Hypoxia-induced energy stress regulates mRNA translation and cell growth

Mol Cell. 2006 Feb 17;21(4):521-31. doi: 10.1016/j.molcel.2006.01.010.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Carrier Proteins / metabolism
  • Cell Line
  • Energy Metabolism*
  • Enzyme Activation
  • Eukaryotic Initiation Factor-2 / antagonists & inhibitors
  • Eukaryotic Initiation Factor-2 / metabolism*
  • Gene Expression Regulation
  • Humans
  • Hypoxia*
  • Hypoxia-Inducible Factor 1 / metabolism
  • Monomeric GTP-Binding Proteins / metabolism
  • Multienzyme Complexes / metabolism
  • Neuropeptides / metabolism
  • Oxygen / metabolism
  • Peptide Elongation Factor 2 / antagonists & inhibitors
  • Peptide Elongation Factor 2 / metabolism*
  • Phosphoproteins / metabolism
  • Protein Biosynthesis*
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Messenger / metabolism*
  • Ras Homolog Enriched in Brain Protein
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / physiology
  • TOR Serine-Threonine Kinases
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • eIF-2 Kinase / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • EIF4EBP1 protein, human
  • Eukaryotic Initiation Factor-2
  • Hypoxia-Inducible Factor 1
  • Multienzyme Complexes
  • Neuropeptides
  • Peptide Elongation Factor 2
  • Phosphoproteins
  • RHEB protein, human
  • RNA, Messenger
  • Ras Homolog Enriched in Brain Protein
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • PERK kinase
  • Protein-Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases, 70-kDa
  • eIF-2 Kinase
  • AMP-Activated Protein Kinases
  • Monomeric GTP-Binding Proteins
  • Oxygen