Mj. Arends et al., SUSCEPTIBILITY TO APOPTOSIS IS DIFFERENTIALLY REGULATED BY C-MYC AND MUTATED HA-RAS ONCOGENES AND IS ASSOCIATED WITH ENDONUCLEASE AVAILABILITY, British Journal of Cancer, 68(6), 1993, pp. 1127-1133
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.