乙酰基转移酶Tip60对JNK信号通路的调控作用及机制研究

JNK信号通路参与并调控了一系列重要的生理活动，包括细胞增殖、分化、迁移、凋亡及应激反应等，其失调与发育缺陷和肿瘤等多种重大疾病的发生与发展密切相关。组蛋白乙酰转移酶Tip60在调控基因转录、DNA损伤修复、细胞凋亡等方面起着关键作用，并在肿瘤发生过程中扮演重要角色。Tip60与JNK信号通路在发育或疾病中是否存在相互作用，共同调控哪些生理过程，目前尚不清楚。我们以果蝇为模式动物，利用JNK信号诱导的细胞凋亡和迁移表型，进行遗传筛选、鉴定和生化分析，发现Tip60可乙酰化转录因子Fos，并通过Fos调控JNK通路介导的细胞凋亡、迁移和肿瘤侵袭。本项目拟在前期研究基础上，深入研究Tip60对JNK-Fos通路的调控作用，阐明其作用机制，并在人类肿瘤细胞及临床样本中加以验证。以期完善和丰富JNK信号的转导网络，为癌症的预防和靶向药物的设计提供新的思路。

The JNK signaling pathway participates in the regulation of a series of important physiological activities, including cell proliferation, differentiation, migration, apoptosis, and stress response. While its deregulation has been implicated in lots of diseases such as developmental defects and tumors. Histone acetyltransferase Tip60 is shown to be vital in regulating gene transcription, DNA damage repair, and apoptosis, and plays an important role in tumorigenesis. However, little is known about whether Tip60 and JNK signaling interact with each other to regulate certain physiological processes in development and disease. We have used Drosophila as a model organism, and activated JNK signaling was shown to induce apoptosis and migration phenotypes. Using this phenotype, we have screened the Drosophila genome and found that Tip60 acetylate the transcription factor Fos to regulate JNK signal-mediated cell death, migration, and tumor invasion. Based on the previous research, this project intends to further study the regulatory effect of Tip60 on the JNK signaling pathway，and elucidate the mechanism. This study not only help us to understand the interactions between JNK signaling pathway and cell factors during development, improve and enrich the transduction network of JNK signals, but also provide novel ideas for the prevention of cancer and the design of targeted drugs.