Dec;155A(12):3144-7 Jiang R, Gao ZL, Sun M, Zhang XY, Wang JC, Wu H. Zinc finger X-chromosomal protein promotes growth and tumorigenesis in human osteosarcoma cells. Pak J Med This article should be referenced as such: Sci. 2013 Jul;29(4):997-1002 Emadi-Baygi M. ZFX (zinc finger protein, X-linked). Atlas Genet Cytogenet Oncol Haematol. 2015; 19(10):625-627.

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Leukaemia Section Short Communication t(1;2)(q12;q37) in acute leukemias Shen Yueyang , Gillan Tanya, Héléne Bruyère Cytogenetics Laboratory, Department of Pathology, Laboratory Medicine, Vancouver, BC, Canada. [email protected]

Published in Atlas Database: November 2014 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0102q12q37ID1317.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62483/11-2014-t0102q12q37ID1317.pdf DOI: 10.4267/2042/62483

This article is an update of : t(1;2)(q12;q37) in acute leukemias. Atlas Genet Cytogenet Oncol Haematol 2015;19(10) Huret JL. t(1;2)(q12;q37). Atlas Genet Cytogenet Oncol Haematol 2000;4(1)

monocytic/monoblastic differentiation and 1 case of Abstract L1 acute lymphoblastic leukemia (ALL). Review on t(1;2)(q12;q37), with data on clinics. Epidemiology Keywords a 76 yr old female patient, a 81 yr old male patient, Acute leukemia ; t(1;2)(q12;q37) a 31 yr old male patient and a 69 yr old male patient (ALL). A t(1;2)(q12;q37 has also been found in Identity myelodysplastic syndrome (RAEB), 2 multiple myeloma cases, and 2 hepatoblastoma cases. Note Prognosis Only a few cases reported to date, poorly known Unknown Cytogenetics Cytogenetics morphological The t(1;2) was balanced in one case and presented as a der(2)t(1;2) in 3 of the 4 cases, resulting in trisomy 1q. The t(1;2) is likely to be a secondary anomaly. The karyotypes were complex in all cases; the t(1;2) was associated with a t(9;22) in one AML case and in the ALL case. In 3 of the 4 cases, the breakpoint on chromosome 1 was G-band analysis - partial karyotype showing localized in the satellite II domain. der(2)t(1;2)(q12;q37) Courtesy Drs. Tanya Gillan and Hŕ Bruyè, Vancouver General Hospital Cytogenetics References LaboratoryClinics and pathology Busson-Le Coniat M, Salomon-Nguyen F, Dastugue N, Disease Maarek O, Lafage-Pochitaloff M, Mozziconacci MJ, Acute leukemias Baranger L, Brizard F, Radford I, Jeanpierre M, Bernard OA, Berger R. Fluorescence in situ hybridization analysis Phenotype/cell stem origin of chromosome 1 abnormalities in hematopoietic disorders: rearrangements of DNA satellite II and new 1 case of M0 acute myeloid leukemia (AML), 1 recurrent translocations. Leukemia. 1999 case of M4 AML, 1 case of M5 AML with Dec;13(12):1975-81

Atlas Genet Cytogenet Oncol Haematol. 2015; 19(10) 628 t(1;2)(q12;q37) in acute leukemias Shen Y, et al.

Jacobs RH, Cornbleet MA, Vardiman JW, Larson RA, Le Beau MM, Rowley JD. Prognostic implications of Beau MM, Rowley JD. Prognostic implications of morphology and karyotype in primary myelodysplastic morphology and karyotype in primary myelodysplastic syndromes. Blood. 1986 Jun;67(6):1765-72 syndromes. Blood. 1986 Jun;67(6):1765-72 This article should be referenced as such: Smadja NV, Bastard C, Brigaudeau C, Leroux D, Fruchart C. Hypodiploidy is a major prognostic factor in multiple Shen Y, Gillan T, Bruyère H. t(1;2)(q12;q37) in acute myeloma. Blood. 2001 Oct 1;98(7):2229-38 leukemias. Atlas Genet Cytogenet Oncol Haematol. 2015; 19(10):628-629. Jacobs RH, Cornbleet MA, Vardiman JW, Larson RA, Le

Atlas Genet Cytogenet Oncol Haematol. 2015; 19(10) 629

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Solid Tumour Section Short Communication

Pseudomyogenic hemangioendothelioma: t(7;19)(q22;q13) SERPINE1/FOSB Charles Walther, Fredrik Mertens Department of Pathology, University, Regional Laboratories, Skne University Hospital, 221 85 Lund, [email protected] (CW; Department of Clinical Genetics, University, Regional Laboratories, Skne University Hospital, Lund University, 221 85 Lund, [email protected] (FM) Sweden Published in Atlas Database: December 2014 Online updated version : http://AtlasGeneticsOncology.org/Tumors/PHEt0719q22q13ID6473.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62484/12-2014-PHEt0719q22q13ID6473.pdf DOI: 10.4267/2042/62484

Abstract Etiology Not known. Pseudomyogenic hemangioendothelioma (PHE) is Epidemiology an intermediate malignant vascular tumor primarily affecting soft tissues in children and young adults. Often young adults. Predominantly male (4.6:1) The molecular basis of this neoplasm is unknown. Clinics Chromosome banding analysis, fluorescence in situ Two thirds of the lesions seen in limbs followed by hybridization (FISH), mRNA sequencing, RT-PCR, trunk and head and neck. Size 0.3-5.5 cm. Often and quantitative real-time PCR have shown that multifocal and ill circumscribed. Situated PHEs are characterized by a balanced translocation subcutanously but often in different tissue planes, t(7;19)(q22;q13), resulting in the fusion of the including bone. Painful nodules in 50% of the SERPINE1 and FOSB genes. The role of cases. Locally aggressive and often recurring but SERPINE1, which is highly expressed in vascular rarely distant metastases. (Hornick et al., 2011) cells, in this gene fusion is probably to provide a strong promoter for FOSB. FOSB encodes a Pathology transcription factor belonging to the FOS family of Spindle cells in fascicles and sheets. Vesicular proteins, which together with members of the JUN nuclei. Distinct eosinophilic cytoplasm. Cells often family of transcription factors are major show a rhabdomyoblast-like appearance. components of the Activating Protein 1 (AP-1) complex. Treatment Keywords Surgical resection Pseudomyogenic hemangioendothelioma; SERPINE1; FOSB; translocation Genetics Clinics and pathology PHE consistently displays a SERPINE1-FOSB fusion gene, resulting from a translocation between Note chromosomes 7 and 19, presumably constituting the Newly recognised entity. Rare. Exact incidence not essential driver mutation in this neoplasm known. (Trombetta et al., 2011).

Atlas Genet Cytogenet Oncol Haematol. 2015; 19(10) 630 Pseudomyogenic hemangioendothelioma: t(7;19)(q22;q13) Walther C and Mertens F SERPINE1/FOSB

Interphase FISH with BAC probes showing normal red (SERPINE1) and green (FOSB) signals and yellow fusion (SERPINE1- FOSB) signal.

Chromatogram showing the fusion junction in a case of PHE. Sixty-one nucleotides from intron 1 of SERPINE1 were inserted at the fusion junction (blue double arrow). The translation start codon in FOSB is indicated (black arrow).

Cytogenetics Protein SERPINE1 (aka PAI-1, plasminogen activator Cytogenetics Morphological inhibitor type 1) encodes a protein that is a member a recurrent translocation t(7;19)(q22;q13) has been of the serine protease inhibitor family, and that seen. inhibits tissue- and urokinase-type plasminogen activators. These activators convert plasminogen to Genes involved and plasmin, which in turn mediates fibrinolysis and proteolytic degradation of extracellular matrix. It is proteins highly expressed in many tumors, being implicated in invasion, angiogenesis and metastasis (Declerck Note et al., 2013). SERPINE1 and FOSB SERPINE1 FOSB Location Location 7q22.1; chr7:100,770,370-100,782,547 19q13.32; chr19:45,971,253-45,978,437 DNA / RNA DNA / RNA 12,178 nt 7,185 nt

Atlas Genet Cytogenet Oncol Haematol. 2015; 19(10) 631

Pseudomyogenic hemangioendothelioma: t(7;19)(q22;q13) Walther C and Mertens F SERPINE1/FOSB

Protein chimera is probably to provide a promoter allowing Member of FOS family of genes, which code for strong expression of FOSB. leucine zipper proteins that act as transcription factors. FOSB consists of 338 amino acids (aa), References with a central basic leucine-zipper region and a Declerck PJ, Gils A. Three decades of research on carboxy-terminal transactivation domain (TAD) plasminogen activator inhibitor-1: a multifaceted serpin. (Milde-Langosh, 2005). Semin Thromb Hemost. 2013 Jun;39(4):356-64 Hornick JL, Fletcher CD. Pseudomyogenic Result of the chromosomal hemangioendothelioma: a distinctive, often multicentric tumor with indolent behavior. Am J Surg Pathol. 2011 anomaly Feb;35(2):190-201 Hybrid Gene Milde-Langosch K. The Fos family of transcription factors and their role in tumourigenesis. Eur J Cancer. 2005 Transcript Nov;41(16):2449-61 RT-PCR and subsequent sequencing of amplified Trombetta D, Magnusson L, von Steyern FV, Hornick JL, products from two cases identified an in-frame Fletcher CD, Mertens F. Translocation t(7;19)(q22;q13)−a SERPINE-/FOSB fusion transcripts in both cases. recurrent chromosome aberration in pseudomyogenic hemangioendothelioma? Cancer Genet. 2011 In both tumors the breakpoints in SERPINE1 were Apr;204(4):211-5 located in the non-coding exon 1. The breakpoint in FOSB was located in the beginning of exon 2 in Walther C, Tayebwa J, Lilljebjörn H, Magnusson L, Nilsson J, von Steyern FV, Øra I, Domanski HA, Fioretos T, Nord one case and in the non-coding exon 1 in the other. KH, Fletcher CD, Mertens F. A novel SERPINE1-FOSB Both cases showed small insertions (61 bp in Case fusion gene results in transcriptional up-regulation of 1, 59 bp in Case 2) of material from intron 1 of FOSB in pseudomyogenic haemangioendothelioma. J SERPINE1 at the fusion junction (Walther et al., Pathol. 2014 Apr;232(5):534-40 2014). This article should be referenced as such: Fusion Protein Walther C, Mertens F. Pseudomyogenic Oncogenesis hemangioendothelioma: t(7;19)(q22;q13) SERPINE1/FOSB. Atlas Genet Cytogenet Oncol The role of SERPINE1 in the SERPINE1-FOSB Haematol. 2015; 19(10):630-632.

Atlas Genet Cytogenet Oncol Haematol. 2015; 19(10) 632 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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