Apocytochrome c blocks caspase-9 activation and Bax-induced apoptosis.
Complex networks of signaling pathways control the apoptotic response and, therefore, cell survival. However, these networks converge on a common machinery, of which the caspase cysteine proteases are key components. Diverse apoptotic stimuli release holocytochrome c from mitochondria, allowing holocytochrome c to bind apoptotic protease activating factor-1 (Apaf-1), which in turn binds caspase-9 both activating this caspase and forming an Apaf-1/caspase-9 holoenzyme. Cytochrome c lacking heme (the apo form) cannot support caspase activation, although the reason for this has not been studied. Here we show that apocytochrome c still binds Apaf-1 and that it can block holo-dependent caspase activation in a cell-free system. In addition we show that overexpression of apocytochrome c blocks Bax-induced apoptosis in cells. Thus it is possible to modulate cell survival by interfering with the Apaf-1/cytochrome c interaction. Given the key role played by Apaf-1/cytochrome c in the apoptotic process, and the role of apoptosis in degenerative disease, this interaction may serve as a novel therapeutic target.
Martin
Angel G
AG
Apoptosis Section, Regulation of Cell Growth Laboratory, NCI, National Institutes of Health, Frederick, Maryland 21702, USA.
Fearnhead
Howard O
HO
D001059:Apoproteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D003574:Cytochrome c Group / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D045304:Cytochromes c; D004789:Enzyme Activation; D006801:Humans; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051028:bcl-2-Associated X Protein
C506592:APAF1 protein, human; D001059:Apoproteins; D053477:Apoptotic Protease-Activating Factor 1; C494826:BAX protein, human; D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases