Bcl-2-regulated apoptosis and cytochrome c release can occur independently of both caspase-2 and caspase-9

Marsden, VS; Ekert, PG; Van Delft, M; Vaux, DL; Adams, JM; Strasser, A

Author(s): Marsden, VS; Ekert, PG; Van Delft, M; Vaux, DL; Adams, JM; Strasser, A;
Details: Publication Year 2004-06-21,Volume 165,Issue #6,Page 775-780
Journal Title: JOURNAL OF CELL BIOLOGY
Publication Type: Journal Article
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.
Publisher: ROCKEFELLER UNIV PRESS
Keywords: ENDOPLASMIC-RETICULUM STRESS; CELL-DEATH; NEUTROPHIL APOPTOSIS; ACTIVATION; UPSTREAM; PATHWAYS; MICE; MITOCHONDRIA; REQUIREMENT; INHIBITORS
Publisher's Version: https://doi.org/10.1083/jcb.200312030
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2004-06-21 12:00:00