Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome.
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.
Marsden
Vanessa S
VS
The Walter and Eliza Hall Institute, Melbourne, 3050, Australia.
O'Connor
Liam
L
O'Reilly
Lorraine A
LA
Silke
John
J
Metcalf
Donald
D
Ekert
Paul G
PG
Huang
David C S
DC
Cecconi
Francesco
F
Kuida
Keisuke
K
Tomaselli
Kevin J
KJ
Roy
Sophie
S
Nicholson
Don W
DW
Vaux
David L
DL
Bouillet
Philippe
P
Adams
Jerry M
JM
Strasser
Andreas
A
D000818:Animals; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D001402:B-Lymphocytes / Q000166:cytology; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism*; D004789:Enzyme Activation; D006410:Hematopoiesis / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology
C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D003574:Cytochrome c Group; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases