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- Title
Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome.
- Authors
Marsden, Vanessa S.; O'Connor, Liam; O'Reilly, Lorraine A.; Silke, John; Metcalf, Donald; Ekert, Paul G.; Huang, David C. S.; Cecconi, Francesco; Kuida, Keisuke; Tomaselli, Kevin J.; Roy, Sophie; Nicholson, Don W.; Vaux, David L.; Bouillet, Philippe; Adams, Jerry M.; Strasser, Andreas
- Abstract
Apoptosis is an evolutionarily conserved cell suicide process executed by cysteine proteases (caspases) and regulated by the opposing factions of the Bcl-2 protein family. Mammalian caspase-9 and its activator Apaf-1 were thought to be essential, because mice lacking either of them display neuronal hyperplasia and their lymphocytes and fibroblasts seem resistant to certain apoptotic stimuli. Because Apaf-1 requires cytochrome c to activate caspase-9, and Bcl-2 prevents mitochondrial cytochrome c release, Bcl-2 is widely believed to inhibit apoptosis by safeguarding mitochondrial membrane integrity. Our results suggest a different, broader role, because Bcl-2 overexpression increased lymphocyte numbers in mice and inhibited many apoptotic stimuli, but the absence of Apaf-1 or caspase-9 did not. Caspase activity was still discernible in cells lacking Apaf-1 or caspase-9, and a potent caspase antagonist both inhibited apoptosis and retarded cytochrome c release. We conclude that Bcl-2 regulates a caspase activation programme independently of the cytochrome c/Apaf-1/caspase-9 ‘apoptosome’, which seems to amplify rather than initiate the caspase cascade.
- Subjects
APOPTOSIS; CYSTEINE proteinases; CAENORHABDITIS elegans; HEMATOPOIESIS
- Publication
Nature, 2002, Vol 419, Issue 6907, p634
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature01101