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HIF2α acts as an mTORC1 activator through the amino acid carrier SLC7A5

Ainara Elorza1, Inés Soro-Arnáiz, Florinda Meléndez-Rodríguez

  • 1Research Unit, Hospital Universitario Santa Cristina, Research Institute Princesa, Autonomous University of Madrid, 28009 Madrid, Spain.

Molecular Cell
|October 30, 2012
PubMed

Insights

Hypoxia-inducible factor 2α (HIF2α) activates mTORC1 by increasing SLC7A5 expression, linking oxygen sensing to cell growth. This explains HIF2α

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The mammalian target of rapamycin (mTOR) pathway regulates cell proliferation but is repressed by hypoxia.
  • Hypoxia-inducible factor 2α (HIF2α) can promote proliferation, creating a paradox with mTOR regulation in hypoxia.

Purpose of the Study:

  • To investigate the effect of HIF2α on mTORC1 regulation.
  • To elucidate the molecular mechanisms linking HIF2α to mTORC1.

Main Methods:

  • Analysis of HIF2α pathway activation and its impact on mTORC1 activity.
  • Measurement of SLC7A5 (solute carrier family 7 member 5) expression.
  • Chromatin immunoprecipitation to assess HIF2α binding to the Slc7a5 promoter.

Main Results:

  • HIF2α activation increases mTORC1 activity.
  • HIF2α upregulates the expression of the amino acid transporter SLC7A5.
  • HIF2α directly binds to the proximal promoter of the Slc7a5 gene.

Conclusions:

  • A novel link exists between the HIF2α pathway and mTORC1 regulation.
  • HIF2α promotes tumor growth in von Hippel-Lindau-deficient cells by upregulating SLC7A5 and mTORC1.
  • HIF2α and hypoxia drive mTORC1 activity and SLC7A5 expression in liver and lung tissues.

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