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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review GAS5 (growth arrest-specific 5 (non-protein coding)) Mirna Mourtada-Maarabouni Institute for Science and Technology in Medicine, Huxley Building, Keele University, Keele, Staffordshire ST5 5BG, UK (MMM) Published in Atlas Database: October 2009 Online updated version : http://AtlasGeneticsOncology.org/Genes/GAS5ID50217ch1q25.html DOI: 10.4267/2042/44823 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology hybridisation, in a screen intended to isolate potential tumor suppressor genes. The functions of GAS5 is not well known as yet, however, emerging evidence implicates this gene in apoptosis, autoimmune disease, leukemias and lymphomas, and other cancers. Identity Other names: NCRNA00030; SNHG2 HGNC (Hugo): GAS5 Location: 1q25.1 Note: GAS5 is also designed as small nucleolar RNA host gene (non-protein coding) 2 and non-protein coding RNA 30. 1q25 locus displays abnormalities in a number of cancers, melanoma, prostate, breast and several types of leukaemia and lymphoma. The GAS5 gene was isolated from NIH 3T3 cells using subtraction DNA/RNA Description The gene spans about 4.98 kb. Orientation minus strand. Number of exons: 12. GenBank: AF141346.1. GAS5 gene hosts multiple small Representation of five of GAS5 splice variants. Boxes numbered 2 to12 represent exons. U79, U80, U47, U81 and U74 represent the box C/D small nucleolar RNAs (snoRNAs). Horizontal lines represent the intronic sequences. Exons, introns and snoRNAs are not drawn to scale (IMAGE clone 6194071, 1249 bp; IMAGE clone 2598129, 1270 bp; IMAGE clone 3585621, 1396 bp; Gas5 3A, 1802 bp; IMAGE clone 5739605, 1802 bp; IMAGE clone 2761825, 1802 bp). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 758 GAS5 (growth arrest-specific 5 (non-protein coding)) Mourtada-Maarabouni M nucleolar RNA (snoRNA) host gene similar to UHG (U22 host gene) which encode, within the 11 introns of the human GAS5 gene, ten box C/D snoRNAs predicted to play a role in the 2'-O-methylation of rRNA. Its 5' end sequence contains an oligopyrimidine tract characteristic of the 5'-TOP class of genes. Systemic lupus erythematosus Note The GAS5 gene is located in the disease susceptibility locus in mouse BXSB strain, which develops glomerulonephritis associated with systemic lupus erythematosus (SLE). Subsequent studies involving genetic analysis of a mouse model of SLE have indicated that GAS5 may well be involved in its pathology. Besides, the human chromosomal locus 1q25 at which the GAS5 gene is encoded has been associated with SLE in genetic studies in humans. Transcription The length of GAS5 transcript is 651 bp (NR_002578 in GenBank). The 5' end sequence of the GAS5 transcript contains an oligopyrimidine tract characteristic of the 5'-TOP class of genes. GAS5 transcripts display several patterns of alternate splicing. The initial GAS5 transcript is subject to complex posttranscriptional processing resulting in several splice variants. However its putative open reading frame is small and poorly conserved during even relatively short periods of evolution, as demonstrated by a number of disruptions caused by frameshift mutations in several mouse strains, and by an interruption by a stop codon after the first 13 amino acids in rat GAS5. The diagram above shows some of GAS5 splice variants which are reported to affect cell fate in different ways. Apoptosis/cell cycle regulation Note A fragment of GAS5 cDNA has been isolated from a retroviral cDNA expression library by using an unbiased functional screen for genes that control apoptosis in lymphocytes. Further studies have shown that GAS5 plays an essential role in normal growth arrest in both T-cell lines and non-transformed lymphocytes. Overexpression of GAS5 causes both an enhancement in apoptosis and a decrease in the rate of progression through the cell cycle in leukeamic T cell lines and primary lymphocytes. Consistent with this, downregulation of endogenous GAS5 inhibits apoptosis and maintains a more rapid cell cycle, indicating that GAS5 expression is both essential and sufficient for normal growth arrest in T-cell lines as well as human peripheral blood T-cells. Overexpression of certain GAS5 transcripts is reported to induce growth arrest and apoptosis in several mammalian cell lines. Protein Note GAS5 exons do not encode a polypeptide product. Mutations Note Chromosomal rearrangements involving GAS5 have been identified in a human B-cell lymphoma where GAS5 gene becomes fused to the BCL6 gene. GAS5 is also involved in a chromosomal rearrangement with Notch1 in radiation-induced murine thymic lymphoma. Oncogenesis Note GAS5 is encoded at 1q25, a locus displaying abnormalities in a number of cancers, e.g. melanoma, prostate, breast, and several types of leukaemia and lymphoma. Gene expression analysis has shown that GAS5 is up-regulated 3.3-fold (the greatest upregulation for any gene in the whole-genome array) by oncogenic kinases associated with myeloproliferative disorders. Chromosomal rearrangements involving GAS5 have also been identified in a human B-cell lymphoma. GAS5 expression levels are reported to regulate both the induction of apoptosis and cell cycle arrest in T-cell lines and non-transformed lymphocytes, suggesting that it may be very significant in the development of leukaemia and lymphoma. Overexpression of certain GAS5 transcripts is reported to induce growth arrest and apoptosis in several human cell lines, including human breast cancer cell lines. GAS5 expression is significantly downregulated in breast cancer tissue compared with those found in untransformed breast epithelial tissue from the same patients, a clear reduction of more than 65% was Implicated in Regulation of cell growth Note The GAS5 gene was isolated from NIH 3T3 cells using subtraction hybridisation, in a screen intended to isolate potential tumor suppressor genes. GAS5 is reported to be ubiquitously expressed during mouse development and adult life, and also to be expressed only at low levels in actively growing Friend leukemia and NIH 3T3 cells, with substantially increased abundance in cells grown to saturation density. The RNA levels of GAS5 appear to be regulated primarily through changes in its rate of degradation rather than through changes in its transcription rate. GAS5 RNA abundance was also found to be increased by amino acid deprivation. Studies also have shown that GAS5 is necessary and sufficient for growth arrest in both untransformed and leukaemic lymphocytes. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 759 GAS5 (growth arrest-specific 5 (non-protein coding)) Mourtada-Maarabouni M Tsuji H, Ishii-Ohba H, Ukai H, Katsube T, Ogiu T. Radiationinduced deletions in the 5' end region of Notch1 lead to the formation of truncated proteins and are involved in the development of mouse thymic lymphomas. Carcinogenesis. 2003 Jul;24(7):1257-68 observed in this study, suggesting that the reduction in GAS5 expression is an early event in oncogenesis. References Tsao BP. Update on human systemic lupus erythematosus genetics. Curr Opin Rheumatol. 2004 Sep;16(5):513-21 Schneider C, King RM, Philipson L. Genes specifically expressed at growth arrest of mammalian cells. Cell. 1988 Sep 9;54(6):787-93 Williams GT, Farzaneh F. The use of gene function to identify the rate-limiting steps controlling cell fate. Cancer Immunol Immunother. 2004 Mar;53(3):160-5 Coccia EM, Cicala C, Charlesworth A, Ciccarelli C, Rossi GB, Philipson L, Sorrentino V. Regulation and expression of a growth arrest-specific gene (gas5) during growth, differentiation, and development. Mol Cell Biol. 1992 Aug;12(8):3514-21 Haywood ME, Rose SJ, Horswell S, Lees MJ, Fu G, Walport MJ, Morley BJ. Overlapping BXSB congenic intervals, in combination with microarray gene expression, reveal novel lupus candidate genes. Genes Immun. 2006 Apr;7(3):250-63 Vacha SJ, Bennett GD, Mackler SA, Koebbe MJ, Finnell RH. Identification of a growth arrest specific (gas 5) gene by differential display as a candidate gene for determining susceptibility to hyperthermia-induced exencephaly in mice. Dev Genet. 1997;21(3):212-22 Lelièvre H, Cervera N, Finetti P, Delhommeau F, Vainchenker W, Bertucci F, Birnbaum D. Oncogenic kinases of myeloproliferative disorders induce both protein synthesis and G1 activators. Leukemia. 2006 Oct;20(10):1885-8 Fleming JV, Hay SM, Harries DN, Rees WD. Effects of nutrient deprivation and differentiation on the expression of growtharrest genes (gas and gadd) in F9 embryonal carcinoma cells. Biochem J. 1998 Feb 15;330 ( Pt 1):573-9 Stange DE, Radlwimmer B, Schubert F, Traub F, Pich A, Toedt G, Mendrzyk F, Lehmann U, Eils R, Kreipe H, Lichter P. Highresolution genomic profiling reveals association of chromosomal aberrations on 1q and 16p with histologic and genetic subgroups of invasive breast cancer. Clin Cancer Res. 2006 Jan 15;12(2):345-52 Muller AJ, Chatterjee S, Teresky A, Levine AJ. The gas5 gene is disrupted by a frameshift mutation within its longest open reading frame in several inbred mouse strains and maps to murine chromosome 1. Mamm Genome. 1998 Sep;9(9):773-4 Williams GT, Hughes JP, Stoneman V, Anderson CL, McCarthy NJ, Mourtada-Maarabouni M, Pickard M, Hedge VL, Trayner I, Farzaneh F. Isolation of genes controlling apoptosis through their effects on cell survival. Gene Ther Mol Biol. 2006 Dec 12;10(B):255-262 Smith CM, Steitz JA. Classification of gas5 as a multi-smallnucleolar-RNA (snoRNA) host gene and a member of the 5'terminal oligopyrimidine gene family reveals common features of snoRNA host genes. Mol Cell Biol. 1998 Dec;18(12):6897909 Mourtada-Maarabouni M, Hedge VL, Kirkham L, Farzaneh F, Williams GT. Growth arrest in human T-cells is controlled by the non-coding RNA growth-arrest-specific transcript 5 (GAS5). J Cell Sci. 2008 Apr 1;121(Pt 7):939-46 Raho G, Barone V, Rossi D, Philipson L, Sorrentino V. The gas 5 gene shows four alternative splicing patterns without coding for a protein. Gene. 2000 Oct 3;256(1-2):13-7 Nakamura Y, Takahashi N, Kakegawa E, Yoshida K, Ito Y, Kayano H, Niitsu N, Jinnai I, Bessho M. The GAS5 (growth arrest-specific transcript 5) gene fuses to BCL6 as a result of t(1;3)(q25;q27) in a patient with B-cell lymphoma. Cancer Genet Cytogenet. 2008 Apr 15;182(2):144-9 Smedley D, Sidhar S, Birdsall S, Bennett D, Herlyn M, Cooper C, Shipley J. Characterization of chromosome 1 abnormalities in malignant melanomas. Genes Chromosomes Cancer. 2000 May;28(1):121-5 Fontanier-Razzaq N, Harries DN, Hay SM, Rees WD. Amino acid deficiency up-regulates specific mRNAs in murine embryonic cells. J Nutr. 2002 Aug;132(8):2137-42 Mourtada-Maarabouni M, Pickard MR, Hedge VL, Farzaneh F, Williams GT. GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene. 2009 Jan 15;28(2):195-208 Johanneson B, Lima G, von Salomé J, Alarcón-Segovia D, Alarcón-Riquelme ME. A major susceptibility locus for systemic lupus erythemathosus maps to chromosome 1q31. Am J Hum Genet. 2002 Nov;71(5):1060-71 This article should be referenced as such: Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) Mourtada-Maarabouni M. GAS5 (growth arrest-specific 5 (nonprotein coding)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):758-760. 760