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Nucleolar p19ARF, unlike mitochondrial smARF, is incapable of inducing p53-independent autophagy

Sharon Reef1, Adi Kimchi

  • 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

Autophagy
|August 23, 2008
PubMed

Insights

The nucleolar p19(ARF) protein does not induce autophagy from within the nucleolus. Only when overexpressed and localized outside the nucleus can p19(ARF) trigger p53-independent autophagy.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • ARF mRNA produces two proteins: nucleolar p19(ARF) and mitochondrial smARF.
  • Both isoforms are elevated by proliferative signals from proto-oncogenes like c-Myc and E2F1.
  • p19(ARF) inhibits cell growth via p53 activation or ribosomal biogenesis inhibition.
  • smARF induces mitochondrial membrane potential dissipation and autophagy independently of p53.

Purpose of the Study:

  • To investigate the role of nucleolar p19(ARF) in autophagy.
  • To determine if nucleolar p19(ARF) can induce p53-independent autophagy from within the nucleolus, as recently proposed.
  • To clarify the localization-dependent functions of ARF isoforms in autophagy.

Main Methods:

  • Ectopic expression of p19(ARF) with restricted nucleolar localization.
  • Analysis of autophagic vesicle formation under different expression conditions.
  • Comparison of p19(ARF) localization and its effect on autophagy.

Main Results:

  • Restricting p19(ARF) expression solely to the nucleolus did not induce autophagic vesicle formation.
  • Extreme overexpression leading to extra-nuclear localization of p19(ARF) triggered p53-independent autophagy.
  • These findings contradict the hypothesis that nucleolar p19(ARF) induces autophagy from within the nucleolus.

Conclusions:

  • Nucleolar p19(ARF) is incapable of inducing autophagy from within the nucleolus.
  • p19(ARF) can induce p53-independent autophagy only when present in extra-nuclear compartments.
  • The function of p19(ARF) in autophagy is dependent on its subcellular localization.

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