Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9.
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.
Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139, USA.
K
K
Kuida
T F
TF
Haydar
C Y
CY
Kuan
Y
Y
Gu
C
C
Taya
H
H
Karasuyama
M S
MS
Su
P
P
Rakic
R A
RA
Flavell
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001921:Brain / Q000002:abnormalities / Q000196:embryology; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D003574:Cytochrome c Group / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D018345:Mice, Knockout; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology
D003574:Cytochrome c Group; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases