Inhibition of GSK-3β decreases NF-κB-Dependent gene expression and impairs the rat liver regeneration
Inhibition of GSK-3β decreases NF-κB-Dependent gene expression and impairs the rat liver regeneration
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DOI：
10.1002/jcb.21358
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发表时间：
2007-12-01
影响因子：
4
通讯作者：
Cai, Zailong
中科院分区：
文献类型：
--
作者：
Chen, Huan;Yang, Shengsheng;Cai, Zailong
丝氨酸-苏氨酸蛋白激酶糖原合成酶激酶（GSK）-3参与调节许多细胞功能，但其在调节肝再生中的作用尚不清楚。在这里，我们研究了GSK-3 β抑制对大鼠部分肝切除术后肝再生的影响。在70%部分肝切除术前30分钟给予强效和选择性GSK-3 β抑制剂SB 216763（0.6 mg/kg静脉注射）或溶剂（10%二甲基亚砜）。通过细胞增殖、凋亡及相关的细胞信号和循环蛋白来评价肝再生。在大鼠肝切除术后30 min内，发现GSK-3 β易位到细胞核，但GSK-3 β抑制剂SB 216763（可磷酸化GSK-3 β上的Ser 9残基）并未减弱GSK-3 β的蓄积。因此，GSK-3 β的抑制降低了核因子-κ B B活性、NF-κ B依赖性基因表达和COX 2表达，但增强了p21（WAF 1/Cip 1）转录。此外，注射SB 216763损害增殖细胞核抗原（PCNA）指数，并增加肝细胞凋亡相比，车辆。GSK-3 β在大鼠肝再生中起重要作用。我们认为这可能与抑制NF-κ B B通路和增强p21（WAF 1/Cip 1）表达有关。
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-3 beta inhibition on liver regeneration after partial hepatectomy in the rat. The potent and selective GSK-3 beta 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-3 beta was found to be translocated to the nucleus, but GSK-3 beta inhibitor SB216763 that could phosphorylate residue Ser9 on GSK-3 beta did not attenuated the accumulation. Consequently, the inhibition of GSK-3 beta decreased the nuclear factor-kappa B activity, the NF-kappa B-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-3 beta plays an important role in rat liver regeneration. We conclude it may partially result from the inhibition of the NF-kappa B pathway and enhancement of p21(WAF1/Cip1) expression.