1. The Walter and Eliza Hall Institute, Melbourne, 3050, Australia
2. Murdoch Children's Research Institute, Melbourne, 3050, Australia
3. Department of Biology, Universita Tor Vergata, Rome, Italy
4. Genomic Pharmacology, Vertex Pharmaceuticals, Cambridge, Massachusetts 02139, USA
5. Idun Pharmaceuticals, San Diego, California 92121, USA
6. Merck-Frosst, Pointe-Claire-Dorval H9H 3L1, Canada
7. These authors contributed equally to this work
8. Present address: Incyte Genomics, Palo Alto, California 94304, USA

Correspondence to: Andreas Strasser^1,10 Correspondence and requests for materials should be addressed to A.S. (e-mail: Email: strasser@wehi.edu.au).

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^{1, 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 stimuli^{3, 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 integrity^{7, 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.