蛋白去磷酸化酶1α调控激活转录因子5的稳定性及其促进神经胶质瘤细胞存活的分子机制研究

蛋白磷酸酶1α（PP1α）作为神经胶质中特异性高表达的分子标记与肿瘤的恶性程度和病.人的预后具有显著的相关性，但机制还不清楚。申请人发现PP1α和调控神经胶质瘤发生发展.的重要转录因子-激活转录因子5（ATF5）相互作用，且促进ATF5蛋白稳定和提高ATF5转录抗凋.亡基因的活性。在此基础上，申请人首先运用蛋白质组学、分子与细胞生物学和体外和体内实.验研究ATF5是否存在PP1α特异性去磷酸化丝氨酸/苏氨酸（S/T）位点，这些位点的磷酸化状.态对ATF5转录活性的影响和其泛素化修饰的相关性。深入研究ATF5在PP1α调控神经胶质瘤细.胞存活和神经胶质瘤生长过程中的作用，揭示PP1α-ATF5蛋白修饰调控-促神经胶质瘤细胞存.活的新机制和新通路，为解释PP1α高表达与神经胶质瘤发展之间的相关性提供新的理论，为.治疗神经胶质瘤提供新策略和为药物开发提供新的靶点与理论依据，具有重要的理论意义和广阔的应用前景。

Protein phosphotase1α (PP1α), as a biomarker, was overexpressed in glioblastoma.samples compare with control, and expression level of PP1α also was related with.progress of glioma. But PP1α function was not addressed in the glioma. Recently,.we found that PP1α could interact with active transcription factor 5(ATF5) and.improve ATF5 transcription activity and stability in glioma cells. It’s well.known that ATF5 was one of most important regulator in glioma formation and glioma.cells survival. Because of these findings, we will use techniques of proteome and.molecular cell biology to find Ser and Thr(S/T) residues being dephosphorylated by.PP1α in ATF5 protein and verify them with experiments in vivo and in vitro. Then.we will try to study whether phosphorylation status of these S/T residues are.involved in regulation of transcription activity and ubiquitination of ATF5. After.that, we plan to investigate ATF5 function in PP1α regulating glioma cells.survival and tumor growth and hope to find a new pathway, PP1α-ATF5 modification,.in promoting glioma cells survival and reveal a new mechanism of PP1α regulating.glioma development. This study could build a new theory about PP1α regulation.glioma and support new therapeutic strategies in clinic research. It also is.useful in new drugs development in the future.