GSK-3β抑制PP2A甲酯酶表达的分子机制研究

项目名称： GSK-3β抑制PP2A甲酯酶表达的分子机制研究

项目编号： No.31500829

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 神经、认识与心理学

项目作者： 靳娜娜

作者单位： 南通大学

项目金额： 20万元

中文摘要： PP2A是最重要的tau蛋白磷酸酶，PP2A催化亚基（PP2A-C）活性受甲基化调控，LCMT-1和PME-1是催化PP2A-C甲基化和去甲基化的酶。我们发现GSK-3β通过抑制PME-1的表达，促进PP2A-C的甲基化，增加其活性。深入探索PME-1的表达调控，我们发现PME-1启动子含有三个LEF1/TCF顺式元件。β-catenin 可以作用于LEF1/TCF元件调控基因表达，β-catenin 是GSK-3β重要的一个靶蛋白，提示GSK-3β可以通过β-catenin/PME-1调控PP2A的甲基化及活性。本项目拟在分子、细胞和动物多层次系统地研究GSK-3β/β-catenin对PME-1表达的调节，揭示GSK-3β影响PP2A-C甲基化和tau磷酸化的分子机制，为AD药物研发提供依据。

中文关键词： 阿尔茨海默病；Tau蛋白；糖元合酶激酶3β；PP2A甲酯酶；转录调控

英文摘要： Protein phosphatase 2A (PP2A) is the major tau phosphatase. Activity of PP2A catalytic subunit(PP2A-C) is regulated by its methylation. The methylation of PP2A-C is regulated by LCMT-1 and PME-1. When we studied the cross talk between PP2A and GSK-3β, we found that upregulation of GSK-3β led to an increase in the methylation and activity of PP2A-C through suppression of PME-1 expression. To further understand the regulation of PME-1 expression by GSK-3β, we analyzed the PME-1 promotor by MatInspector software and found 3 LEF1/TCF cis elements. β-catenin can act on the LEF1/TCF cis elements and regulate the target gene. Our results show that knock down of β-catenin could downregulate the mRNA level of PME-1. β-catenin is one of the important GSK-3β target protein. All of these suggest that GSK-3β upregulates the methylation and activity of PP2A-C through β-catenin/PME-1. In this project, we investigate the mechanism of the regulation of PME-1 by GSK-3β/β-catenin and their effects on the methylation of PP2A and the phosphorylation of tau, which will provide the mechanism and cue on tau pathology.

英文关键词： Alzheimer’s disease;Tau protein;GSK-3β; PP2A methylesterase;Transcription regulation