Inhibition of GSK‐3β decreases NF‐κB‐dependent gene expression and impairs the rat liver regeneration

Abstract Serine‐threonine protein kinase glycogen synthase kinase (GSK)‐3 is involved in regulation of many cell functions, but its role in regulating liver regeneration is unknown. Here we investigated the effects of GSK‐3β inhibition on liver regeneration after partial hepatectomy in the rat. The potent and selective GSK‐3β inhibitor SB216763 (0.6 mg/kg intravenously) or vehicle (10% dimethyl sulfoxide) was administered 30 min before 70% partial hepatectomy. Liver regeneration was estimated by the cell proliferation, apoptosis, and the related cell signaling and cycling proteins. In 30 min after hepatectomy in the rat, GSK‐3β was found to be translocated to the nucleus, but GSK‐3β inhibitor SB216763 that could phosphorylate residue Ser9 on GSK‐3β did not attenuated the accumulation. Consequently, the inhibition of GSK‐3β decreased the nuclear factor‐κB activity, the NF‐κB‐dependent gene expression, and COX2 expression, but enhanced p21 WAF1/Cip1 transcription. Moreover, the injection of SB216763 impaired the proliferation cell nuclear antigen (PCNA) index and increased the apoptosis of liver compared to the vehicle. GSK‐3β plays an important role in rat liver regeneration. We conclude it may partially result from the inhibition of the NF‐κB pathway and enhancement of p21 WAF1/Cip1 expression. J. Cell. Biochem. 102: 1281–1289, 2007. © 2007 Wiley‐Liss, Inc.