Opposing actions of phosphatidylinositol 3-kinase and glycogen synthase kinase-3beta in the regulation of HSF-1 activity

J Neurochem. 2000 Dec;75(6):2401-8. doi: 10.1046/j.1471-4159.2000.0752401.x.


Elevated temperatures activate the survival promoters Akt and heat shock factor-1 (HSF-1), a transcription factor that induces the expression of heat shock proteins (HSPs), such as HSP-70. Because neuronal mechanisms controlling these responses are not known, these were investigated in human neuroblastoma SH-SY5Y cells. Heat shock (45 degrees C) rapidly activated Akt, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and p38, but only Akt was activated in a phosphatidylinositol 3-kinase (PI-3K)-dependent manner, as the PI-3K inhibitors LY294002 and wortmannin blocked Akt activation, but not ERK1/2 or p38 activation. Akt activation was not blocked by inhibition of p38 or ERK1/2, indicating the independence of these signaling systems. Heat shock treatment also caused a rapid increase in HSF-1 DNA binding activity that was partially dependent on PI-3K activity, as both the PI-3K inhibitors attenuated this response. Because Akt inhibits glycogen synthase kinase-3beta (GSK-3beta), an enzyme that facilitates cell death, we tested if GSK-3beta is a negative regulator of HSF-1 activation. Overexpression of GSK-3beta impaired heat shock-induced activation of HSF-1, and also reduced HSP-70 production, which was partially restored by the GSK-3beta inhibitor lithium. Thus, heat shock-induced activation of PI-3K and the inhibitory effect of GSK-3beta on HSF-1 activation and HSP-70 expression imply that Akt-induced inhibition of GSK-3beta contributes to the activation of HSF-1.

Publication types

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

MeSH terms

  • Calcium-Calmodulin-Dependent Protein Kinases / biosynthesis
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • HSP70 Heat-Shock Proteins / biosynthesis
  • Heat Shock Transcription Factors
  • Heat-Shock Response / drug effects
  • Humans
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Neurons / cytology
  • Neurons / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Transcription Factors
  • Transfection
  • p38 Mitogen-Activated Protein Kinases


  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • HSP70 Heat-Shock Proteins
  • Heat Shock Transcription Factors
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Transcription Factors
  • DNA
  • Glycogen Synthase Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Glycogen Synthase Kinase 3