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Vol. 60, Issue 5, 1008-1019, November 2001

Multiple Kinetics of Mitochondrial Cytochrome c Release in Drug-Induced Apoptosis

C. Marc Luetjens, Donat Kögel, Claus Reimertz, Heiko Düßmann, Andrea Renz, Klaus Schulze-Osthoff, Anna-Liisa Nieminen, Monika Poppe, and Jochen H. M. Prehn

Interdisciplinary Center for Clinical Research, Research Group "Apoptosis and Cell Death" (C.M.L., D.K., C.R., H.D., M.P., J.H.M.P.), Division of Immunology and Cell Biology, Department of Experimental Dermatology (A.R., K.S.-O.), and Department of Pharmacology and Toxicology (J.H.M.P.), Westphalian Wilhelms-University, Münster, Germany; and Department of Anatomy, School of Medicine, Case Western Reserve University, Cleveland, Ohio (A.-L.N.)

We investigated cytochrome c release kinetics in response to three apoptosis-inducing agents (tumor necrosis factor-alpha , staurosporine, and valinomycin) in MCF-7/Casp-3 cells stably transfected with enhanced green fluorescent protein (EGFP)-tagged cytochrome c. All three agents induced significant caspase activation in the cultures determined by monitoring the cleavage of fluorigenic caspase substrates in extracts from drug-treated MCF-7/Casp-3 cells, albeit the valinomycin-induced activation was less pronounced. Time-lapse confocal microscopy showed that tumor necrosis factor-alpha and staurosporine caused rapid, one- or multiple-step release of cytochrome c-EGFP from mitochondria. In contrast, valinomycin-induced cytochrome c-EGFP release occurred slowly over several hours. Unlike staurosporine, the valinomycin-induced cytochrome c release was not associated with translocation of the proapoptotic Bax protein to the mitochondria, and was not accompanied by co-release of the proapoptotic Smac protein. Immunoprecipitation experiments revealed that cytochrome c was also released out of the cell into the extracellular space before loss of plasma membrane integrity. Our data indicate the existence of multiple kinetics of cytochrome c release in drug-induced apoptosis.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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