Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome

Vanessa S. Marsden, Liam O'Connor, Lorraine A. O'Reilly, John Silke, Donald Metcalf, Paul G. Ekert, David C. S. Huang, Francesco Cecconi, Keisuke Kuida, Kevin J. Tomaselli, Sophie Roy, Don W. Nicholson, David L. Vaux, Philippe Bouillet, Jerry M. Adams and Andreas Strasser ()
Additional contact information
Vanessa S. Marsden: The Walter and Eliza Hall Institute
Liam O'Connor: The Walter and Eliza Hall Institute
Lorraine A. O'Reilly: The Walter and Eliza Hall Institute
John Silke: The Walter and Eliza Hall Institute
Donald Metcalf: The Walter and Eliza Hall Institute
Paul G. Ekert: The Walter and Eliza Hall Institute
David C. S. Huang: The Walter and Eliza Hall Institute
Francesco Cecconi: Universita Tor Vergata
Keisuke Kuida: Genomic Pharmacology, Vertex Pharmaceuticals
Kevin J. Tomaselli: Idun Pharmaceuticals
Sophie Roy: Merck-Frosst, Pointe-Claire-Dorval
Don W. Nicholson: Merck-Frosst, Pointe-Claire-Dorval
David L. Vaux: The Walter and Eliza Hall Institute
Philippe Bouillet: The Walter and Eliza Hall Institute
Jerry M. Adams: The Walter and Eliza Hall Institute
Andreas Strasser: The Walter and Eliza Hall Institute

Nature, 2002, vol. 419, issue 6907, 634-637

Abstract: 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 family1,2. 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 stimuli3,4,5,6. 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 integrity7,8,9. 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.

Date: 2002
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DOI: 10.1038/nature01101

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