Bcl-2 functions in an antioxidant pathway to prevent apoptosis.
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.
Hockenbery
D M
DM
Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110.
Oltvai
Z N
ZN
Yin
X M
XM
Milliman
C L
CL
Korsmeyer
S J
SJ
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002451:Cell Compartmentation; D002460:Cell Line; D002470:Cell Survival; D003486:Cyanides / Q000494:pharmacology; D005609:Free Radicals; D005938:Glucocorticoids / Q000172:deficiency; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D007377:Interleukin-3 / Q000172:deficiency; D015227:Lipid Peroxidation / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption; D011518:Proto-Oncogene Proteins / Q000302:isolation & purification / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins / Q000096:biosynthesis; D016897:Respiratory Burst / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014812:Vitamin K / Q000494:pharmacology
D000975:Antioxidants; D003486:Cyanides; D005609:Free Radicals; D005938:Glucocorticoids; D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D013481:Superoxides; D014812:Vitamin K; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D010100:Oxygen; D000111:Acetylcysteine