Opposing Actions of Phosphatidylinositol 3-Kinase and Glycogen Synthase Kinase-3β in the Regulation of HSF-1 Activity


  • Lippincott Williams & Wilkins, Inc., Philadelphia

  • 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.

Address correspondence and reprint requests to Dr. R. S. Jope at Department ofPsychiatry and Behavioral Neurobiology, Sparks Center, Room 1057, Universityof Alabama, Birmingham, AL 35294-0017, U.S.A. E-mail:jope@uab.edu


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.