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.

Bibliography

Pubmed IDLast YearTitleAuthors
124992682002Reexpression of the tumor suppressor gene ARHI induces apoptosis in ovarian and breast cancer cells through a caspase-independent calpain-dependent pathway.Bao JJ et al
172305022007Multiple histone deacetylases repress tumor suppressor gene ARHI in breast cancer.Feng W et al
128741002003Reactivation of the silenced and imprinted alleles of ARHI is associated with increased histone H3 acetylation and decreased histone H3 lysine 9 methylation.Fujii S et al
186129972009ARHI, as a novel suppressor of cell growth and downregulated in human hepatocellular carcinoma, could contribute to hepatocarcinogenesis.Huang J et al
194354632009ARHI (DIRAS3), an imprinted tumour suppressor gene, binds to importins and blocks nuclear import of cargo proteins.Huang S et al
190336622008The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells.Lu Z et al
127719402003ARHI is a Ras-related small G-protein with a novel N-terminal extension that inhibits growth of ovarian and breast cancers.Luo RZ et al
114181882001Genomic structure and promoter characterization of an imprinted tumor suppressor gene ARHI.Luo RZ et al
160616512005A 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 et al
107972922000ARHI is the center of allelic deletion on chromosome 1p31 in ovarian and breast cancers.Peng H et al
183021582008Frequent biallelic inactivation and transcriptional silencing of the DIRAS3 gene at 1p31 in oligodendroglial tumors with 1p loss.Riemenschneider MJ et al
154754442004Expression 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 et al
145061552003Loss of the expression of the tumor suppressor gene ARHI is associated with progression of breast cancer.Wang L et al
155468982005Silencing of the maternally imprinted tumor suppressor ARHI contributes to follicular thyroid carcinogenesis.Weber F et al
109873062000The human ARHI tumor suppressor gene inhibits lactation and growth in transgenic mice.Xu F et al
127242312003Epigenetic regulation of ARHI in breast and ovarian cancer cells.Yu Y et al
167573452006Biochemistry and biology of ARHI (DIRAS3), an imprinted tumor suppressor gene whose expression is lost in ovarian and breast cancers.Yu Y et al
98747981999NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas.Yu Y et al
128740232003Aberrant methylation and silencing of ARHI, an imprinted tumor suppressor gene in which the function is lost in breast cancers.Yuan J et al

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
190336622008The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells.160
98747981999NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas.77
182865292008Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation.74
216430142012The tumor-suppressor gene ARHI (DIRAS3) suppresses ovarian cancer cell migration through inhibition of the Stat3 and FAK/Rho signaling pathways.35
127719402003ARHI is a Ras-related small G-protein with a novel N-terminal extension that inhibits growth of ovarian and breast cancers.30
128740232003Aberrant methylation and silencing of ARHI, an imprinted tumor suppressor gene in which the function is lost in breast cancers.30
285190682017Long Noncoding RNA GAS5 Suppresses Cell Growth and Epithelial-Mesenchymal Transition in Osteosarcoma by Regulating the miR-221/ARHI Pathway.30
247697292014ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7.23
161580532006E2F-HDAC complexes negatively regulate the tumor suppressor gene ARHI in breast cancer.21
268322242016Transcriptional silencing of long noncoding RNA GNG12-AS1 uncouples its transcriptional and product-related functions.21

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/diras3