Hypoxia-induced energy stress regulates mRNA translation and cell growth.
Oxygen (O2) deprivation, or hypoxia, has profound effects on cell metabolism and growth. Cells can adapt to low O2 in part through activation of hypoxia-inducible factor (HIF). We report here that hypoxia inhibits mRNA translation by suppressing multiple key regulators, including eIF2alpha, eEF2, and the mammalian target of rapamycin (mTOR) effectors 4EBP1, p70S6K, and rpS6, independent of HIF. Hypoxia results in energy starvation and activation of the AMPK/TSC2/Rheb/mTOR pathway. Hypoxic AMP-activated protein kinase (AMPK) activation also leads to eEF2 inhibition. Moreover, hypoxic effects on cellular bioenergetics and mTOR inhibition increase over time. Mutation of the TSC2 tumor suppressor gene confers a growth advantage to cells by repressing hypoxic mTOR inhibition and hypoxia-induced G1 arrest. Together, eIF2alpha, eEF2, and mTOR inhibition represent important HIF-independent mechanisms of energy conservation that promote survival under low O2 conditions.
Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
Liping
L
Liu
Timothy P
TP
Cash
Russell G
RG
Jones
Brian
B
Keith
Craig B
CB
Thompson
M Celeste
MC
Simon
D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D004734:Energy Metabolism; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D020652:Peptide Elongation Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D015852:Eukaryotic Initiation Factor-2; D051793:Hypoxia-Inducible Factor 1; D020559:Monomeric GTP-Binding Proteins; D009097:Multienzyme Complexes; D009479:Neuropeptides; D010100:Oxygen; D020652:Peptide Elongation Factor 2; D010750:Phosphoproteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D000076205:Ras Homolog Enriched in Brain Protein; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D019892:eIF-2 Kinase; C087000:EIF4EBP1 protein, human; C490211:RHEB protein, human; C000624653:TSC2 protein, human; C546842:MTOR protein, human