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

Gautam N. Bijur, Richard S. Jope

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

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°C) rapidly activated Akt, extracellular signal-regulated kinases 1 and 2 (ERK 1/2), and p38, but only Akt was activated in a phosphatidylinositol 3-kinase (Pl-3K)-dependent manner, as the Pl-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 Pl-3K activity, as both the Pl-3K inhibitors attenuated this response. Because Akt inhibits glycogen synthase kinase-3β (GSK-3β), an enzyme that facilitates cell death, we tested if GSK-3β is a negative regulator of HSF-1 activation. Overexpression of GSK-3β impaired heat shock-induced activation of HSF-1, and also reduced HSP-70 production, which was partially restored by the GSK-3β inhibitor lithium. Thus, heat shock-induced activation of Pl-3K and the inhibitory effect of GSK-3β on HSF-1 activation and HSP-70 expression imply that Akt-induced inhibition of GSK-3β contributes to the activation of HSF-1.

Original languageEnglish (US)
Pages (from-to)2401-2408
Number of pages8
JournalJournal of neurochemistry
Volume75
Issue number6
DOIs
StatePublished - 2000

Keywords

  • Akt
  • Glycogen synthase kinase-3β
  • Heat shock factor-1
  • Heat shock protein-70
  • Lithium
  • Phosphatidylinositol 3-kinase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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