title: HIF2α acts as an mTORC1 activator through the amino acid carrier SLC7A5.
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.
authors.affiliation: Research Unit, Hospital Universitario Santa Cristina, Research Institute Princesa, Autonomous University of Madrid, 28009 Madrid, Spain.
authors.forename: Ainara
authors.initials: A
authors.lastname: Elorza
authors.forename: Inés
authors.initials: I
authors.lastname: Soro-Arnáiz
authors.forename: Florinda
authors.initials: F
authors.lastname: Meléndez-Rodríguez
authors.forename: Victoria
authors.initials: V
authors.lastname: Rodríguez-Vaello
authors.forename: Glenn
authors.initials: G
authors.lastname: Marsboom
authors.forename: Guillermo
authors.initials: G
authors.lastname: de Cárcer
authors.forename: Bárbara
authors.initials: B
authors.lastname: Acosta-Iborra
authors.forename: Lucas
authors.initials: L
authors.lastname: Albacete-Albacete
authors.forename: Angel
authors.initials: A
authors.lastname: Ordóñez
authors.forename: Leticia
authors.initials: L
authors.lastname: Serrano-Oviedo
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Giménez-Bachs
authors.forename: Alicia
authors.initials: A
authors.lastname: Vara-Vega
authors.forename: Antonio
authors.initials: A
authors.lastname: Salinas
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sánchez-Prieto
authors.forename: Rafael
authors.initials: R
authors.lastname: Martín del Río
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Madrid
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
authors.forename: Manuel O
authors.initials: MO
authors.lastname: Landázuri
authors.forename: Julián
authors.initials: J
authors.lastname: Aragonés
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D046912:Multiprotein Complexes; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D027283:Large Neutral Amino Acid-Transporter 1; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011506:Proteins; D058570:TOR Serine-Threonine Kinases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497446:VHL protein, human; C494469:VHL protein, mouse