SMAC/Diablo mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events

Oncogene. 2007 Jun 21;26(29):4189-98. doi: 10.1038/sj.onc.1210196. Epub 2007 Jan 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / metabolism*
  • Apoptosis Regulatory Proteins / physiology
  • Caspase 9 / metabolism
  • Caspase Inhibitors
  • Cell Line, Tumor
  • Cytochromes c / antagonists & inhibitors
  • Cytochromes c / metabolism
  • HCT116 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / deficiency
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Mitochondrial Proteins / physiology*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins / physiology


  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • Caspase Inhibitors
  • DIABLO protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Proto-Oncogene Proteins
  • Cytochromes c
  • Caspase 9