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

Mol Cell. 2012 Dec 14;48(5):681-91. doi: 10.1016/j.molcel.2012.09.017. Epub 2012 Oct 25.

Abstract

The mammalian target of rapamycin (mTOR) pathway, which is essential for cell proliferation, is repressed in certain cell types in hypoxia. However, hypoxia-inducible factor 2α (HIF2α) can act as a proliferation-promoting factor in some biological settings. This paradoxical situation led us to study whether HIF2α has a specific effect on mTORC1 regulation. Here we show that activation of the HIF2α pathway increases mTORC1 activity by upregulating expression of the amino acid carrier SLC7A5. At the molecular level we also show that HIF2α binds to the Slc7a5 proximal promoter. Our findings identify a link between the oxygen-sensing HIF2α pathway and mTORC1 regulation, revealing the molecular basis of the tumor-promoting properties of HIF2α in von Hippel-Lindau-deficient cells. We also describe relevant physiological scenarios, including those that occur in liver and lung tissue, wherein HIF2α or low-oxygen tension drive mTORC1 activity and SLC7A5 expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Binding Sites
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Large Neutral Amino Acid-Transporter 1 / genetics
  • Large Neutral Amino Acid-Transporter 1 / metabolism*
  • Liver / metabolism
  • Lung / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Knockout
  • Mice, SCID
  • Multiprotein Complexes
  • Neoplasm Transplantation
  • Promoter Regions, Genetic
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA Interference
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Time Factors
  • Transfection
  • Tumor Burden
  • Up-Regulation
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Large Neutral Amino Acid-Transporter 1
  • Multiprotein Complexes
  • Proteins
  • endothelial PAS domain-containing protein 1
  • Von Hippel-Lindau Tumor Suppressor Protein
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • VHL protein, human
  • VHL protein, mouse