Cell
Volume 94, Issue 3, 7 August 1998, Pages 325-337
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Article
Reduced Apoptosis and Cytochrome c–Mediated Caspase Activation in Mice Lacking Caspase 9

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Abstract

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.

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