Bcl-2 and Bcl-xL block apoptosis as well as necrosis: possible involvement of common mediators in apoptotic and necrotic signal transduction pathways.
The proto-oncogene bcl-2 and a bcl-2-related gene bcl-x prevent apoptotic cell death induced by various treatments. Although a mechanism has been proposed that involves Bcl-2 activity on reactive oxygen species (ROS), we find that expression of Bcl-2 or Bcl-xL prevents cell death induced by withdrawal of oxygen (hypoxia) and that the cell death does not involve ROS, suggesting that Bcl-2 or Bcl-xL exerts an anti-cell death function by a mechanism other than through regulation of ROS activity. Using electron microscopy, and confocal and non-confocal fluorescence microscopy, we show that hypoxia induces both necrosis and apoptosis. Overexpression of Bcl-2 or Bcl-xL blocks hypoxia-induced apoptosis and, although to a lesser extent, necrosis. The anti-apoptotic proteins Bcl-2 and Bcl-xL effectively inhibit KCN-induced cell death which is characterized by necrotic features including apparently intact chromatin, remarkable mitochondrial swelling with loss of crista structure and loss of plasma membrane integrity. The necrotic cell death is also inhibited by inhibitors of ICE (interleukin-1 beta converting enzyme)(-like) proteases, the common mediators of apoptosis. These results indicate that Bcl-2/Bcl-xL and ICE(-like) proteases modulate both apoptotic and at least some forms of necrotic cell death, suggesting that both cell death pathways involve some common mediators.
Tsujimoto
Y
Y
Department of Medical Genetics, Osaka University Medical School, Suita, Japan.
Shimizu
S
S
Eguchi
Y
Y
Kamiike
W
W
Matsuda
H
H
D000818:Animals; D017209:Apoptosis; D020170:Caspase 1; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002843:Chromatin / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D008114:Liver Neoplasms, Experimental; D008933:Mitochondrial Swelling / Q000187:drug effects; D009336:Necrosis; D016716:PC12 Cells; D011190:Potassium Cyanide / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism*; D011519:Proto-Oncogenes; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494813:Bcl2l1 protein, rat; D002843:Chromatin; D011480:Protease Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051020:bcl-X Protein; D003546:Cysteine Endopeptidases; D020170:Caspase 1; D011190:Potassium Cyanide