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

Nature. 2002 Oct 10;419(6907):634-7. doi: 10.1038/nature01101. Epub 2002 Sep 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Apaf1 protein, mouse
  • Apoptotic Protease-Activating Factor 1
  • Cytochrome c Group
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Casp9 protein, mouse
  • Caspase 9
  • Caspases