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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.

18261723

Projects: HepatoSys

Exp. Cell Res.
Exp. Cell Res. 314(6): 1351-66
31st Dec 2007

Frank Götschel, Claudia Kern, Simona Lang, Titus Sparna, Cordula Markmann, Joseph Schwager, Sabine McNelly, Fritz von Weizsäcker, Stefan Laufer, Andreas Hecht, Irmgard Merfort

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[Sabine Mac Nelly] [Andreas Hecht] [Irmgard Merfort]

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Cell
Views: 1704
  • Created: 30th Aug 2012 at 12:33
  • Last updated: 24th Oct 2013 at 16:23

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