C. Mothersill et al., EXPRESSION OF LETHAL MUTATIONS IS SUPPRESSED IN NEOPLASTICALLY TRANSFORMED-CELLS AND AFTER TREATMENT OF NORMAL-CELLS WITH CARCINOGENS, Radiation research, 145(6), 1996, pp. 714-721
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