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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis* / drug effects
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Caspase 3 / biosynthesis
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Cell Survival / drug effects
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Cells, Cultured
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Cyclic AMP Response Element-Binding Protein / metabolism*
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DNA / metabolism
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Enzyme Induction / drug effects
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Hepatocytes / cytology
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Hepatocytes / drug effects
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Hepatocytes / enzymology*
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I-kappa B Proteins / metabolism
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Indoles / pharmacology
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Interleukin-6 / genetics
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Maleimides / pharmacology
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Mice
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism*
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Protein Binding / drug effects
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Protein Processing, Post-Translational / drug effects
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Protein Transport / drug effects
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Signal Transduction / drug effects
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism*
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Transcription, Genetic / drug effects
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Tumor Necrosis Factor-alpha / pharmacology
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Up-Regulation / drug effects
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Wnt Proteins / metabolism
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beta Catenin / metabolism*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Cyclic AMP Response Element-Binding Protein
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I-kappa B Proteins
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Indoles
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Interleukin-6
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Maleimides
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NF-kappa B
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Nfkbia protein, mouse
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SB 216763
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Transcription Factor AP-1
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Tumor Necrosis Factor-alpha
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Wnt Proteins
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beta Catenin
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NF-KappaB Inhibitor alpha
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DNA
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p38 Mitogen-Activated Protein Kinases
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Glycogen Synthase Kinase 3
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Caspase 3