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P73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis

A E Sayan1, B S Sayan, V Gogvadze

  • 1MRC Toxicology Unit, University of Leicester, Leicester, UK.

Oncogene
|March 26, 2008
PubMed

Insights

The p73 protein, crucial in development and cancer, is cleaved during apoptosis. Its non-nuclear functions, particularly in mitochondria, are vital for programmed cell death progression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The p73 protein, a p53 family member, plays roles in both development and tumorigenesis.
  • Understanding p73's function in apoptosis is critical for cancer research.

Purpose of the Study:

  • To investigate the cleavage of p73 during apoptosis.
  • To explore the role of p73 in death receptor-mediated apoptosis.
  • To elucidate the non-nuclear functions of p73.

Main Methods:

  • In vitro and in vivo cleavage assays using caspase-3 and -8.
  • Subcellular localization studies of p73 and its fragments.
  • siRNA-mediated gene silencing to assess p73 function.
  • Analysis of apoptosis induction and cytochrome c release.

Main Results:

  • p73 is cleaved by caspase-3 and -8 during apoptosis induced by DNA-damaging agents and TRAIL.
  • TAp73 and cleavage products localize to mitochondria.
  • Downregulation of p73 affects sensitivity to TRAIL-induced apoptosis.
  • A transcription-deficient p73 mutant enhances TRAIL-induced apoptosis.
  • Recombinant p73 induces cytochrome c release from isolated mitochondria.

Conclusions:

  • p73 undergoes caspase-mediated cleavage during apoptosis.
  • p73 possesses transcription-independent functions in apoptosis, including mitochondrial roles.
  • These findings highlight novel non-nuclear functions of p73 in programmed cell death.

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