Requirement of cytochrome c for apoptosis in human cells.
During apoptosis, cytochrome c released from mitochondria activates Apaf-1, a cofactor of caspase-9. The evidence that cytochrome c can activate Apaf-1 is abundant, but the proof that cytochrome c is required for apoptosis is limited to two studies that used genetically modified mice. One of these studies concluded that in some tissues apoptosis may require Apaf-1 but not cytochrome c, which indicated the need to analyze the requirement of cytochrome c beyond the mouse models, and in human tumor cells in particular. In this study, we designed tools to silence cytochrome c expression in human cells and tested these tools in an experimental system of oncogenic transformation. We found that cytochrome c was required for apoptosis induced by both DNA damage and, unexpectedly, TNFalpha. Overall, this study established that cytochrome c is required for apoptosis in human cells and provided tools to dissect mechanisms of apoptosis in various experimental models.
Matapurkar
A
A
Cold Spring Harbor Laboratory, One Bungtown Rd, Cold Spring Harbor, NY 11724, USA.
Lazebnik
Y
Y
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics / Q000502:physiology; D053453:Caspase 9 / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045304:Cytochromes c / Q000235:genetics / Q000502:physiology*; D004249:DNA Damage; D005347:Fibroblasts / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D020868:Gene Silencing; D006801:Humans; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; D053453:Caspase 9