Activation of ras oncogenes during hepatocarcinogenesis induced by N-nitrosodiethylamine: Possible involvement of PKC and GAP

The expression of H-ras and N-ras was found to be increased in liver-of rats fed with the carcinogen N-nitrosodiethylamine (NDEA). There were, however, variations in time at which these were expressed and in the extent of expression of the two genes. N-ras appeared to be more aggressive than H-ras. This overexpression could be correlated with an inhibition in the functioning of GTPase activating protein (GAP). The activity of GAP in increasing the intrinsic GTPase activity of p21(ras) was found to be much less in NDEA-treated rats as compared to that in control rats. It was observed that GAP isolated from NDEA-treated rats was extensively phosphorylated by protein kinase C, and this might be the reason for its decreased activity It is speculated that phosphorylated GAP helps keep the p21(ras) in the more active GTP-bound state.