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-induced NF-
B
activation and apoptosis in hepatocytes
Department of Medicine, Biochemistry, and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599
Nuclear
factor-
B (NF-B) prevents hepatocytes from undergoing
apoptosis during development and liver regeneration. Mice with inactivated glycogen synthase kinase (GSK)-3
die from hepatocyte apoptosis during development due to a defect in NF-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-
-induced NF-B activation and
cell death in primary hepatocytes. LiCl, an established inhibitor of
GSK-3, sensitized primary rat hepatocytes toward TNF--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 IB- degradation, IB kinase (IKK) activity, NF-B binding
activity, and p65 nuclear import and export, but decreased
transcription of the NF-B-dependent inducible nitric oxide synthase
gene and a NF-B-driven reporter gene. The p65 sequence revealed four
potential GSK-3 phosphorylation sites within its COOH-terminal
transactivation domains and recombinant GSK-3 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--induced apoptosis through p65 phosphorylation and upregulation of NF-B transactivation.
p65 phosphorylation; p65 transactivation; IB kinase; tumor
necrosis factor-; nuclear factor-B
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