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Am J Physiol Gastrointest Liver Physiol 283: G204-G211, 2002. First published February 20, 2002; doi:10.1152/ajpgi.00016.2002
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Vol. 283, Issue 1, G204-G211, July 2002

Role of glycogen synthase kinase-3 in TNF-alpha -induced NF-kappa B activation and apoptosis in hepatocytes

Robert F. Schwabe and David A. Brenner

Department of Medicine, Biochemistry, and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599

Nuclear factor-kappa B (NF-kappa B) prevents hepatocytes from undergoing apoptosis during development and liver regeneration. Mice with inactivated glycogen synthase kinase (GSK)-3beta die from hepatocyte apoptosis during development due to a defect in NF-kappa B activation (Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, and Woodgett JR. Nature 406: 86-90, 2000). In this study, we determined the role of GSK-3 in TNF-alpha -induced NF-kappa B activation and cell death in primary hepatocytes. LiCl, an established inhibitor of GSK-3, sensitized primary rat hepatocytes toward TNF-alpha -mediated apoptosis resulting in 90% cell death after 24 h. This was accompanied by increased caspase 8-like and 3-like activities, nuclear fragmentation and DNA laddering. LiCl treatment had no effect on Ikappa B-alpha degradation, Ikappa B kinase (IKK) activity, NF-kappa B binding activity, and p65 nuclear import and export, but decreased transcription of the NF-kappa B-dependent inducible nitric oxide synthase gene and a NF-kappa B-driven reporter gene. The p65 sequence revealed four potential GSK-3 phosphorylation sites within its COOH-terminal transactivation domains and recombinant GSK-3beta phosphorylated glutathione S-transferase (GST)-p65(354-551), but not GST-p65(1-305) in vitro. These results indicate that GSK-3 protects hepatocytes from TNF-alpha -induced apoptosis through p65 phosphorylation and upregulation of NF-kappa B transactivation.

p65 phosphorylation; p65 transactivation; Ikappa B kinase; tumor necrosis factor-alpha ; nuclear factor-kappa B


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