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The Bcl-2 oncoprotein functions as a pro-oxidant

¹Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461.

The Journal of Biological Chemistry

|February 24, 1995

Summary

The Bcl-2 oncogene, previously thought to be an antioxidant, actually acts as a pro-oxidant. It generates reactive oxygen species, influencing cellular antioxidant responses and potentially controlling apoptosis.

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Area of Science:

Molecular Biology
Cell Biology
Oncology

Background:

The anti-apoptotic and antioxidant functions of the Bcl-2 oncogene are not fully understood.
Previous research suggested Bcl-2 possesses antioxidant properties, but the underlying mechanism remains elusive.

Purpose of the Study:

To investigate the mechanism of Bcl-2's action, particularly its role in apoptosis and oxidative stress.
To determine whether Bcl-2 functions as an antioxidant or pro-oxidant.

Main Methods:

Expression of Bcl-2 in superoxide dismutase-deficient (SOD-) Escherichia coli.
Measurement of KatG catalase-peroxidase transcription and activity.
Assessment of resistance to hydrogen peroxide and mutation rates.
Analysis of superoxide dismutase activity, reduced glutathione, and DNA damage in a murine B-cell line overexpressing Bcl-2.

Main Results:

Bcl-2 expression in E. coli led to increased KatG transcription and activity, enhanced resistance to hydrogen peroxide, and increased mutation rates.
Bcl-2 expression was linked to increased superoxide dismutase activity, reduced glutathione, and DNA damage in a murine B-cell line.
The transcriptional regulator oxyR and KatG were essential for aerobic survival in E. coli expressing Bcl-2.

Conclusions:

Bcl-2 functions as a pro-oxidant, generating reactive oxygen intermediates (ROIs) rather than acting as an antioxidant.
Bcl-2 influences endogenous cellular antioxidant levels by modulating ROIs, which may regulate the entry into apoptosis.
These findings challenge the established view of Bcl-2's role and suggest a novel mechanism involving oxidative stress in apoptosis regulation.

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