Conversion of ras genes to cancer genes.

The cellular precursor of Harvey and Balb sarcoma virus, termed proto-ras, from certain tumors registers most frequently as an apparent cancer gene in the gene transfer assay with NIH 3T3 cells [1-4]. The viral ras gene is a dominant transforming gene that elicits all features of oncogenic transformation in a single step upon transfer into established and primary human and animal fibroblast cells [5]. This encodes a single transforming protein of 21 kDA, p21 Ha-ras, which is presumed to be involved in the growth regulation of cells similar to Gproteins [6, 7]. However, the role of the cellular ras gene as a human cancer gene is debatable, as only 10% of the DNAs from certain cancer cells produce foci of transformed NIH 3T3 cells in the transfection assay. No consistent correlation between ras activation and any special type of human cancer is observed, thus 3T3-transforming proto-ras may not be necessary for malignancy [8, 9]. Activation of proto-ras in the 3T3 cell assay is due to point mutations in codons 12, 13, 59 or 61 [10-12]. The ras coding region in viruses also differs from the coding region of proto-ras in normal cells at codon 12 (Balb SV) [13] and codons 12 and 59 (HaSV) [14]. By analogy with the proto-ras genes, these point mutations are also thought to activate viral ras in sarcoma viruses [15]. To test this hypothesis, parts of viral ras including codons 12 (HindIII-PvuII fragment; proviral DNA clones: pA12, pB12) or 12 and 59 (SacII-FspI fragment: pA1259-1 or HindIII-FspI fragment: pA1259-2) were ex-