The Bcl-2 oncoprotein functions as a pro-oxidant.
The mechanism by which the bcl-2 oncogene exerts its anti-apoptotic and antioxidant action is unknown. We found that expression of bcl-2 in superoxide dismutase-deficient (SOD-) Escherichia coli resulted in increased transcription of the KatG catalase-peroxidase, a 13-fold increase in KatG activity and a 100-fold increase in resistance to hydrogen peroxide. In addition, mutation rate was increased 3-fold, and katG and oxyR, a transcriptional regulator of katG induction, were required for aerobic survival. These data indicate that Bcl-2 acts as a pro-oxidant 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 overexpressing 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 does not appear to be an antioxidant. Instead, Bcl-2 appears to influence levels of reactive oxygen intermediates that induce endogenous cellular antioxidants. This activity of Bcl-2 may control entry into apoptosis.
Steinman
H M
HM
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461.
D000818:Animals; D000975:Antioxidants; D017209:Apoptosis; D001426:Bacterial Proteins; D002374:Catalase; D004790:Enzyme Induction; D004926:Escherichia coli / Q000235:genetics; D029968:Escherichia coli Proteins; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D016877:Oxidants / Q000378:metabolism*; D010544:Peroxidases / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D016877:Oxidants; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D010544:Peroxidases; D002374:Catalase; C076136:catalase HPI; C051253:katG protein, E coli