RASSF3 and NORE1: identification and cloning of two human homologues of the putative tumor suppressor gene RASSF1.
RASSF1A, one of the two major isoforms of the putative tumor suppressor gene RASSF1, located at 3p21.3, is inactivated in a variety of human cancers including lung, breast, bladder and renal cell carcinomas. We have isolated and cloned two human homologues of this gene, RASSF3 and NORE1, located at 12q14.1 and 1q32.1, respectively. Both RASSF3 and NORE1 share almost 60% homology, at the amino acid level, with RASSF1. The RASSF3 gene contains five exons and encodes a 247 amino acid protein (MW of 28.6 kDa) with a highly conserved Ras association (RalGDS/AF-6) (RA) domain at the C-terminus. RASSF3 is ubiquitously expressed in all normal tissues and cancer cell lines analysed. NORE1, which is homologous to the previously described mouse Nore1 gene, exists in at least two spliced isoforms, A and B. Transcript A encodes a protein of 418 amino acids (MW or 47 kDa) while transcript B contains an ORF of 265 aa (MW of 30.5 kDa). Both share a RA domain, encoded by exons 3 through 6. NORE1A and NORE1B are expressed in most of the normal tissues analysed but they appear to be down-regulated in several cancer cell lines. However, contrary to RASSF1A, gene silencing by methylation of the CpG islands at which the two NORE1 transcripts initiate is not a common event in human primary tumors. RASSF3 and NORE1B are very similar, at the N-terminus, to the splice variant C of RASSF1 (RASSF1C), which does not seem to be involved in tumorigenesis. NORE1A is most closely related to RASSF1A, for sequence homology and genomic organization. However, aberrations in tumors have so far not been found. The presence of a Ras association domain common to NORE1, RASSF1, and RASSF3 suggests their possible involvement in Ras-like signaling pathways.
Tommasi
Stella
S
Biology Department, Beckman Research Institute of the City of Hope, Duarte, California, CA 91010, USA. stommasi@coh.org
Dammann
Reinhard
R
Jin
Seung-Gi
SG
Zhang
Xian-feng
XF
Avruch
Joseph
J
Pfeifer
Gerd P
GP
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D015152:Blotting, Northern; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D003001:Cloning, Molecular; D019175:DNA Methylation; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000473:pathology; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D025521:Tumor Suppressor Proteins; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins; C411762:RASSF1 protein, human; C454041:RASSF3 protein, human; C454042:RASSF5 protein, human; D012333:RNA, Messenger; C454043:Rassf3 protein, mouse; D025521:Tumor Suppressor Proteins; D020559:Monomeric GTP-Binding Proteins