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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS 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 93