IKKa 参与调控UVB诱导p53活化和翻译后修饰反应的分子机制及生物学意义

项目名称： IKKa 参与调控UVB诱导p53活化和翻译后修饰反应的分子机制及生物学意义

项目编号： No.31270797

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 宋伦

作者单位： 中国人民解放军军事医学科学院

项目金额： 70万元

中文摘要： 随着多种新型NF-kB非相关性IKK激酶底物分子的不断发现，IKK激酶的两个催化亚基- - IKKa和IKKb的效应机制研究已完全超越了"IKK/NF-kB信号通路"这一经典范畴。申请人以往在"IKK激酶以NF-kB非依赖方式调控细胞应激损伤反应机制"的长期研究中，先后发现了多种由IKKa或IKKb独立调节的NF-kB非相关性信号蛋白分子及其与IKK激酶协同调控细胞应激损伤反应的系列新机制。近期研究中我们又发现了IKKa能够不依赖于IKKb和NF-kB独立调控p53的磷酸化和乙酰化修饰反应及其转录激活功能并介导UVB诱导的促细胞凋亡效应。鉴于p53在调节UVB引发的DNA损伤反应中的核心地位，揭示IKKa独立调控UVB诱导p53活化的分子机制不仅能够进一步拓展对"IKKa参与DNA损伤效应新机制"和"p53复杂信号调控网络"的认识，同时在细胞应激损伤防御策略研究中具有重要的医学应用价值。

中文关键词： IKKα；p53；磷酸化；乙酰化；ER应激

英文摘要： With the discovery of mutiple NF-kB-independent signaling molecules that are regulated by the catalytic subunits of IKK complex, IKKa and IKKb, the biological roles for these two IKK subunits have gone far beyond NF-kB activation. One of the research interests of our group is to disclose the novel NF-kB-independent functions of IKKa and IKKb under stress conditions. And we have got a lot of data regarding the critical roles for these two IKK subunits in mediating growth arrest, apoptosis and the inflammatory responses by regulating various NF-kB-unrelated signaling molecules in response to the stress signals. Recently, we found that IKKa played a critical role in regulating the phosphorylation, acetylation and transactivation of p53 upon UVB irradiation, which effects were unrelated to the IKKb and NF-kB activities. Due to the critical role for p53 in mediating UVB-induced DNA demage respone, disclosing the molecular mechanism of IKKa in regulating p53 activation is important to extend our knowledge on the NF-kB-independent role for IKKa in response to DNA demage signals as well as the complex regulation network of p53 under stress conditions. Furthermore, our project will be helpful for searching the novel strategies to prevent the photodamage and other DNA damage responses.

英文关键词： IKKα；p53；phosphorylation；acetylation；ER stress