Suppression of apoptosis in C3H mouse liver tumors by activated Ha-ras oncogene

Liver tumors were induced in male C3H mice by a single injection of N-nitro sodiethylamine and characterized with respect to the presence of base subst itutions in the hot-spot position at codon 61 of the Ha-ras proto-oncogene, An increase in Ha-ras mutation prevalence was found with time after induct ion of tumors, suggesting that the activated ras gene provides a selective growth advantage. However, no significant differences in 5-bromodeoxyuridin e labeling indices were evident between ras mutated and ras wild-type tumor s, demonstrating that cell division rates in the two tumor populations were very similar. Apoptotic indices were determined by counting eosinophilic a poptotic bodies. The frequency of occurrence of apoptotic bodies was found to be approximately five times lower in tumors with Haras mutations when co mpared with tumors not showing the mutation. This demonstrates that the act ivated p21(Ras) protein has anti-apoptotic activity in transformed mouse he patocytes in vivo and suggests that the preferential outgrowth of Ha-ras-mu tated hepatoma cells is mediated by suppression of apoptosis rather than by stimulation of cell division.