mTOR regulates autophagy-associated genes downstream of p73

Jennifer M Rosenbluth1, Jennifer A Pietenpol

  • 1Department of Biochemistry, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

Autophagy
|November 13, 2008
PubMed

Insights

The p73 protein, part of the p53 family, induces autophagy and targets autophagy-related genes. Its regulation by mammalian target of rapamycin (mTOR) and cellular stress requires further investigation for disease implications.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • The p53 family, including p53, p63, and p73, comprises transcription factors with shared structural and sequence characteristics.
  • Mammalian target of rapamycin (mTOR) kinase regulates cellular growth and autophagy in response to nutrients and growth factors.
  • While p53's role in autophagy is context-dependent, p73's function is less understood, though recent studies suggest it induces autophagy.

Purpose of the Study:

  • To investigate the role of p73 in regulating autophagy and autophagy-associated genes.
  • To explore the relationship between p73, mTOR signaling, and cellular stress responses.
  • To elucidate the mechanisms by which p73 controls autophagy gene expression.

Main Methods:

  • Gene signature-based analyses to assess mTOR activity effects on p73.
  • Chromatin immunoprecipitation (ChIP) to identify p73 binding sites on autophagy-related genes (e.g., ATG5, ATG7, UVRAG).

Main Results:

  • Gene signature analyses indicate mTOR activity inhibits p73.
  • p73 induces cellular autophagy and upregulates multiple autophagy-associated genes downstream of mTOR.
  • ChIP assays confirm endogenous p73 binding to regulatory regions of key autophagy genes like ATG5, ATG7, and UVRAG.

Conclusions:

  • p73 actively induces autophagy and regulates critical autophagy genes, particularly downstream of mTOR.
  • The precise mechanisms of p73-mediated gene regulation under cellular stress remain to be elucidated.
  • Understanding p73's regulation of autophagy is crucial given the p53 family's involvement in tumor suppression, aging, and neurodegeneration.

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