EXPRESSION OF LETHAL MUTATIONS IS SUPPRESSED IN NEOPLASTICALLY TRANSFORMED-CELLS AND AFTER TREATMENT OF NORMAL-CELLS WITH CARCINOGENS

Recent evidence from our laboratory suggests that the fraction of cell s with lethal mutations is lost from the population by apoptosis. The relationship of this process to genetic instability and carcinogenesis is unclear. To examine this, tumorigenic cell populations derived fro m spontaneously occurring, neoplastically transformed C3H 10T1/2 foci and from radiation-induced foci were compared with wild-type C3H 10T1/ 2 cell populations to determine the frequency of induction of lethal m utations postirradiation, Lethal mutations did not occur in the progen y of cells from type 3 foci derived from cultures of spontaneously occ urring or radiation-induced neoplastically transformed cells but were very frequent in the progeny of irradiated wild-type cells. Normal hum an cells (HPV-immortalized human keratinocytes and primary human norma l uroepithelium) were then treated with carcinogens or transfected wit h the Ha-ras oncogene to see if these carcinogenic events affected the yield of lethal mutations postirradiation. In each case, cells which were exposed to a carcinogenic agent had reduced numbers of lethal mut ations, elevated levels of stable p53 and Bcl-2 proteins and reduced e vidence of apoptosis. It is suggested that lethal mutations may repres ent an active safety mechanism which may deal with radiation-induced g enomic instability and which is disabled early in carcinogenesis. (C) 1996 by Radiation Research Society