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

¹ The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
² Murdoch Children's Research Institute, Melbourne, Victoria 3052, Australia

Address correspondence to Andreas Strasser, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. Tel.: 61-3-9345-2555. Fax: 61-3-9347-0852. email: strasser{at}wehi.edu.au

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.

Key Words: apoptosis; caspase-2; caspase-9; Bcl-2; cytochrome c

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