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, Andreas Strasser

Research output: Contribution to journalArticlepeer-review

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 safe-guarding 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 languageEnglish
Pages (from-to)634-637
Number of pages4
JournalNature
Volume419
Issue number6907
DOIs
Publication statusPublished - Oct 10 2002

ASJC Scopus subject areas

  • General

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