RNA结合蛋白对JNK信号通路的调控作用及机制研究

RNA结合蛋白（RBP）通过与RNA相互作用，参与其剪切、转运、定位、稳定及翻译等过程，发挥转录后调控功能。JNK信号通路从果蝇到人类高度保守，在动物发育过程中起重要作用，其失调与癌症等重大疾病的发生发展密切相关。但是，RBP是否参与JNK信号通路的调控，目前仍不清楚。我们以果蝇为模式动物，在眼中过表达TNF同源物Egr，可激活JNK通路介导的细胞凋亡并产生小眼表型。我们利用此表型筛选了部分RBP基因，发现Rox8参与调节JNK信号通路。前期结果提示Rox8通过结合Egr mRNA的3’UTR，增加其稳定性，从而调控JNK信号通路及其介导的细胞死亡、增殖和迁移等行为。本项目拟在前期工作基础上，对所有RBP基因进行遗传筛选，发现JNK信号通路新的调控因子，研究其分子功能，阐明其作用机理，拓展RBP在信号转导中的功能，完善现有的信号转导网络，为癌症等相关疾病的复杂致病机制提供新的诠释。

RNA binding proteins (RBP) play important roles in post-transcriptional regulation by interacting with RNAs and regulating their splicing, transportation, cellular localization, stability and translation. The JNK signaling pathway, which is highly conserved from fly to human, play pivotal roles in animal development, while dysregulation of this pathway has been closely associated with the development of various diseases including cancer. Yet, it remains unknown whether RBP regulates the JNK pathway. We have used Drosophila as the model organism to express the TNF ortholog Egr in the developing eye, and obtained a small eye phenotype resulted from JNK-mediated cell death. We have performed a pilot screen for some RBP genes based on the small eye phenotype, and identified Rox8 as a regulator of the JNK signaling pathway. Our preliminary data suggest that Rox8 stabilizes Egr mRNA by binding to its 3’ UTR. Based on these results, we plan to carry out a genetic screen for all the RBP genes, and identify additional regulators of the JNK signaling. We will characterize the molecular functions of these RBPs, identify their targets, and determine their regulatory mechanisms. This study not only expand our knowledge about the roles of RBPs in signal transduction, but also provide novel mechanistic insight for the development of complex diseases, such as cancers.