Inhibition of GSK3 differentially modulates NF-kappaB, CREB, AP-1 and beta-catenin signaling in hepatocytes, but fails to promote TNF-alpha-induced apoptosis

Exp Cell Res. 2008 Apr 1;314(6):1351-66. doi: 10.1016/j.yexcr.2007.12.015. Epub 2007 Dec 31.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Caspase 3 / biosynthesis
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • DNA / metabolism
  • Enzyme Induction / drug effects
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology*
  • I-kappa B Proteins / metabolism
  • Indoles / pharmacology
  • Interleukin-6 / genetics
  • Maleimides / pharmacology
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Protein Binding / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Protein Transport / drug effects
  • Signal Transduction / drug effects
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*
  • Transcription, Genetic / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology
  • Up-Regulation / drug effects
  • Wnt Proteins / metabolism
  • beta Catenin / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Cyclic AMP Response Element-Binding Protein
  • I-kappa B Proteins
  • Indoles
  • Interleukin-6
  • Maleimides
  • NF-kappa B
  • Nfkbia protein, mouse
  • SB 216763
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • Wnt Proteins
  • beta Catenin
  • NF-KappaB Inhibitor alpha
  • DNA
  • p38 Mitogen-Activated Protein Kinases
  • Glycogen Synthase Kinase 3
  • Caspase 3