Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9

Cell. 1998 Aug 7;94(3):325-37. doi: 10.1016/s0092-8674(00)81476-2.


Caspases are essential components of the mammalian cell death machinery. Here we test the hypothesis that Caspase 9 (Casp9) is a critical upstream activator of caspases through gene targeting in mice. The majority of Casp9 knockout mice die perinatally with a markedly enlarged and malformed cerebrum caused by reduced apoptosis during brain development. Casp9 deletion prevents activation of Casp3 in embryonic brains in vivo, and Casp9-deficient thymocytes show resistance to a subset of apoptotic stimuli, including absence of Casp3-like cleavage and delayed DNA fragmentation. Moreover, the cytochrome c-mediated cleavage of Casp3 is absent in the cytosolic extracts of Casp9-deficient cells but is restored after addition of in vitro-translated Casp9. Together, these results indicate that Casp9 is a critical upstream activator of the caspase cascade in vivo.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Brain / abnormalities
  • Brain / embryology
  • Caspase 3
  • Caspase 9
  • Caspases*
  • Cysteine Endopeptidases / deficiency
  • Cysteine Endopeptidases / genetics*
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Endopeptidases / physiology
  • Cytochrome c Group / metabolism*
  • Enzyme Activation / genetics
  • Gene Expression Regulation, Developmental
  • Humans
  • Hydrolysis
  • Mice
  • Mice, Knockout
  • Sequence Deletion
  • T-Lymphocytes / physiology
  • Thymus Gland / cytology


  • Cytochrome c Group
  • CASP3 protein, human
  • CASP9 protein, human
  • Casp3 protein, mouse
  • Casp9 protein, mouse
  • Caspase 3
  • Caspase 9
  • Caspases
  • Cysteine Endopeptidases