RASSF1 (Ras association (RalGDS/AF-6) domain family member)

2001-12-01 Debora Angeloni , Michael I. Lerman Affiliation

Laboratory of Immunobiology, National Cancer Institute, Frederick Cancer Research Facility Bldg. 560 Rm. 12 26 Frederick, MD 21702, USA

Identity

HGNC

RASSF1

LOCATION

3p21.31

IMAGE

LEGEND

Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics

LOCUSID

11186

ALIAS

123F2,NORE2A,RASSF1A,RDA32,REH3P21

FUSION GENES

Show Gene Fusions

DNA/RNA

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.

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).

Pseudogene

no known pseudogenes.

Proteins

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.

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.

Localisation

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.

Mutations

Note

single nucleotide polymorphism (SNP) in exon 1a: AAG (Lys21)/CAG (Gln21).

Somatic

Mutations were rarely found. In non small cell lung cancer four were found: GAC (Asp129) to GAG (Glu129); ATT (Ile135) to ACT (Thr135); CGG (Arg257) to CAG (Gln257); GCC (Ala336) to ACC (Thr336).

Implicated in

Entity name

clear 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).

Bibliography

Pubmed ID	Last Year	Title	Authors
11313894	2001	Methylation associated inactivation of RASSF1A from region 3p21.3 in lung, breast and ovarian tumours.	Agathanggelou A et al
11333291	2001	Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression.	Burbee DG et al
11585730	2001	Frequent epigenetic inactivation of RASSF1A by aberrant promoter hypermethylation in human gastric adenocarcinoma.	Byun DS et al
10888881	2000	Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3.	Dammann R et al
11429703	2001	The CpG island of the novel tumor suppressor gene RASSF1A is intensely methylated in primary small cell lung carcinomas.	Dammann R et al
11306494	2001	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.	Dammann R et al
11390984	2001	The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis.	Dreijerink K et al
11559536	2001	Frequent epigenetic inactivation of RASSF1A in human bladder carcinoma.	Lee MG et al
11085536	2000	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.	Lerman MI et al
11358799	2001	High frequency of promoter hypermethylation of RASSF1A in nasopharyngeal carcinoma.	Lo KW et al
11585766	2001	Epigenetic inactivation of the RASSF1A 3p21.3 tumor suppressor gene in both clear cell and papillary renal cell carcinoma.	Morrissey C et al
10998413	2000	Ras uses the novel tumor suppressor RASSF1 as an effector to mediate apoptosis.	Vos MD et al
11668500	2001	Hypermethylation of the CpG island of the RASSF1A gene in ovarian and renal cell carcinomas.	Yoon JH et al

Other Information

Locus ID:

NCBI: 11186
MIM: 605082
HGNC: 9882
Ensembl: ENSG00000068028

Variants:

dbSNP: 11186
ClinVar: 11186
TCGA: ENSG00000068028
COSMIC: RASSF1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000068028	ENST00000327761	Q9NS23
ENSG00000068028	ENST00000357043	Q9NS23
ENSG00000068028	ENST00000359365	Q9NS23
ENSG00000068028	ENST00000395117	Q9NS23
ENSG00000068028	ENST00000395126	Q9NS23
ENSG00000068028	ENST00000482447	Q9NS23
ENSG00000068028	ENST00000616212	Q9NS23

Expression (GTEx)

100

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Bladder cancer	KEGG	ko05219
Non-small cell lung cancer	KEGG	ko05223
Pathways in cancer	KEGG	hsa05200
Bladder cancer	KEGG	hsa05219
Non-small cell lung cancer	KEGG	hsa05223
Hippo signaling pathway	KEGG	hsa04390
Hippo signaling pathway	KEGG	ko04390
MicroRNAs in cancer	KEGG	hsa05206
MicroRNAs in cancer	KEGG	ko05206
Ras signaling pathway	KEGG	hsa04014
Hippo signaling pathway -multiple species	KEGG	ko04392
Hippo signaling pathway -multiple species	KEGG	hsa04392

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PK	PD	PMIDs
PA10040	cetuximab	Chemical	ClinicalAnnotation, VariantAnnotation	ambiguous		PD
PA446108	Colorectal Neoplasms	Disease	ClinicalAnnotation, VariantAnnotation	ambiguous		PD

References

Pubmed ID	Year	Title	Citations
18337602	2008	DNA methylation markers and early recurrence in stage I lung cancer.	188
17889669	2007	RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein.	152
15867337	2005	Role of the Ras-association domain family 1 tumor suppressor gene in human cancers.	130
12024041	2002	The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation.	98
14743218	2004	The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC-Cdc20 complex.	89
17379520	2007	RASSF1A is part of a complex similar to the Drosophila Hippo/Salvador/Lats tumor-suppressor network.	83
14601057	2003	DNA methylation of RASSF1A, HIN-1, RAR-beta, Cyclin D2 and Twist in in situ and invasive lobular breast carcinoma.	77
19062280	2008	NDR kinase is activated by RASSF1A/MST1 in response to Fas receptor stimulation and promotes apoptosis.	73
18349282	2008	DNA methylation in tumor and matched normal tissues from non-small cell lung cancer patients.	71
15736067	2005	The tumor suppressor RASSF1A in human carcinogenesis: an update.	70

Citation

Debora Angeloni ; Michael I. Lerman

RASSF1 (Ras association (RalGDS/AF-6) domain family member)

Atlas Genet Cytogenet Oncol Haematol. 2001-12-01

Online version: http://atlasgeneticsoncology.org/gene/377/rassf1