| Written | 2009-09 | Yinhua Yu, Zhen Lu, Robert Z Luo, Robert C Bast Jr |
| The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 354, Houston, TX 77030, USA |
| Identity |
| Alias (NCBI) | ARHI | NOEY2 | RHOI |
| HGNC (Hugo) | DIRAS3 |
| HGNC Alias symb | NOEY2 |
| HGNC Previous name | ARHI |
| HGNC Previous name | ras homolog gene family, member I | DIRAS family, GTP-binding RAS-like 3 |
| LocusID (NCBI) | 9077 |
| Atlas_Id | 702 |
| Location | 1p31.3 [Link to chromosome band 1p31] |
| Location_base_pair | Starts at 68045886 and ends at 68051631 bp from pter ( according to GRCh38/hg38-Dec_2013) [Mapping DIRAS3.png] |
| Local_order | Telomeric to GNG12, RMU7-80P and centromeric to GPR177, RPS7P4. |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| GNG12 (1p31.3)::DIRAS3 (1p31.3) | WLS (1p31.3)::DIRAS3 (1p31.3) |
| Note | DIRAS3 is also known as NOEY2 and ARHI (Ras homologue member I). |
| DNA/RNA |
 | |
| The DIRAS3 gene contains two exons interrupted by a large intron. The red-blocked and opened boxes represent the coding and non-coding regions, respectively. There are three CpG island regions. Blue: CPG island I; green: CpG island II; grey: CpG island III. | |
| Description | DIRAS3 encompasses a 7.2-kb region and includes 2.0 kb of the 5'- flanking region, two exons, an intron, and a 1.2-kb 3'-flanking region. The first exon contains only the 5'-noncoding region consisting of 81 nucleotides, whereas the second exon contains the entire protein-coding region. The two exons are separated by an intron of 3.2 kb. There are three CpG island regions. CPG island I (nucleotide (nt) -1232 to -914) is located about 1 kb upstream of the transcription initiation site; CpG island II (nt -206 to +79) is near the transcription initiation region and adjacent exon 1; CpG island III (nt +3343 to +3691) is located in the protein-encoding region of exon 2. |
| Transcription | The entire protein-coding region is located within exon 2 and encodes a 229-residue small GTP-binding protein. |
| Pseudogene | No known pseudogenes. |
| Protein |
 | |
| DIRAS3 protein. | |
| Description | DIRAS3 encodes a 26-kDa GTPase. The DIRAS3 gene ORF contains three motifs typical of Ras/Rap family members: (1) a highly conserved GTP binding domain, (2) a putative effector domain YLPTIENTY, and (3) the membrane localizing CAAX motif at the COOH terminus. DIRAS3 contains a unique 34 amino-acid extension at the N-terminus and differs from other members of Ras-superfamily. |
| Expression | DIRAS3 is expressed in brain, heart, liver, lung, pancreas, breast and ovary. |
| Localisation | DIRAS is associated at the cell membrane through its prenylation at the C-terminal cysteine residue. Mutation of the conserved CAAX box at the C-terminus led to a loss of its membrane association. |
| Function | DIRAS3 is a maternally imprinted tumor suppressor gene that belongs to the Ras superfamily of small G proteins. DIRAS3 regulates cell cycle, motility, angiogenesis, autophagy and tumor dormancy. Introduction of this gene into cancer cells that lack DIRAS3 expression inhibits proliferation and motility of cancer cells. DIRAS3 truncates signaling through the Ras/MAP pathway, induces p21WAF1/CIP1, down-regulates cyclin D1, and triggers apoptosis. DIRAS3 is required for autophagy and that re-expression of DIRAS3 protein in ovarian cancer cells will induce autophagic cell death in culture. In xenografts, re-expression of DIRAS3 also induces autophagy, but can also promote tumor dormancy in the presence of factors that promote survival in the cancer microenvironment. |
| Homology | DIRAS3 shares 56% amino acid homology with Rap1A, 56% with Rap1B, 58% with Rap 2A, 62% with Rap2B, 59% with K-Ras, and 54% with H-Ras. DIRAS3 shares about 40% homology with DIRAS1 and DIRAS2. |
| Mutations |
| Note | Mutations have not been detected. |
| Implicated in |
| Note | |
| Entity | Solid cancers |
| Disease | Ovarian cancer, breast cancer, pancreatic cancer, hepatocellular carcinoma, oligodendroglial tumor, follicular thyroid cancer. |
| Prognosis | Loss of DIRAS3 expression is associated with tumor progression in breast cancer and decreased disease-free survival in ovarian cancer. |
| Oncogenesis | DIRAS3 is monoallelically expressed and maternally imprinted, expression from the paternal allele of DIRAS3 can be lost through LOH, CpG methylation, and transcriptional regulation. DIRAS3 is downregulated in 60% of ovarian and breast cancers: LOH was found in 40% of ovarian and breast cancers. Mutations have not been detected, but the remaining allele is silenced in ovarian cancer and breast cancer by methylation in approximately 10-15 % of cases. In the remaining cancers, DIRAS3 is downregulated by transcriptional mechanisms that involve E2F1 and E2F4, as well as by the loss of RNA binding proteins that decrease the half-life of DIRAS3 mRNA. |
| Bibliography |
| Reexpression of the tumor suppressor gene ARHI induces apoptosis in ovarian and breast cancer cells through a caspase-independent calpain-dependent pathway. |
| Bao JJ, Le XF, Wang RY, Yuan J, Wang L, Atkinson EN, LaPushin R, Andreeff M, Fang B, Yu Y, Bast RC Jr. |
| Cancer Res. 2002 Dec 15;62(24):7264-72. |
| PMID 12499268 |
| Multiple histone deacetylases repress tumor suppressor gene ARHI in breast cancer. |
| Feng W, Lu Z, Luo RZ, Zhang X, Seto E, Liao WS, Yu Y. |
| Int J Cancer. 2007 Apr 15;120(8):1664-8. |
| PMID 17230502 |
| Reactivation of the silenced and imprinted alleles of ARHI is associated with increased histone H3 acetylation and decreased histone H3 lysine 9 methylation. |
| Fujii S, Luo RZ, Yuan J, Kadota M, Oshimura M, Dent SR, Kondo Y, Issa JP, Bast RC Jr, Yu Y. |
| Hum Mol Genet. 2003 Aug 1;12(15):1791-800. |
| PMID 12874100 |
| ARHI, as a novel suppressor of cell growth and downregulated in human hepatocellular carcinoma, could contribute to hepatocarcinogenesis. |
| Huang J, Lin Y, Li L, Qing D, Teng XM, Zhang YL, Hu X, Hu Y, Yang P, Han ZG. |
| Mol Carcinog. 2009 Feb;48(2):130-40. |
| PMID 18612997 |
| ARHI (DIRAS 3), an imprinted tumor suppressor gene, binds to importins, and blocks nuclear import process of cargo proteins. |
| Huang S, Chang IS, Lin W, Ye W, Luo RZ, Lu Z, Lu Y, Zhang K, Liao WS, Tao T, Bast Jr RC, Chen X, Yu Y. |
| Biosci Rep. 2009 May 13. [Epub ahead of print] |
| PMID 19435463 |
| The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. |
| Lu Z, Luo RZ, Lu Y, Zhang X, Yu Q, Khare S, Kondo S, Kondo Y, Yu Y, Mills GB, Liao WS, Bast RC Jr. |
| J Clin Invest. 2008 Dec;118(12):3917-29. Epub 2008 Nov 20. |
| PMID 19033662 |
| ARHI is a Ras-related small G-protein with a novel N-terminal extension that inhibits growth of ovarian and breast cancers. |
| Luo RZ, Fang X, Marquez R, Liu SY, Mills GB, Liao WS, Yu Y, Bast RC. |
| Oncogene. 2003 May 15;22(19):2897-909. |
| PMID 12771940 |
| Genomic structure and promoter characterization of an imprinted tumor suppressor gene ARHI. |
| Luo RZ, Peng H, Xu F, Bao J, Pang Y, Pershad R, Issa JP, Liao WS, Bast RC Jr, Yu Y. |
| Biochim Biophys Acta. 2001 Jun 28;1519(3):216-22. |
| PMID 11418188 |
| A Ras homologue member I directly inhibits signal transducers and activators of transcription 3 translocation and activity in human breast and ovarian cancer cells. |
| Nishimoto A, Yu Y, Lu Z, Mao X, Ren Z, Watowich SS, Mills GB, Liao WS, Chen X, Bast RC Jr, Luo RZ. |
| Cancer Res. 2005 Aug 1;65(15):6701-10. |
| PMID 16061651 |
| ARHI is the center of allelic deletion on chromosome 1p31 in ovarian and breast cancers. |
| Peng H, Xu F, Pershad R, Hunt KK, Frazier ML, Berchuck A, Gray JW, Hogg D, Bast RC Jr, Yu Y. |
| Int J Cancer. 2000 Jun 1;86(5):690-4. |
| PMID 10797292 |
| Frequent biallelic inactivation and transcriptional silencing of the DIRAS3 gene at 1p31 in oligodendroglial tumors with 1p loss. |
| Riemenschneider MJ, Reifenberger J, Reifenberger G. |
| Int J Cancer. 2008 Jun 1;122(11):2503-10. |
| PMID 18302158 |
| Expression of the tumor suppressor gene ARHI in epithelial ovarian cancer is associated with increased expression of p21WAF1/CIP1 and prolonged progression-free survival. |
| Rosen DG, Wang L, Jain AN, Lu KH, Luo RZ, Yu Y, Liu J, Bast RC Jr. |
| Clin Cancer Res. 2004 Oct 1;10(19):6559-66. |
| PMID 15475444 |
| Loss of the expression of the tumor suppressor gene ARHI is associated with progression of breast cancer. |
| Wang L, Hoque A, Luo RZ, Yuan J, Lu Z, Nishimoto A, Liu J, Sahin AA, Lippman SM, Bast RC Jr, Yu Y. |
| Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3660-6. |
| PMID 14506155 |
| Silencing of the maternally imprinted tumor suppressor ARHI contributes to follicular thyroid carcinogenesis. |
| Weber F, Aldred MA, Morrison CD, Plass C, Frilling A, Broelsch CE, Waite KA, Eng C. |
| J Clin Endocrinol Metab. 2005 Feb;90(2):1149-55. Epub 2004 Nov 16. |
| PMID 15546898 |
| The human ARHI tumor suppressor gene inhibits lactation and growth in transgenic mice. |
| Xu F, Xia W, Luo RZ, Peng H, Zhao S, Dai J, Long Y, Zou L, Le W, Liu J, Parlow AF, Hung MC, Bast RC Jr, Yu Y. |
| Cancer Res. 2000 Sep 1;60(17):4913-20. |
| PMID 10987306 |
| Epigenetic regulation of ARHI in breast and ovarian cancer cells. |
| Yu Y, Fujii S, Yuan J, Luo RZ, Wang L, Bao J, Kadota M, Oshimura M, Dent SR, Issa JP, Bast RC Jr. |
| Ann N Y Acad Sci. 2003 Mar;983:268-77. (REVIEW) |
| PMID 12724231 |
| Biochemistry and biology of ARHI (DIRAS3), an imprinted tumor suppressor gene whose expression is lost in ovarian and breast cancers. |
| Yu Y, Luo R, Lu Z, Wei Feng W, Badgwell D, Issa JP, Rosen DG, Liu J, Bast RC Jr. |
| Methods Enzymol. 2006;407:455-68. |
| PMID 16757345 |
| NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas. |
| Yu Y, Xu F, Peng H, Fang X, Zhao S, Li Y, Cuevas B, Kuo WL, Gray JW, Siciliano M, Mills GB, Bast RC Jr. |
| Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):214-9. |
| PMID 9874798 |
| Aberrant methylation and silencing of ARHI, an imprinted tumor suppressor gene in which the function is lost in breast cancers. |
| Yuan J, Luo RZ, Fujii S, Wang L, Hu W, Andreeff M, Pan Y, Kadota M, Oshimura M, Sahin AA, Issa JP, Bast RC Jr, Yu Y. |
| Cancer Res. 2003 Jul 15;63(14):4174-80. |
| PMID 12874023 |
| Citation |
| This paper should be referenced as such : |
| Guénard, F ; Durocher, F |
| DHX9 (DEAH (Asp-Glu-Ala-His) box polypeptide 9) |
| Atlas Genet Cytogenet Oncol Haematol. 2010;14(6):547-549. |
| Free journal version : [ pdf ] [ DOI ] |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Fri Oct 8 21:16:11 CEST 2021 |
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