COP1 Functions as a FoxO1 Ubiquitin E3 Ligase to Regulate FoxO1-mediated Gene Expression
COP1 Functions as a FoxO1 Ubiquitin E3 Ligase to Regulate FoxO1-mediated Gene Expression
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DOI：
10.1074/jbc.m801011200
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发表时间：
2008-12-19
影响因子：
4.8
通讯作者：
Du, Keyong
中科院分区：
文献类型：
--
作者：
Kato, Satomi;Ding, Jixin;Du, Keyong
COP1是一种无名指结构域E3泛素连接酶，参与植物发育、哺乳动物细胞存活、生长和代谢。在此我们报道，胰岛素可增强其表达的COP1调节FoxO1蛋白的稳定性。我们发现在Fao肝癌细胞中，COP1的异位表达使内源性FoxO1蛋白水平降低，而敲低COP1表达则使内源性FoxO1蛋白水平升高，且不影响其他因子，如C/EBPα和CREB（环腺苷酸反应元件结合蛋白）。我们进一步表明，COP1与FoxO1结合，增强其泛素化，并通过泛素 - 蛋白酶体途径促进其降解。为了确定COP1介导的FoxO1蛋白降解的生物学意义，我们检测了COP1对FoxO1介导的基因表达的影响，发现COP1抑制FoxO1报告基因以及FoxO1的靶基因，如葡萄糖 - 6 - 磷酸酶和磷酸烯醇式丙酮酸羧激酶，这两个是FoxO1在糖异生调节中的关键靶基因，同时Fao细胞中肝葡萄糖生成也相应发生变化。我们认为，通过作为FoxO1的E3连接酶发挥作用，COP1可能在肝脏葡萄糖代谢的调节中起作用。
COP1 is a Ring-Finger E3 ubiquitin ligase that is involved in plant development, mammalian cell survival, growth, and metabolism. Here we report that COP1, whose expression is enhanced by insulin, regulates FoxO1 protein stability. We found that in Fao hepatoma cells, ectopic expression of COP1 decreased, whereas knockdown of COP1 expression increased the level of endogenous FoxO1 protein without impacting other factors such as C/EBP alpha and CREB (cAMP-response element-binding protein). We further showed that COP1 binds FoxO1, enhances its ubiquitination, and promotes its degradation via the ubiquitin-proteasome pathway. To determine the biological significance of COP1-mediated FoxO1 protein degradation, we have examined the impact of COP1 on FoxO1-mediated gene expression and found that COP1 suppressed FoxO1 reporter gene as well as FoxO1 target genes such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, two key targets for FoxO1 in the regulation of gluconeogenesis, with corresponding changes of hepatic glucose production in Fao cells. We suggest that by functioning as a FoxO1 E3 ligase, COP1 may play a role in the regulation of hepatic glucose metabolism.