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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.

Original publication

DOI

10.1038/nature01101

Type

Journal article

Journal

Nature

Publication Date

10/10/2002

Volume

419

Pages

634 - 637

Keywords

Animals, Apoptosis, Apoptotic Protease-Activating Factor 1, B-Lymphocytes, Caspase 9, Caspases, Cells, Cultured, Cytochrome c Group, Enzyme Activation, Hematopoiesis, Mice, Mice, Inbred C57BL, Proteins, Proto-Oncogene Proteins c-bcl-2, T-Lymphocytes