PMID- 23103253
OWN - NLM
STAT- MEDLINE
DCOM- 20130219
LR  - 20211203
IS  - 1097-4164 (Electronic)
IS  - 1097-2765 (Linking)
VI  - 48
IP  - 5
DP  - 2012 Dec 14
TI  - HIF2alpha acts as an mTORC1 activator through the amino acid carrier SLC7A5.
PG  - 681-91
LID - S1097-2765(12)00817-9 [pii]
LID - 10.1016/j.molcel.2012.09.017 [doi]
AB  - 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 2alpha (HIF2alpha) can act as a proliferation-promoting factor 
      in some biological settings. This paradoxical situation led us to study whether 
      HIF2alpha has a specific effect on mTORC1 regulation. Here we show that activation of 
      the HIF2alpha pathway increases mTORC1 activity by upregulating expression of the 
      amino acid carrier SLC7A5. At the molecular level we also show that HIF2alpha binds 
      to the Slc7a5 proximal promoter. Our findings identify a link between the 
      oxygen-sensing HIF2alpha pathway and mTORC1 regulation, revealing the molecular basis 
      of the tumor-promoting properties of HIF2alpha in von Hippel-Lindau-deficient cells. 
      We also describe relevant physiological scenarios, including those that occur in 
      liver and lung tissue, wherein HIF2alpha or low-oxygen tension drive mTORC1 activity 
      and SLC7A5 expression.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Elorza, Ainara
AU  - Elorza A
AD  - Research Unit, Hospital Universitario Santa Cristina, Research Institute 
      Princesa, Autonomous University of Madrid, 28009 Madrid, Spain.
FAU - Soro-Arnaiz, Ines
AU  - Soro-Arnaiz I
FAU - Melendez-Rodriguez, Florinda
AU  - Melendez-Rodriguez F
FAU - Rodriguez-Vaello, Victoria
AU  - Rodriguez-Vaello V
FAU - Marsboom, Glenn
AU  - Marsboom G
FAU - de Carcer, Guillermo
AU  - de Carcer G
FAU - Acosta-Iborra, Barbara
AU  - Acosta-Iborra B
FAU - Albacete-Albacete, Lucas
AU  - Albacete-Albacete L
FAU - Ordonez, Angel
AU  - Ordonez A
FAU - Serrano-Oviedo, Leticia
AU  - Serrano-Oviedo L
FAU - Gimenez-Bachs, Jose Miguel
AU  - Gimenez-Bachs JM
FAU - Vara-Vega, Alicia
AU  - Vara-Vega A
FAU - Salinas, Antonio
AU  - Salinas A
FAU - Sanchez-Prieto, Ricardo
AU  - Sanchez-Prieto R
FAU - Martin del Rio, Rafael
AU  - Martin del Rio R
FAU - Sanchez-Madrid, Francisco
AU  - Sanchez-Madrid F
FAU - Malumbres, Marcos
AU  - Malumbres M
FAU - Landazuri, Manuel O
AU  - Landazuri MO
FAU - Aragones, Julian
AU  - Aragones J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121025
PL  - United States
TA  - Mol Cell
JT  - Molecular cell
JID - 9802571
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Large Neutral Amino Acid-Transporter 1)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 6.3.2.- (VHL protein, human)
RN  - EC 6.3.2.- (VHL protein, mouse)
SB  - IM
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors/genetics/*metabolism
MH  - Binding Sites
MH  - Carcinoma, Renal Cell/genetics/*metabolism/pathology
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Gene Expression Regulation, Neoplastic
MH  - HEK293 Cells
MH  - Humans
MH  - Kidney Neoplasms/genetics/*metabolism/pathology
MH  - Large Neutral Amino Acid-Transporter 1/genetics/*metabolism
MH  - Liver/metabolism
MH  - Lung/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, SCID
MH  - Multiprotein Complexes
MH  - Neoplasm Transplantation
MH  - Promoter Regions, Genetic
MH  - Proteins/genetics/*metabolism
MH  - RNA Interference
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - Time Factors
MH  - Transfection
MH  - Tumor Burden
MH  - Up-Regulation
MH  - Von Hippel-Lindau Tumor Suppressor Protein/genetics/metabolism
EDAT- 2012/10/30 06:00
MHDA- 2013/02/21 06:00
CRDT- 2012/10/30 06:00
PHST- 2011/08/24 00:00 [received]
PHST- 2012/07/02 00:00 [revised]
PHST- 2012/09/11 00:00 [accepted]
PHST- 2012/10/30 06:00 [entrez]
PHST- 2012/10/30 06:00 [pubmed]
PHST- 2013/02/21 06:00 [medline]
AID - S1097-2765(12)00817-9 [pii]
AID - 10.1016/j.molcel.2012.09.017 [doi]
PST - ppublish
SO  - Mol Cell. 2012 Dec 14;48(5):681-91. doi: 10.1016/j.molcel.2012.09.017. Epub 2012 
      Oct 25.