Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization.
A current view is that cytotoxic stress, such as DNA damage, induces apoptosis by regulating the permeability of mitochondria. Mitochondria sequester several proteins that, if released, kill by activating caspases, the proteases that disassemble the cell. Cytokines activate caspases in a different way, by assembling receptor complexes that activate caspases directly; in this case, the subsequent mitochondrial permeabilization accelerates cell disassembly by amplifying caspase activity. We found that cytotoxic stress causes activation of caspase-2, and that this caspase is required for the permeabilization of mitochondria. Therefore, we argue that cytokine-induced and stress-induced apoptosis act through conceptually similar pathways in which mitochondria are amplifiers of caspase activity rather than initiators of caspase activation.
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Patrice
P
Lassus
Ximena
X
Opitz-Araya
Yuri
Y
Lazebnik
D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D053143:Caspase 2; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D003574:Cytochrome c Group / Q000378:metabolism; D004249:DNA Damage; D004789:Enzyme Activation; D004794:Enzyme Repression; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D010539:Permeability; D021381:Protein Transport; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D022661:RNA, Untranslated; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051028:bcl-2-Associated X Protein
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D003574:Cytochrome c Group; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D022661:RNA, Untranslated; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D005047:Etoposide; D053143:Caspase 2; D020169:Caspases