Bcl-2 functions in an antioxidant pathway to prevent apoptosis

David M. Hockenbery, Zoltan N. Oltvai, Xiao Ming Yin, Curt L. Milliman, Stanley J. Korsmeyer

Research output: Contribution to journalArticlepeer-review

3202 Scopus citations

Abstract

Bcl-2 inhibits most types of apoptotic cell death, implying a common mechanism of lethality. Bcl-2 is localized to intracellular sites of oxygen free radical generation including mitochondria, endoplasmic reticula, and nuclear membranes. Antioxidants that scavenge peroxides, N-acetylcysteine and glutathione peroxidase, countered apoptotic death, while manganese superoxide dismutase did not. Bcl-2 protected cells from H2O2- and menadione-induced oxidative deaths. Bcl-2 did not prevent the cyanide-resistant oxidative burst generated by menadione. Two model systems of apoptosis showed no increment in cyanide-resistant respiration, and generation of endogenous peroxides continued at an inherent rate that was unaltered by Bcl-2. Following an apoptotic signal, cells sustained progressive lipid peroxidation. Overexpression of Bcl-2 functioned to suppress lipid peroxidation completely. We propose a model in which Bcl-2 regulates an antioxidant pathway at sites of free radical generation.

Original languageEnglish (US)
Pages (from-to)241-251
Number of pages11
JournalCell
Volume75
Issue number2
DOIs
StatePublished - Oct 22 1993

Bibliographical note

Funding Information:
The consistency of the morphological and biochemical patterns defined as apoptosis within different cell types and species, during normal development and as a response to external stimuli, suggests a common cause of cellular mortality. This thesis is supported by the concept of an endogenous program responsible for cell death and the presence of gene products that are positive and nega- tive regulators of apoptosis. The best studied negative regulator of apoptosis is the bcl-2 proto-oncogene product. It provides the strongest evidence for a shared mammalian pathway of death by its ability to block a wide variety of cell death models.

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