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- Title
SMAC/Diablo mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events.
- Authors
Yu, J.; Wang, P.; Ming, L.; Wood, M. A.; Zhang, L.
- Abstract
p53-upregulated modulator of apoptosis (PUMA) is a BH3-only Bcl-2 family protein and an essential mediator of DNA damage-induced apoptosis. PUMA is localized in the mitochondria and induces apoptosis through the mitochondrial pathway. However, the mechanisms of PUMA-induced apoptosis remain unclear. In this study, we found that second mitochondria-derived activator of caspase (SMAC)/Diablo, a mitochondrial apoptogenic protein, mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events. SMAC is consistently released into the cytosol in colon cancer cells undergoing PUMA-induced apoptosis. In SMAC-deficient cells, execution of PUMA-induced apoptosis is abrogated, in company with decreases in caspase activation, cytosolic release of cytochrome c and collapse of mitochondrial membrane potential. Reconstituting SMAC expression restored these events in the SMAC-deficient cells. Furthermore, SMAC and agents that mimic the inhibitor of apoptosis proteins (IAPs) inhibition function of SMAC significantly sensitize cells to PUMA-induced apoptosis. These results demonstrate an important role of SMAC in executing DNA damage-induced and PUMA-mediated apoptosis and suggest that SMAC participates in a feedback amplification loop to promote cytochrome c release and other mitochondrial events in apoptosis.Oncogene (2007) 26, 4189–4198; doi:10.1038/sj.onc.1210196; published online 22 January 2007
- Subjects
MITOCHONDRIA; P53 antioncogene; APOPTOSIS; DNA damage; CYTOCHROME c; MITOCHONDRIAL membranes
- Publication
Oncogene, 2007, Vol 26, Issue 29, p4189
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1210196