The Bcl-2 Oncoprotein Functions as a Pro-oxidant (*)
- § To whom correspondence should be addressed: Dept. of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-3010; Fax: 718-892-0703; steinman{at}aecom.yu.edu.
Abstract
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.
Footnotes
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↵* This work was supported by National Institutes of Health Grants GM 40468, National Science Foundation Grant MCB 9220055, and a grant from The Amyotrophic Lateral Sclerosis Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 The abbreviations used are:
- SOD
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superoxide dismutase
- ROI
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reactive oxygen intermediate(s)
- BSO
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buthionine sulfoximine.
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↵2Hydrogen peroxide concentration was not diminished in medium without E. coli.
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- Received December 9, 1994.
- Revision received December 26, 1994.
- © 1995 by The American Society for Biochemistry and Molecular Biology, Inc.
