磷酸化和乙酰化修饰对STAT3功能的调节

Functional Regulation of STAT3 by Phosphorylation and Acetylation Modifications

STAT3是细胞因子和生长因子受体的胞质转录因子。当细胞因子与JAK相连受体结合时,JAK通过自身磷酸化而被激活,激活后的JAK可磷酸化一个或多个受体位点并呈递给STAT3而与之结合。随后STAT3发生Tyr705和Ser727位点的磷酸化并从受体上解离,而后转移至细胞核中调控基因表达。近来有研究表明STAT3的Lys685可发生乙酰化修饰,并且它对STAT3二聚体的稳定形成非常重要。为了进一步研究STAT3的乙酰化与磷酸化修饰之间的关系以及对STAT3活性调节的影响,本文应用Western印迹和荧光素酶报告基因检测等方法发现CBP可以增强STAT3Ser727的磷酸化,增强STAT3的转录活性。此外,STAT3 Tyr705去磷酸化能减弱STAT3的乙酰化水平,而且Tyr705的磷酸化修饰对STAT3的转录活性影响很大。上述结果对于如何靶向持续激活的STAT3用于肿瘤治疗提供了依据。

STAT3 is a cytoplasmic transcriptional factor of cytokine and growth factor receptor. When cytokine binds Janus kinases （JAKs）-associated receptor, JAKs are activated by itself phosphorylation. Activated JAK can phosphorylate one or more receptor chains to generate docking sites for binding STAT3, and then STAT3 is phosphorylated on Tyr705 and Ser727 sites. Phosphorylated STAT3 dissociate from the receptor and form dimers, then translocate into the nucleus to regulate the gene expression. Recent studies indicated that Lys685 site of STAT3 can be modified by acetylation, which contributed to the formation of stable STAT3 dimers. In this study, to better understand the relationship between acetylation and phosphorylation modification of STAT3 and the important effect for regulation of STAT3 activity, we used Western blot and luciferase reporter assay etc to find that CBP can enhance the phosphorylation of Ser727 site and promote the transcriptional activation of STAT3. Moreover, the dephosphorylation of Tyr705 stie weakens to the level of STAT3 acetylation. The phosphorylation of Tyr705 site has a great influence on STAT3 transcriptional activation. The results provide a basis for cancer therapy through how to target the sustained activated STAT3.