5 ras Oncogenes

Abstract

I. DISCOVERY OF ras GENES
ras oncogenes were first recognized as the transforming genes of Harvey and Kirsten murine sarcoma viruses (Ha-MSV, Ki-MSV). These highly oncogenic retroviruses were generated during passage of murine leukemia viruses through laboratory strains of rats (Harvey 1964; Kirsten and Mayer 1967). Subsequent molecular analysis showed that Ha-MSV and Ki-MSV contained sequences in their genomes that were not present in the genomes of the parental viruses; these newly acquired sequences appeared to be the result of viral transduction of cellular genes and were thus likely to be responsible for oncogenic transformation. This was directly confirmed when it was shown that subgenomic fragments of Ha-MSV containing only cell-derived sequences were able to transform cells (Chang et al. 1980; De Feo et al. 1981; Ellis et al. 1981).

The proteins produced by Ha-MSV and Ki-MSV were identified using antibodies from rats bearing tumors induced by these viruses; these antibodies reacted with a 21,000-dalton phosphoprotein (p21) produced by Ha-MSV transformed cells. The gene for Ha-MSV p21 was mapped to the region of viral DNA known to be of cellular origin. Furthermore, p21 proteins could be detected in normal, untransformed cells (Langbeheim et al. 1980). Therefore, it was concluded that the p21 gene was the oncogene of Ha-MSV and Ki-MSV (and other closely related viruses) and that this oncogene was derived from a proto-oncogenic form present in normal cells. The genes encoding p21 proteins are now referred to as ras genes (from rat sarcoma genes).

Since these early studies, the...