PERK介导UVB诱导光损伤信号途径活化及其调控机制研究

p53信号途径的诱导活化是介导B波段紫外线(UVB)引发急慢性光损伤反应的关键信号传递事件。申请人发现：内质网应激感应蛋白PERK能够通过结合并调节p53的翻译后修饰反应进而介导UVB在光敏感靶细胞中促发的细胞凋亡效应；提示了PERK激酶在介导光损伤反应中的全新功能及其偶联p53信号通路的崭新模式。同时，IKK激酶催化亚基IKKα能够在UVB刺激反应中以NF-kB非相关方式调节PERK的诱导活化并由此介导p53依赖的促细胞凋亡效应；这为PERK激酶介导光损伤效应的上游调控机制研究提供了新线索，也为深度挖掘IKK激酶偶联内质网应激反应的未知通讯机制提供了新框架。因此，本项目计划探究“IKKa-PERK-p53”促细胞凋亡信号通路的级联活化反应机制，有望为“PERK激酶、IKK激酶以及p53信号网络的新功能机制及新调控机制”研究提供重要研究发现，同时也可为环境光损伤防控策略研究提供新思路。

Activation of p53 pathway plays a critical role in mediating the acute and chronic photodamage responses induced by the ultraviolet B (UVB) irradiation. Recently, we have found that PERK, one of the endoplasmic reticulum (ER) stress sensors, contributed to UVB-induced apoptosis in the photo-sensitive cells by regulating p53 phosphorylation, indicating the undiscovered function of PERK involving in mediating UVB-induced photodamages via cross-linking with p53. Furthermore, we have also revealed new function of the catalytic subunit of the IKK complex, IKKa, in triggering PERK activation and p53-dependent apoptosis in a NF-kB unrelated manner. These data have not only provided new clue for investigating the signaling events involving in regulating PERK and p53 activities, but also provided a framework for the in-depth exploration of the communication between IKKa and the ER stress responses triggered by PERK. Therefore, discovering the signal transduction mechanism involving in IKKa-PERK-p53 pathway activation is expected to extend our knowledge on the NF-kB-independent role of IKKa, the novel activity of PERK, and the complex regulatory mechanism of p53 network in response to stress signals, which might be also helpful for searching the novel strategies to prevent the photodamages induced by UVB.