Download Gene Section RASSF1 (Ras association (RalGDS/AF-6) domain family member 1)

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
RASSF1 (Ras association (RalGDS/AF-6) domain
family member 1)
Debora Angeloni, Michael I Lerman
Laboratory of Immunobiology, National Cancer Institute, Frederick Cancer Research Facility Bldg. 560 Rm.
13 34 Frederick, MD 21702, USA (DA, MIL)
Published in Atlas Database: December 2001
Online updated version: http://AtlasGeneticsOncology.org/Genes/RASSF1ID377.html
DOI: 10.4267/2042/37832
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2002 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
DNA/RNA
Other names: 123F2; RDA32; REH3P21
HGNC (Hugo): RASSF1
Location: 3p21.3
Local order: telomeric to BLU and centromeric to
FUS1
Description
The genomic size of the gene is about 7.6 kb.
Transcription
At least three alternative transcripts were identified (A,
B and C) that originate from alternative splicing and
promoter usage. Exons 3 to 6 are common to all forms.
Transcript A has two 5' exons (designated 1a and 2ab),
this cDNA is 1,873 bp (ORF: 340 amino acids).
RASSF1B first exon is designated 1b and is different
from RASSF1A. Exon two is 2ab as in transcript A.
cDNA size: 1,664 bp. Transcript RASSF1C first exon
is designated 2g, cDNA size 1700 bp (ORF 270 amino
acids).
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular
Cytogenetics.
Pseudogene
Note
RASSF1 is also known as NORE2A. More correctly,
NORE must be considered a paralog of RASSF1, a
human ortholog of mouse NoreA. Genomic clones:
cosmid LUCA 12 and LUCA 13.
No known pseudogenes.
Grey: exon 1a, green: exon 1b; blue: exon 2ab; yellow : exon 2g; brown: exons 3,4, 5, 6. Arrows: transcription start sites. CpG: location of
CpG islands. RASSF1A and RASSF1B start with exon 1a and 1b respectively. The second exon (2ab) is common to both forms. Exon 2g
is the first exon of RASSF1C and is present in this transcript only.
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2)
91
RASSF1 (Ras association (RalGDS/AF-6) domain family member 1)
Angeloni D, Lerman MI
(Glu129); ATT (Ile135) to ACT (Thr135); CGG
(Arg257) to CAG (Gln257); GCC (Ala336) to ACC
(Thr336).
Protein
Implicated in
Cear cell renal carcinoma and papillary
renal carcinoma; lung cancer; ovarian
cancer; prostate cancer; gastric
adenocarcinoma; bladder carcinoma;
nasopharingeal carcinoma; breast
cancer
Note
The mechanism of inactivation of this tumor suppressor
consists in promoter hypermethylation. The gene
promoter was found hypermetylated in 90 % of primary
kidney tumors and 40 % of lung tumors.
Hypermethylation and loss of transcription were
causally related. Hypermethylation occurs in variable
percentage in other tumors and indicate a role for this
gene in malignant progression (62 % of bladder
carcinoma; 49 % of breast tumors; 40 % of ovarian
tumors; 12 % of colon cancer).
Schematic representation of RASSF1 protein variants, as
deduced from the transcripts.
Description
The carboxy terminus of RASSF1A shows about 55%
identity to the mouse protein Nore1 and the rat protein
Maxp1, both are Ras effector proteins (Nore1 was
shown to interact in vivo with Ras upon receptor
activation in a GTP-dependent manner). RASSF1A N
terminus has high homology with a domain known as
protein kinase C conserved region 1 domain (a
cysteine-rich diacylglycerol/ phorbol ester binding
domain). RASSF1B most likely is constituted only of
the Ras association domain.
References
Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP.
Epigenetic inactivation of a RAS association domain family
protein from the lung tumour suppressor locus 3p21.3. Nat
Genet. 2000 Jul;25(3):315-9
Lerman MI, Minna JD. The 630-kb lung cancer homozygous
deletion region on human chromosome 3p21.3: identification
and evaluation of the resident candidate tumor suppressor
genes. The International Lung Cancer Chromosome 3p21.3
Tumor Suppressor Gene Consortium. Cancer Res. 2000 Nov
1;60(21):6116-33
Expression
RASSF1A and RASSF1C are expressed in heart, brain,
placenta, lung, liver, skeletal muscle, kidney, pancreas,
spleen, thymus, prostate, testis, small intestine, colon,
peripheral blood leukocytes. RASSF1B is expressed
predominantly in cells of hematopoietic origin.
Vos MD, Ellis CA, Bell A, Birrer MJ, Clark GJ. Ras uses the
novel tumor suppressor RASSF1 as an effector to mediate
apoptosis. J Biol Chem. 2000 Nov 17;275(46):35669-72
Localisation
Agathanggelou A, Honorio S, Macartney DP, Martinez A, Dallol
A, Rader J, Fullwood P, Chauhan A, Walker R, Shaw JA,
Hosoe S, Lerman MI, Minna JD, Maher ER, Latif F.
Methylation associated inactivation of RASSF1A from region
3p21.3 in lung, breast and ovarian tumours. Oncogene. 2001
Mar 22;20(12):1509-18
Not determined.
Function
RASSF1 binds Ras in a GTP-dependent manner and
may serve as the effector that mediates Ras apoptotic
effects. Alternatively, it may sequester RAS proteins
thereby regulating the availability of these proteins for
signaling.
Burbee DG, Forgacs E, Zöchbauer-Müller S, Shivakumar L,
Fong K, Gao B, Randle D, Kondo M, Virmani A, Bader S,
Sekido Y, Latif F, Milchgrub S, Toyooka S, Gazdar AF, Lerman
MI, Zabarovsky E, White M, Minna JD. Epigenetic inactivation
of RASSF1A in lung and breast cancers and malignant
phenotype suppression. J Natl Cancer Inst. 2001 May
2;93(9):691-9
Mutations
Note
Single nucleotide polymorphism (SNP) in exon 1a:
AAG (Lys21)/CAG (Gln21).
Byun DS, Lee MG, Chae KS, Ryu BG, Chi SG. Frequent
epigenetic inactivation of RASSF1A by aberrant promoter
hypermethylation in human gastric adenocarcinoma. Cancer
Res. 2001 Oct 1;61(19):7034-8
Somatic
Dammann R, Takahashi T, Pfeifer GP. The CpG island of the
novel tumor suppressor gene RASSF1A is intensely
methylated in primary small cell lung carcinomas. Oncogene.
2001 Jun 14;20(27):3563-7
Mutations were rarely found. In non small cell lung
cancer four were found: GAC (Asp129) to GAG
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2)
92
RASSF1 (Ras association (RalGDS/AF-6) domain family member 1)
Dammann R, Yang G, Pfeifer GP. Hypermethylation of the cpG
island of Ras association domain family 1A (RASSF1A), a
putative tumor suppressor gene from the 3p21.3 locus, occurs
in a large percentage of human breast cancers. Cancer Res.
2001 Apr 1;61(7):3105-9
promoter hypermethylation of RASSF1A in nasopharyngeal
carcinoma. Cancer Res. 2001 May 15;61(10):3877-81
Morrissey C, Martinez A, Zatyka M, Agathanggelou A, Honorio
S, Astuti D, Morgan NV, Moch H, Richards FM, Kishida T, Yao
M, Schraml P, Latif F, Maher ER. Epigenetic inactivation of the
RASSF1A 3p21.3 tumor suppressor gene in both clear cell and
papillary renal cell carcinoma. Cancer Res. 2001 Oct
1;61(19):7277-81
Dreijerink K, Braga E, Kuzmin I, Geil L, Duh FM, Angeloni D,
Zbar B, Lerman MI, Stanbridge EJ, Minna JD, Protopopov A, Li
J, Kashuba V, Klein G, Zabarovsky ER. The candidate tumor
suppressor gene, RASSF1A, from human chromosome 3p21.3
is involved in kidney tumorigenesis. Proc Natl Acad Sci U S A.
2001 Jun 19;98(13):7504-9
Yoon JH, Dammann R, Pfeifer GP. Hypermethylation of the
CpG island of the RASSF1A gene in ovarian and renal cell
carcinomas. Int J Cancer. 2001 Oct 15;94(2):212-7
Lee MG, Kim HY, Byun DS, Lee SJ, Lee CH, Kim JI, Chang
SG, Chi SG. Frequent epigenetic inactivation of RASSF1A in
human bladder carcinoma. Cancer Res. 2001 Sep
15;61(18):6688-92
This article should be referenced as such:
Angeloni D, Lerman MI. RASSF1 (Ras association
(RalGDS/AF-6) domain family member 1). Atlas Genet
Cytogenet Oncol Haematol. 2002; 6(2):91-93.
Lo KW, Kwong J, Hui AB, Chan SY, To KF, Chan AS, Chow
LS, Teo PM, Johnson PJ, Huang DP. High frequency of
Atlas Genet Cytogenet Oncol Haematol. 2002; 6(2)
Angeloni D, Lerman MI
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