SUSCEPTIBILITY TO APOPTOSIS IS DIFFERENTIALLY REGULATED BY C-MYC AND MUTATED HA-RAS ONCOGENES AND IS ASSOCIATED WITH ENDONUCLEASE AVAILABILITY

Oncogenes and oncosuppressors can derugulate cell replication in tumou rs, and recently have been shown to influence the probability of apopt osis. The effects of human c-myc and mutated (T24) Ha-ras oncogenes on susceptibility to apoptosis were investigated by introducting them in to immortalised rat fibroblasts. The resulting family of transfectants showed closely similar measures of proliferation, but widely divergen t rates of apoptosis, differing by up to fifteen-fold, that correlated inversely with population expansion rates in vitro. T24-ras transfect ants with moderate or high p21ras expression showed reduced apoptosis, and this was reversed by pharmacological inhibition of membrane local isation of p21ras by mevinolin. In contrast. c-mvc stimulated apoptosi s, and this was further enhanced by serum deprivation. Inducibility of effector proteins represents one possible mechanism of genetic contro l of the susceptibility to apoptosis, and its investigation showed tha t c-myc was associated with expression by viable cells of latent calci um/magnesium sensitive endonuclease activity characteristic of apoptos is. In contrast, endonuclease activity was not detected in viable cell s of a T24-ras transfectant expressing high levels of p21ras. Thus, th ere appeared to be differential regulation of susceptibility to apopto sis, positively by c-mvc and negatively by activated ras, and this was associated with availability of endonuclease activity. Genetic modula tion of apoptosis in human neoplasms is likely to influence net growth rate, retention of cells acquiring new mutations and response to cert ain chemotherapeutic agents.