Title: Expression cloning for arsenite-resistance resulted in isolation of tumor-suppressor fau cDNA: possible involvement of the ubiquitin system in arsenic carcinogenesis.
Authors: Rossman, T G; Wang, Z
Published In Carcinogenesis, (1999 Feb)
Abstract: Arsenic is a human carcinogen whose mechanism of action is unknown. Previously, this laboratory demonstrated that arsenite acts as a comutagen by interfering with DNA repair, although a specific DNA repair enzyme sensitive to arsenite has not been identified. A number of stable arsenite-sensitive and arsenite-resistant sublines of Chinese hamster V79 cells have now been isolated. In order to gain understanding of possible targets for arsenite's action, one arsenite-resistant subline, As/R28A, was chosen as a donor for a cDNA expression library. The library from arsenite-induced As/R28A cells was transfected into arsenite-sensitive As/S5 cells, and transfectants were selected for arsenite-resistance. Two cDNAs, asr1 and asr2, which confer arsenite resistance to arsenite-hypersensitive As/S5 cells as well as to wild-type cells, were isolated. asr1 shows almost complete homology with the rat fau gene, a tumor suppressor gene which contains a ubiquitin-like region fused to S30 ribosomal protein. Arsenite was previously shown to inhibit ubiquitin-dependent proteolysis. These results suggest that the tumor suppressor fau gene product or some other aspect of the ubiquitin system may be a target for arsenic toxicity and that disruption of the ubiquitin system may contribute to the genotoxicity and carcinogenicity of arsenite.
PubMed ID: 10069470
MeSH Terms: Amino Acid Sequence; Animals; Arsenite Transporting ATPases; Arsenites/toxicity*; Base Sequence; Cells, Cultured/drug effects; Cricetinae; Cricetulus; DNA, Complementary/genetics; DNA, Complementary/isolation & purification*; Drug Resistance/genetics; Genes, Tumor Suppressor; Molecular Sequence Data; Rats; Ribosomal Proteins/genetics; Ribosomal Proteins/isolation & purification*; Teratogens/toxicity*; Transfection