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DIRAS3 (DIRAS family, GTP-binding RAS-like 3)

Identity

Other namesARHI
NOEY2
RHOI
HGNC (Hugo) DIRAS3
LocusID (NCBI) 9077
Location 1p31.3
Location_base_pair Starts at 68511645 and ends at 68516460 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Telomeric to GNG12, RMU7-80P and centromeric to GPR177, RPS7P4.
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

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.
  

External links

Nomenclature
HGNC (Hugo)DIRAS3   687
Entrez_Gene (NCBI)DIRAS3  9077  DIRAS family, GTP-binding RAS-like 3
Cards
AtlasDIRAS3ID702ch1p31
GeneCards (Weizmann)DIRAS3
Ensembl (Hinxton)ENSG00000162595 [Gene_View]  chr1:68511645-68516460 [Contig_View]  DIRAS3 [Vega]
AceView (NCBI)DIRAS3
Genatlas (Paris)DIRAS3
SOURCE (Stanford)NM_004675
Genomic and cartography
GoldenPath (UCSC)DIRAS3  -  1p31.3   chr1:68511645-68516460 -  1p31   [Description]    (hg19-Feb_2009)
EnsemblDIRAS3 - 1p31 [CytoView]
Mapping of homologs : NCBIDIRAS3 [Mapview]
OMIM605193   
Gene and transcription
Genbank (Entrez)AK021882 AK096393 BC005362 CR541870 CR541892
RefSeq transcript (SRS)NM_004675
RefSeq transcript (Entrez)NM_004675
RefSeq genomic (SRS)AC_000133 NC_000001 NC_018912 NG_011753 NT_032977 NW_001838579 NW_004077990
RefSeq genomic (Entrez)AC_000133 NC_000001 NC_018912 NG_011753 NT_032977 NW_001838579 NW_004077990
Consensus coding sequences : CCDS (NCBI)DIRAS3
Cluster EST : UnigeneHs.194695 [ SRS ] Hs.194695 [ NCBI ]
CGAP (NCI)Hs.194695
Alternative Splicing : Fast-db (Paris)GSHG0001256
Alternative Splicing GalleryENSG00000162595
Gene ExpressionDIRAS3 [ NCBI-GEO ]   DIRAS3 [ EBI - ARRAY_EXPRESS ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO95661 (SRS) O95661 (Uniprot)
NextProtO95661
With graphics : InterProO95661
Splice isoforms : SwissVarO95661(Swissvar)
Domaine pattern : Prosite (SRS)RAS (PS51421)   
Domaine pattern : Prosite (Expaxy)RAS (PS51421)   
Domains : Interpro (SRS)Small_GTP-bd_dom    Small_GTPase    Small_GTPase_Ras   
Domains : Interpro (EBI)Small_GTP-bd_dom    Small_GTPase    Small_GTPase_Ras   
Related proteins : CluSTrO95661
Domain families : Pfam (SRS)Ras (PF00071)   
Domain families : Pfam (Sanger)Ras (PF00071)   
Domain families : Pfam (NCBI)pfam00071   
DMDM9077
Blocks (Seattle)O95661
Human Protein AtlasENSG00000162595
HPRD05547
IPIIPI00032112   
Protein Interaction databases
DIP (DOE-UCLA)O95661
IntAct (EBI)O95661
FunCoupENSG00000162595
REACTOMEDIRAS3
Protein Interaction Database9077
BioGRIDDIRAS3
InParanoidO95661
Interologous Interaction database O95661
IntegromeDBDIRAS3
Polymorphism : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)DIRAS3
SNP (GeneSNP Utah)DIRAS3
SNP : HGBaseDIRAS3
Genetic variants : HAPMAPDIRAS3
Somatic Mutations in Cancer : COSMICDIRAS3 
CONAN: Copy Number AnalysisDIRAS3 
Mutations and Diseases : HGMDDIRAS3
OMIM605193   
GENETests605193   
Disease Genetic AssociationDIRAS3
Huge Navigator DIRAS3 [HugePedia]  DIRAS3 [HugeCancerGEM]
Genomic VariantsDIRAS3  DIRAS3 [DGVbeta]
snp3D : Map Gene to Disease9077
General knowledge
Homologs : HomoloGeneDIRAS3
Homology/Alignments : Family Browser (UCSC)DIRAS3
Phylogenetic Trees/Animal Genes : TreeFamDIRAS3
Chemical/Protein Interactions : CTD9077
Chemical/Pharm GKB GenePA24980
Clinical trialDIRAS3
Cancer Resource (Charite)ENSG00000162595
Ontology : AmiGOregulation of cyclin-dependent protein kinase activity  GTPase activity  protein binding  GTP binding  plasma membrane  regulation of gene expression by genetic imprinting  small GTPase mediated signal transduction  
Ontology : EGO-EBIregulation of cyclin-dependent protein kinase activity  GTPase activity  protein binding  GTP binding  plasma membrane  regulation of gene expression by genetic imprinting  small GTPase mediated signal transduction  
Other databases
Probes
Litterature
PubMed28 Pubmed reference(s) in Entrez
PubGeneDIRAS3
iHOPDIRAS3

Bibliography

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
 
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
 
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
 
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
 
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
 
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 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
 
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
 
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
 
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
 
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
 
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
 
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
 
E2F-HDAC complexes negatively regulate the tumor suppressor gene ARHI in breast cancer.
Lu Z, Luo RZ, Peng H, Huang M, Nishmoto A, Hunt KK, Helin K, Liao WS, Yu Y.
Oncogene. 2006 Jan 12;25(2):230-9.
PMID 16158053
 
Transcriptional and posttranscriptional down-regulation of the imprinted tumor suppressor gene ARHI (DRAS3) in ovarian cancer.
Lu Z, Luo RZ, Peng H, Rosen DG, Atkinson EN, Warneke C, Huang M, Nishmoto A, Liu J, Liao WS, Yu Y, Bast RC Jr.
Clin Cancer Res. 2006 Apr 15;12(8):2404-13.
PMID 16638845
 
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
 
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
 
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
 
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
 
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
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written09-2009Yinhua 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

Citation

This paper should be referenced as such :
Yu Y, Lu Z, Luo RZ, Bast RC Jr . DIRAS3 (DIRAS family, GTP-binding RAS-like 3). Atlas Genet Cytogenet Oncol Haematol. September 2009 .
URL : http://AtlasGeneticsOncology.org/Genes/DIRAS3ID702ch1p31.html

This paper is referenced by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/44814/1/09-2009-DIRAS3ID702ch1p31.pdf   [ Bibliographic record ]

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indexed on : Wed May 1 13:03:31 CEST 2013
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