Inhibition of GSK-3beta decreases NF-kappaB-dependent gene expression and impairs the rat liver regeneration.
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-3beta inhibition on liver regeneration after partial hepatectomy in the rat. The potent and selective GSK-3beta 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-3beta was found to be translocated to the nucleus, but GSK-3beta inhibitor SB216763 that could phosphorylate residue Ser9 on GSK-3beta did not attenuated the accumulation. Consequently, the inhibition of GSK-3beta decreased the nuclear factor-kappaB activity, the NF-kappaB-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-3beta plays an important role in rat liver regeneration. We conclude it may partially result from the inhibition of the NF-kappaB pathway and enhancement of p21 (WAF1/Cip1) expression.
Chen
Huan
H
Clinical Research Center, Changhai Hospital, Shanghai 200433, China.
Yang
Shengsheng
S
Yang
Zhifeng
Z
Ma
Li
L
Jiang
Dandan
D
Mao
Jifang
J
Jiao
Binghua
B
Cai
Zailong
Z
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006498:Hepatectomy; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000494:pharmacology; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; C417521:SB 216763; D051546:Cyclooxygenase 2; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3