SUPPRESSION OF APOPTOSIS BY BCL-2 OR BCL-X(L) PROMOTES SUSCEPTIBILITYTO MUTAGENESIS

Bcl-2 appears to contribute to neoplasia primarily by promoting cell s urvival, rather than by stimulating cellular proliferation. Bcl-2, and the related protein Bcl-x(L) each suppress apoptosis induced by a wid e variety of stimuli in many different cell types. Here we report that suppression of apoptosis by Bcl-2 or Bcl-x(L) markedly elevates the l evels of radiation-induced mutations. This enhanced mutagenesis is the result of an increase in mutation frequency (mutations per survivor) together with a moderate increase in viability. Ectopic expression of either Bcl-2 or Bcl-x(L) enhances radiation mutagenesis in cells with wtp53. Surprisingly, we found that ectopic expression of Bcl-x(L) also promotes mutagenesis in p53(-) cells. These results support the hypot hesis that apoptosis plays a crucial role in maintaining genomic integ rity by selectively eliminating highly mutated cells from the populati on.