title: Inhibition of GSK3 differentially modulates NF-kappaB, CREB, AP-1 and beta-catenin signaling in hepatocytes, but fails to promote TNF-alpha-induced apoptosis.
abstract: Glycogen synthase kinase-3 (GSK-3) is known to modulate cell survival and apoptosis through multiple intracellular signaling pathways. However, its hepatoprotective function and its role in activation of NF-kappaB and anti-apoptotic factors are poorly understood and remain controversial. Here we investigated whether inhibition of GSK-3 could induce apoptosis in the presence of TNF-alpha in primary mouse hepatocytes. We show that pharmacological inhibition of GSK-3 in primary mouse hepatocytes does not lead to TNF-alpha-induced apoptosis despite reduced NF-kappaB activity. Enhanced stability of IkappaB-alpha appears to be responsible for lower levels of nuclear NF-kappaB and hence reduced transactivation. Additionally, inhibition of GSK-3 was accompanied by marked upregulation of beta-catenin, AP-1, and CREB transcription factors. Stimulation of canonical Wnt signaling and CREB activity led to elevated levels of anti-apoptotic factors. Hence, survival of primary mouse hepatocytes may be caused by the activation and/or upregulation of other key regulators of liver homeostasis and regeneration. These signaling molecules may compensate for the compromised anti-apoptotic function of NF-kappaB and allow survival of hepatocytes in the presence of TNF-alpha and GSK-3 inhibition.
authors.affiliation: Institute of Molecular Medicine and Cell Research, University of Freiburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Götschel
authors.forename: Claudia
authors.initials: C
authors.lastname: Kern
authors.forename: Simona
authors.initials: S
authors.lastname: Lang
authors.forename: Titus
authors.initials: T
authors.lastname: Sparna
authors.forename: Cordula
authors.initials: C
authors.lastname: Markmann
authors.forename: Joseph
authors.initials: J
authors.lastname: Schwager
authors.forename: Sabine
authors.initials: S
authors.lastname: McNelly
authors.forename: Fritz
authors.initials: F
authors.lastname: von Weizsäcker
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
authors.forename: Andreas
authors.initials: A
authors.lastname: Hecht
authors.forename: Irmgard
authors.initials: I
authors.lastname: Merfort
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000096:biosynthesis; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D020672:I-kappa B Proteins / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D020672:I-kappa B Proteins; D007211:Indoles; D015850:Interleukin-6; D008301:Maleimides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C417521:SB 216763; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D051153:Wnt Proteins; D051176:beta Catenin; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3