Download Gene Section DIRAS3 (DIRAS family, GTP binding RAS like 3)

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Gene Section
Review
DIRAS3 (DIRAS family, GTP-binding RAS-like 3)
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 (YY, ZL, RZL, RCBJr)
Published in Atlas Database: September 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/DIRAS3ID702ch1p31.html
DOI: 10.4267/2042/44814
This article is an update of :
Guénard F, Durocher F. DHX9 (DEAH (Asp-Glu-Ala-His) box polypeptide 9). Atlas Genet Cytogenet Oncol Haematol 2010;14(6):547-549
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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.
Identity
Other names: ARHI; NOEY2; RHOI
HGNC (Hugo): DIRAS3
Location: 1p31.3
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).
Transcription
DNA/RNA
The entire protein-coding region is located within exon
2 and encodes a 229-residue small GTP-binding
protein.
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
Pseudogene
No known pseudogenes.
The DIRAS3 gene contains two exons interrupted by a large intron. The red-blocked and opened boxes represent the coding and noncoding regions, respectively. There are three CpG island regions. Blue: CPG island I; green: CpG island II; grey: CpG island III.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
714
DIRAS3 (DIRAS family, GTP-binding RAS-like 3)
Yu Y, et al.
DIRAS3 protein.
Protein
Implicated in
Description
Solid cancers
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.
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.
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 Cterminus 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, downregulates 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, reexpression of DIRAS3 also induces autophagy, but can
also promote tumor dormancy in the presence of factors
that promote survival in the cancer microenvironment.
References
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. NOEY2 (ARHI), an
imprinted putative tumor suppressor gene in ovarian and
breast carcinomas. Proc Natl Acad Sci U S A. 1999 Jan
5;96(1):214-9
Peng H, Xu F, Pershad R, Hunt KK, Frazier ML, Berchuck A,
Gray JW, Hogg D, Bast RC Jr, Yu Y. ARHI is the center of
allelic deletion on chromosome 1p31 in ovarian and breast
cancers. Int J Cancer. 2000 Jun 1;86(5):690-4
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. The
human ARHI tumor suppressor gene inhibits lactation and
growth in transgenic mice. Cancer Res. 2000 Sep
1;60(17):4913-20
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.
Luo RZ, Peng H, Xu F, Bao J, Pang Y, Pershad R, Issa JP,
Liao WS, Bast RC Jr, Yu Y. Genomic structure and promoter
characterization of an imprinted tumor suppressor gene ARHI.
Biochim Biophys Acta. 2001 Jun 28;1519(3):216-22
Bao JJ, Le XF, Wang RY, Yuan J, Wang L, Atkinson EN,
LaPushin R, Andreeff M, Fang B, Yu Y, Bast RC Jr.
Reexpression of the tumor suppressor gene ARHI induces
apoptosis in ovarian and breast cancer cells through a
caspase-independent calpain-dependent pathway. Cancer
Res. 2002 Dec 15;62(24):7264-72
Mutations
Note
Mutations have not been detected.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
715
DIRAS3 (DIRAS family, GTP-binding RAS-like 3)
Yu Y, et al.
Fujii S, Luo RZ, Yuan J, Kadota M, Oshimura M, Dent SR,
Kondo Y, Issa JP, Bast RC Jr, Yu Y. Reactivation of the
silenced and imprinted alleles of ARHI is associated with
increased histone H3 acetylation and decreased histone H3
lysine 9 methylation. Hum Mol Genet. 2003 Aug
1;12(15):1791-800
the tumor suppressor gene ARHI in breast cancer. Oncogene.
2006 Jan 12;25(2):230-9
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.
Transcriptional and posttranscriptional down-regulation of the
imprinted tumor suppressor gene ARHI (DRAS3) in ovarian
cancer. Clin Cancer Res. 2006 Apr 15;12(8):2404-13
Luo RZ, Fang X, Marquez R, Liu SY, Mills GB, Liao WS, Yu Y,
Bast RC. ARHI is a Ras-related small G-protein with a novel Nterminal extension that inhibits growth of ovarian and breast
cancers. Oncogene. 2003 May 15;22(19):2897-909
Yu Y, Luo R, Lu Z, Wei Feng W, Badgwell D, Issa JP, Rosen
DG, Liu J, Bast RC Jr. Biochemistry and biology of ARHI
(DIRAS3), an imprinted tumor suppressor gene whose
expression is lost in ovarian and breast cancers. Methods
Enzymol. 2006;407:455-68
Wang L, Hoque A, Luo RZ, Yuan J, Lu Z, Nishimoto A, Liu J,
Sahin AA, Lippman SM, Bast RC Jr, Yu Y. Loss of the
expression of the tumor suppressor gene ARHI is associated
with progression of breast cancer. Clin Cancer Res. 2003 Sep
1;9(10 Pt 1):3660-6
Feng W, Lu Z, Luo RZ, Zhang X, Seto E, Liao WS, Yu Y.
Multiple histone deacetylases repress tumor suppressor gene
ARHI in breast cancer. Int J Cancer. 2007 Apr 15;120(8):16648
Yu Y, Fujii S, Yuan J, Luo RZ, Wang L, Bao J, Kadota M,
Oshimura M, Dent SR, Issa JP, Bast RC Jr. Epigenetic
regulation of ARHI in breast and ovarian cancer cells. Ann N Y
Acad Sci. 2003 Mar;983:268-77
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. The tumor suppressor
gene ARHI regulates autophagy and tumor dormancy in
human ovarian cancer cells. J Clin Invest. 2008
Dec;118(12):3917-29
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.
Aberrant methylation and silencing of ARHI, an imprinted
tumor suppressor gene in which the function is lost in breast
cancers. Cancer Res. 2003 Jul 15;63(14):4174-80
Riemenschneider MJ, Reifenberger J, Reifenberger G.
Frequent biallelic inactivation and transcriptional silencing of
the DIRAS3 gene at 1p31 in oligodendroglial tumors with 1p
loss. Int J Cancer. 2008 Jun 1;122(11):2503-10
Rosen DG, Wang L, Jain AN, Lu KH, Luo RZ, Yu Y, Liu J, Bast
RC Jr. Expression of the tumor suppressor gene ARHI in
epithelial ovarian cancer is associated with increased
expression of p21WAF1/CIP1 and prolonged progression-free
survival. Clin Cancer Res. 2004 Oct 1;10(19):6559-66
Huang J, Lin Y, Li L, Qing D, Teng XM, Zhang YL, Hu X, Hu Y,
Yang P, Han ZG. ARHI, as a novel suppressor of cell growth
and downregulated in human hepatocellular carcinoma, could
contribute to hepatocarcinogenesis. Mol Carcinog. 2009
Feb;48(2):130-40
Nishimoto A, Yu Y, Lu Z, Mao X, Ren Z, Watowich SS, Mills
GB, Liao WS, Chen X, Bast RC Jr, Luo RZ. A Ras homologue
member I directly inhibits signal transducers and activators of
transcription 3 translocation and activity in human breast and
ovarian cancer cells. Cancer Res. 2005 Aug 1;65(15):6701-10
Huang S, Chang IS, Lin W, Ye W, Luo RZ, Lu Z, Lu Y, Zhang
K, Liao WS, Tao T, Bast RC Jr, Chen X, Yu Y. ARHI (DIRAS3),
an imprinted tumour suppressor gene, binds to importins and
blocks nuclear import of cargo proteins. Biosci Rep. 2009 Dec
15;30(3):159-68
Weber F, Aldred MA, Morrison CD, Plass C, Frilling A,
Broelsch CE, Waite KA, Eng C. Silencing of the maternally
imprinted tumor suppressor ARHI contributes to follicular
thyroid carcinogenesis. J Clin Endocrinol Metab. 2005
Feb;90(2):1149-55
This article should be referenced as such:
Yu Y, Lu Z, Luo RZ, Bast RC Jr. DIRAS3 (DIRAS family, GTPbinding RAS-like 3). Atlas Genet Cytogenet Oncol Haematol.
2010; 14(8):714-716.
Lu Z, Luo RZ, Peng H, Huang M, Nishmoto A, Hunt KK, Helin
K, Liao WS, Yu Y. E2F-HDAC complexes negatively regulate
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
716