PMID- 12777372
OWN - NLM
STAT- MEDLINE
DCOM- 20030924
LR  - 20220330
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 32
DP  - 2003 Aug 8
TI  - A novel hypoxia-inducible factor-independent hypoxic response regulating 
      mammalian target of rapamycin and its targets.
PG  - 29655-60
AB  - Hypoxia triggers a reversible inhibition of protein synthesis thought to be 
      important for energy conservation in O2-deficient environments. The mammalian 
      target of rapamycin (mTOR) pathway integrates multiple environmental cues to 
      regulate translation in response to nutrient availability and stress, suggesting 
      it as a candidate for O2 regulation. We show here that hypoxia rapidly and 
      reversibly triggers hypophosphorylation of mTOR and its effectors 4E-BP1, p70S6K, 
      rpS6, and eukaryotic initiation factor 4G. Hypoxic regulation of these 
      translational control proteins is dominant to activation via multiple distinct 
      signaling pathways such as insulin, amino acids, phorbol esters, and serum and is 
      independent of Akt/protein kinase B and AMP-activated protein kinase 
      phosphorylation, ATP levels, ATP:ADP ratios, and hypoxia-inducible factor-1 
      (HIF-1). Finally, hypoxia appears to repress phosphorylation of translational 
      control proteins in a manner analogous to rapamycin and independent of 
      phosphatase 2A (PP2A) activity. These data demonstrate a new mode of regulation 
      of the mTOR pathway and position this pathway as a powerful point of control by 
      O2 of cellular metabolism and energetics.
FAU - Arsham, Andrew M
AU  - Arsham AM
AD  - Committee on Genetics, University of Chicago, Chicago, Illinois 60615, USA.
FAU - Howell, Jessica J
AU  - Howell JJ
FAU - Simon, M Celeste
AU  - Simon MC
LA  - eng
GR  - 63310/PHS HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20030530
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Eukaryotic Initiation Factor-4G)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (Ribosomal Protein S6)
RN  - 0 (Transcription Factors)
RN  - 61D2G4IYVH (Adenosine Diphosphate)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Adenosine Diphosphate/metabolism
MH  - Adenosine Triphosphate/metabolism
MH  - Blotting, Western
MH  - Carrier Proteins/metabolism
MH  - Cell Cycle Proteins
MH  - Cell Line
MH  - DNA-Binding Proteins/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - Eukaryotic Initiation Factor-4G/metabolism
MH  - Gene Expression Regulation
MH  - Humans
MH  - Hypoxia
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Nuclear Proteins/*metabolism
MH  - Oxygen/metabolism
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Protein Biosynthesis
MH  - Protein Kinases/*biosynthesis
MH  - Ribosomal Protein S6/metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - Time Factors
MH  - *Transcription Factors
EDAT- 2003/06/05 05:00
MHDA- 2003/09/25 05:00
CRDT- 2003/06/05 05:00
PHST- 2003/06/05 05:00 [pubmed]
PHST- 2003/09/25 05:00 [medline]
PHST- 2003/06/05 05:00 [entrez]
AID - S0021-9258(20)84230-6 [pii]
AID - 10.1074/jbc.M212770200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 Aug 8;278(32):29655-60. doi: 10.1074/jbc.M212770200. Epub 2003 
      May 30.