Atlas of Genetics and Cytogenetics in Oncology and Haematology

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

Written2009-09Yinhua 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

(Note : for Links provided by Atlas : click)


HGNC Alias symbNOEY2
HGNC Previous nameARHI
HGNC Previous nameras 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).


  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.


  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.


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.


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


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


HGNC (Hugo)DIRAS3   687
LRG (Locus Reference Genomic)LRG_1034
Entrez_Gene (NCBI)DIRAS3    DIRAS family GTPase 3
AliasesARHI; NOEY2
GeneCards (Weizmann)DIRAS3
Ensembl hg19 (Hinxton)ENSG00000162595 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000162595 [Gene_View]  ENSG00000162595 [Sequence]  chr1:68045886-68051631 [Contig_View]  DIRAS3 [Vega]
ICGC DataPortalENSG00000162595
Genatlas (Paris)DIRAS3
SOURCE (Princeton)DIRAS3
Genetics Home Reference (NIH)DIRAS3
Genomic and cartography
GoldenPath hg38 (UCSC)DIRAS3  -     chr1:68045886-68051631 -  1p31.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)DIRAS3  -     1p31.3   [Description]    (hg19-Feb_2009)
GoldenPathDIRAS3 - 1p31.3 [CytoView hg19]  DIRAS3 - 1p31.3 [CytoView hg38]
Genome Data Viewer NCBIDIRAS3 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AK021882 AK096393 BC005362 CR541870 CR541892
RefSeq transcript (Entrez)NM_004675
Consensus coding sequences : CCDS (NCBI)DIRAS3
Gene ExpressionDIRAS3 [ NCBI-GEO ]   DIRAS3 [ EBI - ARRAY_EXPRESS ]   DIRAS3 [ SEEK ]   DIRAS3 [ MEM ]
Gene Expression Viewer (FireBrowse)DIRAS3 [ Firebrowse - Broad ]
GenevisibleExpression of DIRAS3 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9077
GTEX Portal (Tissue expression)DIRAS3
Human Protein AtlasENSG00000162595-DIRAS3 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO95661   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO95661  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO95661
Domaine pattern : Prosite (Expaxy)RAS (PS51421)   
Domains : Interpro (EBI)P-loop_NTPase    Small_GTP-bd_dom    Small_GTPase    Small_GTPase_Ras-type   
Domain families : Pfam (Sanger)Ras (PF00071)   
Domain families : Pfam (NCBI)pfam00071   
Conserved Domain (NCBI)DIRAS3
PDB Europe6NAZ   
Structural Biology KnowledgeBase6NAZ   
SCOP (Structural Classification of Proteins)6NAZ   
CATH (Classification of proteins structures)6NAZ   
AlphaFold pdb e-kbO95661   
Human Protein Atlas [tissue]ENSG00000162595-DIRAS3 [tissue]
Protein Interaction databases
IntAct (EBI)O95661
Ontologies - Pathways
Ontology : AmiGOregulation of cyclin-dependent protein serine/threonine kinase activity  GTPase activity  protein binding  GTP binding  plasma membrane  regulation of gene expression by genetic imprinting  small GTPase mediated signal transduction  GDP binding  
Ontology : EGO-EBIregulation of cyclin-dependent protein serine/threonine kinase activity  GTPase activity  protein binding  GTP binding  plasma membrane  regulation of gene expression by genetic imprinting  small GTPase mediated signal transduction  GDP binding  
NDEx NetworkDIRAS3
Atlas of Cancer Signalling NetworkDIRAS3
Wikipedia pathwaysDIRAS3
Orthology - Evolution
GeneTree (enSembl)ENSG00000162595
Phylogenetic Trees/Animal Genes : TreeFamDIRAS3
Homologs : HomoloGeneDIRAS3
Homology/Alignments : Family Browser (UCSC)DIRAS3
Gene fusions - Rearrangements
Fusion : MitelmanGNG12::DIRAS3 [1p31.3/1p31.3]  
Fusion : QuiverDIRAS3
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerDIRAS3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)DIRAS3
Exome Variant ServerDIRAS3
GNOMAD BrowserENSG00000162595
Varsome BrowserDIRAS3
ACMGDIRAS3 variants
Genomic Variants (DGV)DIRAS3 [DGVbeta]
DECIPHERDIRAS3 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisDIRAS3 
ICGC Data PortalDIRAS3 
TCGA Data PortalDIRAS3 
Broad Tumor PortalDIRAS3
OASIS PortalDIRAS3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICDIRAS3  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DDIRAS3
Mutations and Diseases : HGMDDIRAS3
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)DIRAS3
DoCM (Curated mutations)DIRAS3
CIViC (Clinical Interpretations of Variants in Cancer)DIRAS3
NCG (London)DIRAS3
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry DIRAS3
NextProtO95661 [Medical]
Target ValidationDIRAS3
Huge Navigator DIRAS3 [HugePedia]
ClinGenDIRAS3 (curated)
Clinical trials, drugs, therapy
Protein Interactions : CTDDIRAS3
Pharm GKB GenePA24980
Clinical trialDIRAS3
DataMed IndexDIRAS3
PubMed68 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:16:11 CEST 2021

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