THE BCL-2 ONCOPROTEIN FUNCTIONS AS A PROOXIDANT

The mechanism by which the bcl-2 oncogene exerts its anti-apoptotic an d antioxidant action is unknown. We found that expression of bcl-2 in superoxide dismutase-deficient (SOD-) Escherichia coli resulted in inc reased transcription of the KatG catalase-peroxidase, a 13-fold increa se in KatG activity and a 100-fold increase in resistance to hydrogen peroxide. In addition, mutation rate was increased 3-fold, and katG an d oxyR, a transcriptional regulator of katG induction, were required f or aerobic survival. These data indicate that Bcl-2 acts as a pro-oxid ant in E. coli, i.e. Bcl-2 generates reactive oxygen intermediates. In support of a pro-oxidant mechanism in eukaryotic cells, we found a 73 % increase in superoxide dismutase activity in a murine B-cell line ov erexpressing Bcl-2. Increases in reduced glutathione and in oxyradical damage to DNA, previously observed in other overexpressing cell lines , are additional evidence for a pro-oxidant mechanism. Thus, Bcl-2 doe s not appear to be an antioxidant. Instead, Bcl-2 appears to influence levels of reactive oxygen intermediates that induce endogenous cellul ar antioxidants. This activity of Bcl-2 may control, entry into apopto sis.