Calcium signaling stimulates translation of HIF-alpha during hypoxia

FASEB J. 2006 Mar;20(3):466-75. doi: 10.1096/fj.05-5086com.

Abstract

Hypoxia-inducible factors (HIFs) are ubiquitous transcription factors that mediate adaptation to hypoxia by inducing specific sets of target genes. It is well accepted that hypoxia induces accumulation and activity of HIFs by causing stabilization of their alpha subunits. We have demonstrated that hypoxia stimulates translation of HIF-1alpha and -2alpha proteins by distributing HIF-alpha mRNAs to larger polysome fractions. This requires influx of extracellular calcium, stimulation of classical protein kinase C-alpha (cPKC-alpha), and the activity of mammalian target of rapamycin, mTOR. The translational component contributes to approximately 40-50% of HIF-alpha proteins accumulation after 3 h of 1% O2. Hypoxia also inhibits general protein synthesis and mTOR activity; however, cPKC-alpha inhibitors or rapamycin reduce mTOR activity and total protein synthesis beyond the effects of hypoxia alone. These data show that during general inhibition of protein synthesis by hypoxia, cap-mediated translation of selected mRNAs is induced through the mTOR pathway. We propose that calcium-induced activation of cPKC-alpha hypoxia partially protects an activity of mTOR from hypoxic inhibition. These results provide an important physiologic insight into the mechanism by which hypoxia-stimulated influx of calcium selectively induces the translation of mRNAs necessary for adaptation to hypoxia under conditions repressing general protein synthesis.

Publication types

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

MeSH terms

  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator / analysis
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Benzylamines / pharmacology
  • Butadienes / pharmacology
  • Calcium Signaling*
  • Carbazoles / pharmacology
  • Cell Hypoxia / physiology*
  • Cell Line / drug effects
  • Cell Line / metabolism
  • Cycloheximide / pharmacology
  • Flavonoids / pharmacology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Indoles / pharmacology
  • Ionomycin / pharmacology
  • Isoquinolines / pharmacology
  • Kidney
  • Nitriles / pharmacology
  • PC12 Cells / drug effects
  • PC12 Cells / metabolism
  • Polyribosomes / metabolism
  • Protein Biosynthesis*
  • Protein Kinase C-alpha / antagonists & inhibitors
  • Protein Kinase C-alpha / metabolism
  • Protein Kinases / physiology
  • Protein Synthesis Inhibitors / pharmacology
  • RNA Caps / physiology
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Rats
  • Sirolimus / pharmacology
  • Sulfonamides / pharmacology
  • TOR Serine-Threonine Kinases

Substances

  • ARNT protein, rat
  • Basic Helix-Loop-Helix Transcription Factors
  • Benzylamines
  • Butadienes
  • Carbazoles
  • Flavonoids
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indoles
  • Isoquinolines
  • KN 92
  • Nitriles
  • Protein Synthesis Inhibitors
  • RNA Caps
  • RNA, Messenger
  • RNA, Small Interfering
  • Sulfonamides
  • U 0126
  • Go 6976
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • KN 93
  • endothelial PAS domain-containing protein 1
  • Ionomycin
  • Cycloheximide
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Protein Kinase C-alpha
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Sirolimus