Phosphatidylinositol 3-kinase/Akt signaling is neither required for hypoxic stabilization of HIF-1 alpha nor sufficient for HIF-1-dependent target gene transcription

J Biol Chem. 2002 Apr 26;277(17):15162-70. doi: 10.1074/jbc.M111162200. Epub 2002 Feb 21.


The serine/threonine kinase Akt/PKB and the oxygen-responsive transcription factor HIF-1 share the ability to induce such processes as angiogenesis, glucose uptake, and glycolysis. Akt activity and HIF-1 are both essential for development and implicated in tumor growth. Upon activation by products of phosphatidylinositol 3-kinase (PI3K), Akt phosphorylates downstream targets that stimulate growth and inhibit apoptosis. Previous reports suggest that Akt may achieve its effects on angiogenesis and glucose metabolism by stimulating HIF-1 activity. We report here that, whereas serum stimulation can induce a slight accumulation of HIF-1 alpha protein in a PI3K/Akt pathway-dependent fashion, hypoxia induces much higher levels of HIF-1 alpha protein and HIF-1 DNA binding activity independently of PI3K and mTOR activity. In addition, we find the effects of constitutively active Akt on HIF-1 activity are cell-type specific. High levels of Akt signaling can modestly increase HIF-1 alpha protein, but this increase does not affect HIF-1 target gene expression. Therefore, the PI3K/Akt pathway is not necessary for hypoxic induction of HIF-1 subunits or activity, and constitutively active Akt is not itself sufficient to induce HIF-1 activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Hypoxia*
  • Cell Line
  • Electrophoretic Mobility Shift Assay
  • Enzyme Inhibitors / pharmacology
  • Glucose Transporter Type 1
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Kinetics
  • Mice
  • Monosaccharide Transport Proteins / biosynthesis
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Signal Transduction*
  • Transcription Factors / metabolism*
  • Transcription Factors / physiology
  • Transcription, Genetic / physiology*


  • Enzyme Inhibitors
  • Glucose Transporter Type 1
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Monosaccharide Transport Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • SLC2A1 protein, human
  • Transcription Factors
  • AKT1 protein, human
  • Akt1 protein, rat
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt