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Vol. 18, Issue 1, 84-93, January 2007

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Loss of Caspase-9 Reveals Its Essential Role for Caspase-2 Activation and Mitochondrial Membrane Depolarization

Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf D-40225, Germany

Submitted April 3, 2006; Revised September 27, 2006; Accepted October 25, 2006
Monitoring Editor: Gerard Evan

Caspase-9 plays an important role in apoptosis induced by genotoxic stress. Irradiation and anticancer drugs trigger mitochondrial outer membrane permeabilization, resulting in cytochrome c release and caspase-9 activation. Two highly contentious issues, however, remain: It is unclear whether the loss of the mitochondrial membrane potential _M contributes to cytochrome c release and whether caspases are involved. Moreover, an unresolved question is whether caspase-2 functions as an initiator in genotoxic stress-induced apoptosis. In the present study, we have identified a mutant Jurkat T-cell line that is deficient in caspase-9 and resistant to apoptosis. Anticancer drugs, however, could activate proapoptotic Bcl-2 proteins and cytochrome c release, similarly as in caspase-9–proficient cells. Interestingly, despite these alterations, the cells retained _M. Furthermore, processing and enzyme activity of caspase-2 were not observed in the absence of caspase-9. Reconstitution of caspase-9 expression restored not only apoptosis but also the loss of _M and caspase-2 activity. Thus, we provide genetic evidence that caspase-9 is indispensable for drug-induced apoptosis in cancer cells. Moreover, loss of _M can be functionally separated from cytochrome c release. Caspase-9 is not only required for _M loss but also for caspase-2 activation, suggesting that these two events are downstream of the apoptosome.

* These authors contributed equally to this work.

Address correspondence to: Ingo Schmitz (ingo-schmitz{at}uni-duesseldorf.de) or Klaus Schulze-Osthoff (kso{at}uni-duesseldorf.de)

Abbreviations used: _M, mitochondrial membrane potential; MOMP, mitochondrial outer membrane permeabilization; PTP, permeability transition pore.

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