Lippincott Williams & Wilkins, Inc., Philadelphia
Opposing Actions of Phosphatidylinositol 3-Kinase and Glycogen Synthase Kinase-3β in the Regulation of HSF-1 Activity
Article first published online: 29 JUL 2008
Journal of Neurochemistry
Volume 75, Issue 6, pages 2401–2408, December 2000
How to Cite
Bijur, G. N. and Jope, R. S. (2000), Opposing Actions of Phosphatidylinositol 3-Kinase and Glycogen Synthase Kinase-3β in the Regulation of HSF-1 Activity. Journal of Neurochemistry, 75: 2401–2408. doi: 10.1046/j.1471-4159.2000.0752401.x
Abbreviations used: EMSA, electrophoretic mobility shift assay;ERK, extracellular signal-regulated protein kinase; GSK-3β, glycogensynthase kinase-3β; HA, hemagglutinin; HSF-1, heat shock factor-1; HSP,heat shock protein; PI-3K, phosphatidylinositol 3-kinase.
- Issue published online: 29 JUL 2008
- Article first published online: 29 JUL 2008
- Phosphatidylinositol 3-kinase;
- Heat shock factor-1;
- Glycogen synthase kinase-3β;
- Heat shock protein-70;
Abstract: Elevated temperatures activate the survival promoters Aktand heat shock factor-1 (HSF-1), a transcription factor that induces theexpression of heat shock proteins (HSPs), such as HSP-70. Because neuronalmechanisms controlling these responses are not known, these were investigatedin human neuroblastoma SH-SY5Y cells. Heat shock (45°C) rapidly activatedAkt, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and p38, butonly Akt was activated in a phosphatidylinositol 3-kinase (PI-3K)-dependentmanner, as the PI-3K inhibitors LY294002 and wortmannin blocked Aktactivation, but not ERK1/2 or p38 activation. Akt activation was not blockedby inhibition of p38 or ERK1/2, indicating the independence of these signalingsystems. Heat shock treatment also caused a rapid increase in HSF-1 DNAbinding activity that was partially dependent on PI-3K activity, as both thePI-3K inhibitors attenuated this response. Because Akt inhibits glycogensynthase 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 theGSK-3β inhibitor lithium. Thus, heat shock-induced activation of PI-3Kand the inhibitory effect of GSK-3β on HSF-1 activation and HSP-70expression imply that Akt-induced inhibition of GSK-3β contributes to theactivation of HSF-1.