title: Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome.
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.affiliation: The Walter and Eliza Hall Institute, Melbourne, 3050, Australia.
authors.forename: Vanessa S
authors.initials: VS
authors.lastname: Marsden
authors.forename: Liam
authors.initials: L
authors.lastname: O'Connor
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: O'Reilly
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ekert
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kuida
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tomaselli
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.forename: Don W
authors.initials: DW
authors.lastname: Nicholson
authors.forename: David L
authors.initials: DL
authors.lastname: Vaux
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.forename: Jerry M
authors.initials: JM
authors.lastname: Adams
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
mesh_terms: 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
chemical_list: 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