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Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex

James Brugarolas1, Kui Lei, Rebecca L Hurley

  • 1Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Genes & Development
|November 17, 2004
PubMed

Insights

Hypoxia inhibits mammalian target of rapamycin (mTOR) via the TSC1/TSC2 complex and REDD1 gene, independent of AMPK. This mechanism is crucial for tumor suppression, as TSC2-deficient cells proliferate abnormally under hypoxia.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Cancer Biology

Background:

  • Mammalian target of rapamycin (mTOR) regulates protein synthesis and is inhibited by energy depletion and hypoxia.
  • Energy depletion inhibits mTOR via AMP-activated protein kinase (AMPK) and LKB1-mediated TSC2 phosphorylation.
  • The mechanism of hypoxia-induced mTOR inhibition remains unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism by which hypoxia inhibits mTOR.
  • To investigate the role of the TSC1/TSC2 complex and hypoxia-inducible genes in this process.
  • To determine the implications of mTOR inhibition by hypoxia for tumor suppression.

Main Methods:

  • Investigated mTOR inhibition in cells under hypoxic conditions.
  • Utilized genetic disruption of the TSC1/TSC2 complex and REDD1.
  • Assessed mTOR activity by measuring phosphorylation of targets S6K and 4E-BP1.
  • Monitored Hypoxia-inducible factor (HIF) accumulation.
  • Analyzed the requirement for de novo mRNA synthesis and REDD1 gene expression.

Main Results:

  • Hypoxia inhibits mTOR through the TSC1/TSC2 complex and the hypoxia-inducible gene REDD1.
  • Disruption of TSC1/TSC2 abrogates hypoxia-induced mTOR inhibition and leads to HIF accumulation.
  • Hypoxia-induced mTOR inhibition does not require AMPK or LKB1, unlike energy depletion.
  • REDD1 gene expression is upregulated by hypoxia and is essential for mTOR inhibition.
  • REDD1 overexpression inhibits mTOR activity in a TSC1/TSC2-dependent manner.

Conclusions:

  • Hypoxia inhibits mTOR via a novel pathway involving TSC1/TSC2 and REDD1, distinct from energy depletion.
  • This mechanism is critical for suppressing aberrant cell proliferation under hypoxic stress.
  • Dysregulation of this pathway, as seen in TSC2-deficient cells, contributes to tumor growth in hypoxic environments.

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