Cell
Volume 75, Issue 2, 22 October 1993, Pages 241-251
Journal home page for Cell

Article
Bcl-2 functions in an antioxidant pathway to prevent apoptosis

https://doi.org/10.1016/0092-8674(93)80066-NGet rights and content

Summary

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.

References (67)

  • McCordJ.M.A. et al.

    Superoxide-dependent production of hydroxyl radical catalysed by an iron-EDTA complex

    FEBS Lett.

    (1978)
  • McDonnellT.J. et al.

    bcl-2—immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation

    Cell

    (1989)
  • MiyashitaT. et al.

    Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line

    Blood

    (1993)
  • SentmanC.L. et al.

    bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes

    Cell

    (1991)
  • StrasserA. et al.

    bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship

    Cell

    (1991)
  • SulstonJ.E. et al.

    Post-embryonic cell lineages of the nematode, Caenorhabditis elegans

    Dev. Biol.

    (1977)
  • ThorH. et al.

    The metabolism of menadione (2-methyl-1,4-naphthoquinone) by isolated hepatocytes

    J. Biol. Chem.

    (1982)
  • WeisigerR.A. et al.

    Mitochondrial superoxide dismutase, site of synthesis and intramitochondrial localization

    J. Biol. Chem.

    (1973)
  • WongG.H.W. et al.

    Manganous superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor

    Cell

    (1989)
  • WyllieA.H. et al.

    Cell death: the significance of apoptosis

    Int. Rev. Cytol.

    (1980)
  • AbateC. et al.

    Redox regulation of Fox and Jun DNA-binding activity in vitro

    Science

    (1990)
  • AbramsJ.M. et al.

    Programmed cell death during Drosophila embryogenesis

    Development

    (1993)
  • AmstadP. et al.

    The balance between Cu, Zn-superoxide dismutase and catalase affects the sensitivity of mouse epidermal cells to oxidative stress

    Biochemistry

    (1991)
  • ApplegateL.A. et al.

    Induction of heme oxygenase: a general response to oxidative stress in cultured mammalian cells

    Cancer Res.

    (1991)
  • BassD.A. et al.

    Flow cytometric studies of oxidative product formation by neutrophils: a graded response to membrane stimulation

    J. Immunol.

    (1983)
  • BlokJ. et al.

    Bacteriophage DNA as a model for correlation of radical damage to DNA and biological effects

  • BoissyR.E. et al.

    Separation of pigmented and albino melanocytes and the concomitant evaluation of endogenous peroxide content using flow cytometry

    Cytometry

    (1989)
  • BoverisA. et al.

    The mitochondrial generation of hydrogen peroxide

    Biochem. J.

    (1973)
  • Chen-LevyZ. et al.

    The Bcl-2 candidate proto-oncogene product is a 24-kilodalton integral-membrane protein highly expressed in lymphoid cell lines and lymphomas carrying the t(14;18)

    Mol. Cell. Biol.

    (1989)
  • CrawfordD. et al.

    Oxidant stress induces the proto-oncogenes c-fos and c-myc in mouse epidermal cells

    Oncogene

    (1988)
  • DeweyD.L.

    Effect of oxygen and nitric oxide on the radiosensitivity of human cells in tissue culture

    Nature

    (1960)
  • ErnsterL.

    Oxygen as an environmental poison

    Chemica Scripta

    (1986)
  • GutteridgeJ.M.C.

    Aspects to consider when detecting and measuring lipid peroxidation

    Free Radical Res. Commun.

    (1986)
  • Cited by (3379)

    View all citing articles on Scopus
    View full text