Hypoxia activates Akt and induces phosphorylation of GSK-3 in PC12 cells

Cell Signal. 2001 Jan;13(1):23-7. doi: 10.1016/s0898-6568(00)00128-5.


Akt is a serine/threonine kinase that has been shown to play a central role in promoting cell survival and opposing apoptosis. We evaluated the effect of hypoxia on Akt in rat pheochromocytoma (PC12) cells. PC12 cells were exposed to varying levels of hypoxia, including 21%, 15%, 10%, 5%, and 1% O(2). Hypoxia dramatically increased phosphorylation of Akt (Ser(473)). This effect peaked after 6 h exposure to hypoxia, but persisted strongly for up to 24 h. Phosphorylation of Akt was paralleled with a progressive increase in phosphorylation of glycogen synthase kinase-3 (GSK-3), one of its downstream substrates. The effect of hypoxia on phosphorylation of Akt was completely blocked by pretreatment of the cells with wortmannin (100 nM), indicating that this effect is mediated by phosphatidylinositol 3-kinase (P13K). In contrast, whereas hypoxia also strongly induced phosphorylation of the transcription factors CREB and EPAS1, these effects persisted in the presence of wortmannin. Thus, hypoxia regulates both P13K-dependent and P13K-independent signaling pathways. Furthermore, activation of the P13K and Akt signaling pathways may be one mechanism by which cells adapt and survive under conditions of hypoxia.

Publication types

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

MeSH terms

  • Androstadienes / metabolism
  • Androstadienes / pharmacology
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Hypoxia / physiology*
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • PC12 Cells
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Phosphotransferases / metabolism*
  • Protein Isoforms
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Signal Transduction / physiology
  • Substrate Specificity
  • Transcription Factors / drug effects
  • Transcription Factors / metabolism
  • Wortmannin


  • Androstadienes
  • Protein Isoforms
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Phosphotransferases
  • Phosphatidylinositol 3-Kinases
  • Glycogen Synthase Kinases
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3
  • Wortmannin