Oncogenic Activation of Ras Proteins

Abstract

The Discovery that the viral oncogenes carried by the Harvey (v-H-ras) and Kirsten (v-K-ras) sarcoma viruses were transduced versions of normal cellular genes supported the idea that alterations in certain key cellular genes (cellular H-, K-, and N-ras) could contribute to human carcinogenesis (Ellis et al. 1981; Chang et al. 1982b). The identification of transforming versions of human ras genes in DNA isolated from human tumor cells in gene transfer assays confirmed this possibility (Der et al. 1982; Parada et al. 1982; Santos et al. 1982; Shimizu et al. 1983). Molecular cloning and analyses of these tumor-derived ras sequences quickly established that conversion of the normal genes to the oncogenic versions was due simply to single amino acid substitutions, primarily at residues 12 (Tabin et al. 1982; Reddy et al. 1982; Taparowsky et al. 1982), 13 (Bos et al. 1985), and 61 (Yuasa et al. 1983). Concurrent with the development and application of sensitive molecular techniques for the detection of genetic point mutations in tumor DNAs was the finding that oncogenic ras sequences were frequently associated with a broad spectrum of human malignancies (reviewed in Bos 1988, 1989).