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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review RBM5 (RNA binding motif protein 5) Mirna Mourtada-Maarabouni School of Life Sciences, Keele University, Keele ST5 5BG, UK Published in Atlas Database: February 2007 Online updated version: http://AtlasGeneticsOncology.org/Genes/RBM5ID42069ch3p21.html DOI: 10.4267/2042/38444 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology Transcription Identity Full length RBM5 has 3.1 Kb, 2448 bp open reading frame. The gene encodes a number of alternative splice variants, identified by reverse transcription polymerase chain reaction. One splice variant lacks exon 6, RBM5delta6. Three other RNA splice variants retain intronic sequences, RBM5+5+6 retains introns 5 and 6, RBM5+6 retains intron 6 and clone 26 which is a partial cDNA containing an open reading frame and terminates within intron 6. A 326 bp antisense cDNA that maps to the intronic region of RBM5, je2, has also been identified. Both, RBM5delta6 and clone 26 cDNAs have been cloned. Hugo: RBM5 Other names: LUCA-15; H37; G15 Location: 3p21.3 Note: 3p21.3 is a putative human lung cancer tumor suppressor region. RBM5/LUCA-15 is a putative tumor suppressor gene. DNA/RNA Description The gene spans about 30.03 Kb. Orientation plus strand. At least 25 exons. RBM5/LUCA-15 splice variants. Boxes represent the exons, intronic sequences are represented by horizontal lines. The arrows point to the STOP codon in the protein coding sequence. Atlas Genet Cytogenet Oncol Haematol. 2007;11(3) 213 RBM5 (RNA binding motif protein 5) Mourtada-Maarabouni M Function Protein RBM5/LUCA-15 is among the 35 genes located within the 370 kb overlapping lung cancer homozygous deletion region at 3p21.3. RBM5 has been implicated in the control of cell death by apoptosis and cell proliferation. RBM5's involvement in apoptosis and malignancy has been the focus of many recent studies, with all results converging on a role for RBM5/LUCA15 as a Tumor Suppressor Gene (TSG). RBM5 splice variants have been shown to function as regulators of apoptosis. Stable expression of Je2, in human T-cell lines CEM-C7 and Jurkat produced marked inhibition of Fas-mediated apoptosis and conferred protection from apoptosis induced by other stimuli. RBM5delta6 inhibits CD95-mediated apoptosis as well as accelerating cell proliferation. Overexpression of the full length RBM5 in CEM-C7 and Jurkat T-cell lines suppressed cell proliferation both by inducing apoptosis and by inducing cell cycle arrest in G1. Consistently, RBM5/LUCA-15 overexpression also inhibited human lung cancer cell growth (A549 non-small cell lung cancer line) by increasing apoptosis and inducing cell cycle arrest in G1. This inhibition of cell growth was reported to be associated with decreased cyclin A and phosphorylated RB and an increase in the level of the proapototic protein Bax. Introducing RBM5/LUCA-15 into breast cancer cells that had 3p21-22 deletions reduced both anchorage-dependent and anchorage-independent growth. RBM5/LUCA-15 also is reported to suppress anchorage-dependent and anchorage-independent growth in A9 mouse fibrosarcoma cells and to inhibit their tumour forming activity in nude mice. RBM5/LUCA-15 was one of the nine genes downregulated in metastasis and it has been included in the 17 common gene signature associated with metastasis identified in multiple solid tumour types. Solid tumours carrying this gene expression signature had high rates of metastasis and poor clinical outcome. Microarraybased analysis of changes in gene expression caused by the modulation of the level of RBM5/LUCA-15 were carried out. Among 5603 genes on cDNA microarray, 35 genes, well known for their roles in the cell cycle as well as in apoptosis, were found to be differentially expressed as a result of RBM5/LUCA-15 overexpression in CEM-C7 cells. These RBM5/LUCA-15 modulated genes include a number of cyclin-dependent kinase complexes, most notably CDK2 and three putative oncogenes which are down-regulated by RBM5/LUCA-15. These are Pim-1, a serine/threonine kinase, ITPA (inosine triphosphate pyrophosphatase) and Amplified in Breast cancer 1 (AIB1). Other functionally important genes modulated by RBM5/LUCA-15 are well established to play specific anti apoptotic roles such as BIRC4 (AIP3), Description Full length RBM5 encodes a protein with a molecular mass of about 90 kDa (815 amino acids). The protein has two RNA Binding Domains (RBD), also recognized as RNA Recognition Motif (RRM). RBM5 structure also features other functional motifs, which includes two putative zinc-finger DNA binding motifs, two bipartite nuclear localisation signals and a G-patch domain (a conserved domain in eukaryotic RNAprocessing proteins and type D retroviral polyproteins), suggesting a role for RBM5/LUCA-15 in RNA processing. In addition, the C-terminal region of RBM5/LUCA-15 contains several domains including a glutamine rich domain (362-385), which is thought to serve as protein-protein interaction site in certain RNAand DNA- binding proteins. RBM5delta6 encodes a protein of 17 kDa, due to a frameshift mutation caused by the deletion of exon 6. The only functional motif retained by this truncated protein is the arginine/glycine-rich amino terminal region. A putative 21 kDa is reported to be encoded by RBM5+5+6 and clone 26, as revealed by an in vitro transcription/translation study in rabbit reticulocyte lysate. Expression Full length RBM5 and its alternative splice variants RNA are widely expressed in both primary tissue and cell lines. Northern blot analysis revealed higher expression in skeletal and heart muscles and pancreas. The expression of the full length RBM5 mRNA is reported to be high in adult thymus and low in the foetal thymus, suggesting that its expression is developmentally regulated. Full length RBM5/LUCA15 is reported to be down-regulated in breast cancer specimens, in 82% of primary non-small-cell lung carcinoma specimens and in many lung cancer cell lines and in vestibular schwannomas (27 fold reduction). The expression of RBM5delta6 RNA is highest in transformed cells. The full length RBM5 protein is ubiquitously expressed in human tissues. It was found to be downregulated in 73% of primary nonsmall-cell lung carcinoma specimens compared to normal adjacent tissue. RBM5/LUCA-15 was one of the antigens identified by autologous antibody in patients with renal carcinoma. Overexpression of je2, the 326 bp antisense sequence, resulted in the downregulation of the RBM5 protein (95 kDa) and the upregulation of the 17 kDa protein (RBM5delta6). Localisation RBM5 protein includes bipartite nuclear localisation signals suggesting its localisation to the nucleus. Atlas Genet Cytogenet Oncol Haematol. 2007;11(3) 214 RBM5 (RNA binding motif protein 5) Mourtada-Maarabouni M BIRC3 (cIAP2, MIHC), Mcl-1, a member of the Bcl-2 family of apoptosis suppressors, and TRAF1, supporting a role for RBM5/LUCA-15 in apoptosis. Other genes upregulated by RBM5/LUCA-15 include Stat5b, Annexin I and Bone Morphogenetic Protein 5 (BMP5), implicated in apoptosis, immunosuppression and organ development respectively. References Daly MC, Xiang RH, Buchhagen D, Hensel CH, Garcia DK, Killary AM, Minna JD, Naylor SL. A homozygous deletion on chromosome 3 in a small cell lung cancer cell line correlates with a region of tumour suppressor activity. Oncogene 1993;8:1721-1729. Burd C.G. and Dreyfuss G. Conserved structures and diversity of functions of RNA-binding proteins. Science 1994;265(5172):615-621. Homology RBM5 shares 30% amino acid sequence homology with its immediate telomeric neighbor, the putative tumor suppressor gene RBM6. Another RNA Binding Motif protein that shares high homology with RBM5 (53% at the amino acid level) is RBM10. The RBM10 gene is located on the X chromosome at p11.23. No function has yet been determined for RBM10. The mouse RBM5 gene is 90% identical on cDNA level and 97% on protein level. The fly proteome contain three similar proteins, of which CG4887 gene product shows 43% similarity. The rat binding protein S1-1 has similar domain structure and is close in amino acid sequence to RBM5. Kashuba VI, Szeles A, Allikmets R, Nilsson AS, Bergerheim US, Modi W, Grafodatsky A, Dean M, Stanbridge EJ, Winberg G, klein G., Zabarovsky E.R., and Kisselev L. A group of NotI jumping and linking clones cover 2.5 Mb in the 3p21-p22 region suspected to contain a tumour suppressor gene. Cancer Genet Cytogenet 1995;81(2):144-150. Daigo Y., Nishiwaki T., Kawasoe T., Tamari M., Suchiya E., and Nakamura Y. Molecular cloning of a candidate tumour suppressor gene, DLC1, from chromosome 3p21.3. Cancer Res 1996;59:1966-1972. Wei MH, Latif F, Bader S, Kashuba V, Chen JY, Duh FM, Sekido Y, Lee C.C, Geil L, Kuzmin I, Zabarovsky E, Klein G, Zbar B, Minna JD, and Lerman MI. Construction of a 600kilobase cosmid clone contig and generation of a transcriptional map surrounding the lung cancer tumour suppressor gene (TSG) locus on human chromosome 3p21.3: progress toward the isolation of a lung cancer TSG. Cancer Res 1996;56:1487-1492. Mutations Imreh S, Kost-Alimova M, Kholodnyuk I, Yang Y,Szeles A, Kiss H, Liu F, Foster K, Zabarovsky E, Stanbridge E, and Klein G. Differential elimination of 3p and retention of 3q segments in human/mouse microcell hybrids during tumour growth. Genes Chrom. Cancer 1997;20:224-233. Note: Mutations in the RMB5 gene have not been found in lung cancer. RBM5 is reported to be downregulated in RAS-transformed Rat-1 cells, in samples from breast cancer, in human schwannomas and in about 75% of primary lung cancers specimens. RBM5 was one of the nine genes down-regulated in metastasis in primary tumors and it has been included in the 17 common gene signature associated with metastasis identified in multiple solid tumour types. Solid tumours carrying this gene expression signature had high rates of metastasis and poor clinical outcomes. Kok K, Naylor SL, Buys CH. Deletion of the short arm of chromosome 3 in solid tumours and the search for suppressor genes. Adv Cancer Res 1997;71:27-92. Güre AO, Altorki NK, Stockert E, Scanlan MJ, Old LJ, Chen YT. Human lung cancer antigens recognized by autologous antibodies: definition of a novel cDNA derived from the tumour suppressor gene locus on chromosome 3p21.3. Cancer Res 1998;58(5):1034-1041. Aravind L and Koonin EV. G-patch: a new conserved domain in eukaryotic RNA-processing proteins and type D retroviral polyproteins. Trends Biochem. Sci 1999;24:342-344. Implicated in Drabkin HA, West JD, Hotfilder M, Heng YM, Erickson P, Calvo R, Dalmau J, Gemmill RM, Sablitzky F. DEF-3(g16/NYLU-12), an RNA binding protein from the 3p21.3 homozygous deletion region in SCLC. Oncogene 1999;18(16):2589-2597. Lung cancer and many other cancers Disease RBM5 is located at the human chromosomal locus 3p21.3, which is strongly associated with lung cancer and many other cancers, including head and neck, renal, breast and female genital tract. More than 90% of freshly microdissected primary lung cancers display loss of heterozygosity (LOH) of 3p21.3. RBM5 is implicated in apoptosis and in cell cycle regulation. Oncogenesis The ability of RBM5/LUCA-15 to inhibit the growth of transformed cells fulfils one of the criteria for a tumor suppressor. The simultaneous changes in proliferation and inhibition of apoptosis brought about by dysregulation of the RBM5/LUCA-15 locus are likely to be of major significance in oncogenesis. Atlas Genet Cytogenet Oncol Haematol. 2007;11(3) Hotfilder M, Baxendale S, Cross MA, and Sablitzky F. Def-2, 3, -6 and -8, novel mouse genes differentially expressed in the haemopoietic system. Br. J. Haematol 1999;106:335-344. Scanlan MJ, Gordan JD, Williamson B, Stockert E, Bander NH, Jongeneel V, Güre AO, Jäger D, Jäger E, Knuth A, Chen YT, Old LJ. Antigens recognized by autologous antibody in patients with renal-cell carcinoma. Int J Cancer 1999;83(4):456-464. Timmer T, Terpstra P, van den Berg A, Veldhuis PM, Ter Elst A, Voutsinas G, Hulsbeek MM, Draaijers TG, Looman MW, Kok K, Naylor SL, Buys CH. A comparison of genomic structures and expression patterns of two closely related flanking genes in a critical lung cancer region at 3p21.3. Eur J Hum Genet 1999;7(4):478-486. Edamatsu H, Kaziro Y, Itoh H. LUCA15, a putative tumour suppressor gene encoding an RNA-binding nuclear protein, is down-regulated in ras-transformed Rat-1 cells. Genes Cells 2000;5:849-858. 215 RBM5 (RNA binding motif protein 5) Mourtada-Maarabouni M Lerman MI, Minna JD. The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumour suppressor genes. Cancer Res 2000;60:6116-6133. Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumours. Nat Genet 2003;33(1):49-53. Sutherland LC, Rintala-Maki ND, White RD, Morin CD. RNA Binding Motif (RBM) proteins: A novel family of apoptosis modulators?. J Cell Biochem 2005;94(1):5-24. (Review). Sutherland LC, Edwards SE, Cable HC, Poirier GG, Miller BA, Cooper CS, Williams GT. LUCA-15-encoded sequence variants regulate CD95-mediated apoptosis. Oncogene 2000;19(33):3774-3781. Mourtada-Maarabouni M, Keen J, Clark J, Cooper CS, Williams GT. Candidate tumor suppressor LUCA15/RBM5/H37 modulates expression of apoptosis and cell cycle genes. Exp Cell Res 2006;312(10):1745-1752. Mourtada-Maarabouni M, Sutherland LC, Williams GT. Candidate tumour suppressor LUCA-15 can regulate multiple apoptosis pathways. Apoptosis 2002;7:421-432. Maarabouni MM, Williams GT. The antiapoptotic RBM5/LUCA15/H37 gene and its role in apoptosis and human cancer research update. ScientificWorldJournal 2006;6:1705-1712. (Review). Mourtada-Maarabouni M and Willimas GT. RBM5/LUCA-15-tumour suppression by control of apoptosis and the cell cycle?. ScientificWorldJournal 2002;4(2):1885-1890. (Review). Oh JJ, West AR, Fishbein MC, Slamon DJ. A candidate tumour suppressor gene, H37, from the human lung cancer tumour suppressor locus 3p21.3. Cancer Res 2002;62(11):3207-3213. Oh JJ, Razfar A, Delgado I, Reed RA, Malkina A, Boctor B, Slamon DJ. 3p21.3 Tumour suppressor gene H37/Luca15/RBM5 inhibits growth of human lung cancer cells through cell cycle arrest and apoptosis. Cancer Res 2006;66(7):3419-3427. Welling DB, Lasak JM, Akhmametyeva E, Ghaheri B, Chang LS. cDNA microarray analysis of vestibular schwannomas. Otol Neurotol 2002;23(5):736-748. This article should be referenced as such: Mourtada-Maarabouni M. RBM5 (RNA binding motif protein 5). Atlas Genet Cytogenet Oncol Haematol.2007; 11(3):213-216. Mourtada-Maarabouni M, Sutherland LC, Meredith JM, Williams GT. Simultaneous acceleration of the cell cycle and suppression of apoptosis by splice variant delta-6 of the candidate tumour suppressor LUCA-15/RBM5. Genes Cells 2003;8(2):109-119. Atlas Genet Cytogenet Oncol Haematol. 2007;11(3) 216