Opposing actions of phosphatidylinositol 3-kinase and glycogen synthase kinase-3beta in the regulation of HSF-1 activity.
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.
Bijur
G N
GN
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 335294-0017, USA.
Jope
R S
RS
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000187:drug effects; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004247:DNA; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; C494918:AKT1 protein, human