title: Bcl-2-regulated apoptosis and cytochrome c release can occur independently of both caspase-2 and caspase-9.
abstract: Apoptosis in response to developmental cues and stress stimuli is mediated by caspases that are regulated by the Bcl-2 protein family. Although caspases 2 and 9 have each been proposed as the apical caspase in that pathway, neither is indispensable for the apoptosis of leukocytes or fibroblasts. To investigate whether these caspases share a redundant role in apoptosis initiation, we generated caspase-2(-/-)9(-/-) mice. Their overt phenotype, embryonic brain malformation and perinatal lethality mirrored that of caspase-9(-/-) mice but were not exacerbated. Analysis of adult mice reconstituted with caspase-2(-/-)9(-/-) hematopoietic cells revealed that the absence of both caspases did not influence hematopoietic development. Furthermore, lymphocytes and fibroblasts lacking both remained sensitive to diverse apoptotic stimuli. Dying caspase-2(-/-)9(-/-) lymphocytes displayed multiple hallmarks of caspase-dependent apoptosis, including the release of cytochrome c from mitochondria, and their demise was antagonized by several caspase inhibitors. These findings suggest that caspases other than caspases 2 and 9 can promote cytochrome c release and initiate Bcl-2-regulated apoptosis.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
authors.forename: Vanessa S
authors.initials: VS
authors.lastname: Marsden
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ekert
authors.forename: Mark
authors.initials: M
authors.lastname: Van Delft
authors.forename: David L
authors.initials: DL
authors.lastname: Vaux
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 / Q000502:physiology*; D053143:Caspase 2; D053453:Caspase 9; D020169:Caspases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045304:Cytochromes c / Q000032:analysis*; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D045304:Cytochromes c; C506434:Casp9 protein, mouse; D053143:Caspase 2; D053453:Caspase 9; D020169:Caspases