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

J Yu1, P Wang, L Ming

  • 1Department of Pharmacology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

Oncogene
|January 24, 2007
PubMed

Insights

Second mitochondria-derived activator of caspase (SMAC) mediates p53-upregulated modulator of apoptosis (PUMA)-induced apoptosis by regulating mitochondrial events. SMAC is crucial for caspase activation and cytochrome c release in PUMA-mediated apoptosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • p53-upregulated modulator of apoptosis (PUMA) is a key mediator of DNA damage-induced apoptosis via the mitochondrial pathway.
  • The precise mechanisms underlying PUMA-induced apoptosis, particularly its mitochondrial regulation, require further elucidation.

Purpose of the Study:

  • To investigate the role of second mitochondria-derived activator of caspase (SMAC)/Diablo in PUMA-mediated apoptosis.
  • To elucidate the mechanisms by which SMAC regulates PUMA-induced mitochondrial events.

Main Methods:

  • Analysis of SMAC release in colon cancer cells undergoing PUMA-induced apoptosis.
  • Assessment of apoptosis execution in SMAC-deficient cells.
  • Restoration of SMAC expression in deficient cells.
  • Evaluation of cellular sensitization to PUMA-induced apoptosis by SMAC and IAP inhibitors.

Main Results:

  • SMAC is consistently released into the cytosol during PUMA-induced apoptosis in colon cancer cells.
  • SMAC deficiency abrogates PUMA-induced apoptosis, inhibiting caspase activation, cytochrome c release, and mitochondrial membrane potential collapse.
  • Restoring SMAC expression rescues these apoptotic events.
  • SMAC sensitizes cells to PUMA-induced apoptosis, suggesting a role in a feedback amplification loop.

Conclusions:

  • SMAC plays a critical role in executing DNA damage-induced and PUMA-mediated apoptosis.
  • SMAC is essential for promoting cytochrome c release and other mitochondrial events during apoptosis.
  • SMAC may participate in a feedback loop to amplify apoptotic signaling.

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