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Opposing Actions of Phosphatidylinositol 3‐Kinase and Glycogen Synthase Kinase‐3β in the Regulation of HSF‐1 Activity
Author(s) -
Bijur Gautam N.,
Jope Richard S.
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0752401.x
Subject(s) - protein kinase b , ly294002 , wortmannin , gsk 3 , phosphatidylinositol , microbiology and biotechnology , kinase , heat shock , p38 mitogen activated protein kinases , heat shock protein , gsk3b , biology , pi3k/akt/mtor pathway , signal transduction , chemistry , protein kinase a , biochemistry , gene
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.