A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets.
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.
Arsham
Andrew M
AM
Committee on Genetics, University of Chicago, Chicago, Illinois 60615, USA.
Howell
Jessica J
JJ
Simon
M Celeste
MC
D048868:Adaptor Proteins, Signal Transducing; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000096:biosynthesis*; D038601:Ribosomal Protein S6 / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014157:Transcription Factors
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C087000:EIF4EBP1 protein, human; D039603:Eukaryotic Initiation Factor-4G; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D010750:Phosphoproteins; D038601:Ribosomal Protein S6; D014157:Transcription Factors; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D010100:Oxygen