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

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 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.

authors

  • Marsden, Vanessa S
  • O'Connor, Liam
  • O'Reilly, Lorraine A
  • Silke, John
  • Metcalf, Donald
  • Ekert, Paul G
  • Huang, David CS
  • Cecconi, Francesco
  • Kuida, Keisuke
  • Tomaselli, Kevin J
  • Roy, Sophie
  • Nicholson, Don W
  • Vaux, David L
  • Bouillet, Philippe
  • Adams, Jerry M
  • Strasser, Andreas

publication date

  • October 2002

published in