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

2009-09-01   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

HGNC
LOCATION
1p31.3
LOCUSID
ALIAS
ARHI,NOEY2
FUSION GENES

DNA/RNA

Atlas Image
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.

Proteins

Atlas Image
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 name
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.

Article Bibliography

Pubmed IDLast YearTitleAuthors

Other Information

Locus ID:

NCBI: 9077
MIM: 605193
HGNC: 687
Ensembl: ENSG00000162595

Variants:

dbSNP: 9077
ClinVar: 9077
TCGA: ENSG00000162595
COSMIC: DIRAS3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000162595ENST00000370981O95661
ENSG00000162595ENST00000646789O95661

Expression (GTEx)

0
50
100
150

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
381693242024DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas.0
382037332024Expression of RASSF1A, DIRAS3, and AKAP9 Genes in Thyroid Lesions: Implications for Differential Diagnosis and Prognosis of Thyroid Carcinomas.0
381693242024DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas.0
382037332024Expression of RASSF1A, DIRAS3, and AKAP9 Genes in Thyroid Lesions: Implications for Differential Diagnosis and Prognosis of Thyroid Carcinomas.0
375985412023DIRAS3 regulates autophagy in an endometriosis epithelial cell line.1
375985412023DIRAS3 regulates autophagy in an endometriosis epithelial cell line.1
320654822020A risk signature with four autophagy-related genes for predicting survival of glioblastoma multiforme.48
324849262020Elimination of dormant, autophagic ovarian cancer cells and xenografts through enhanced sensitivity to anaplastic lymphoma kinase inhibition.7
329493952020The Role of Methylation in the CpG Island of the ARHI Promoter Region in Cancers.2
320654822020A risk signature with four autophagy-related genes for predicting survival of glioblastoma multiforme.48
324849262020Elimination of dormant, autophagic ovarian cancer cells and xenografts through enhanced sensitivity to anaplastic lymphoma kinase inhibition.7
329493952020The Role of Methylation in the CpG Island of the ARHI Promoter Region in Cancers.2
310776132019Epigenetic inhibition of the tumor suppressor ARHI by light at night-induced circadian melatonin disruption mediates STAT3-driven paclitaxel resistance in breast cancer.34
310884022019Oncogenic Ras is downregulated by ARHI and induces autophagy by Ras/AKT/mTOR pathway in glioblastoma.5
318258282019DIRAS3 (ARHI) Blocks RAS/MAPK Signaling by Binding Directly to RAS and Disrupting RAS Clusters.34

Citation

Yinhua Yu ; Zhen Lu ; Robert Z Luo ; Robert C Bast Jr

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

Atlas Genet Cytogenet Oncol Haematol. 2009-09-01

Online version: http://atlasgeneticsoncology.org/gene/702/meetings/js/favicon/manifest.json