一种新型泛素结合酶UBE2W对NF-kB信号通路的调控和分子机制研究

NF-kB signaling pathway is one of the key signaling pathways in cells, which involves in the regulation of multiple biological processes such as cell immunity, inflammation and tumor. The post-translational modification of regulating NF-kB pathway has been a hotspot in life sciences at present, but the specific mechanism is still not clear. In the present study, our lab found that the novel ubiquitin-conjugating enzyme UBE2W maybe acts as another key negative regulator of the NF-kB pathway. In this project, through the biological experiments such as co-immunoprecipitation and in vitro kinase assay, we will use UBE2W gene overexpression or knockdown stable cell lines to study how UBE2W or the UBE2W complex regulates the activation and function of the NF-kB pathway, to analyze how it regulates ubiquitination of the key proteins in NF-kB pathway, and to elucidate the molecular mechanism and molecular regulatory networks of interaction. In this project, how UBE2W make function in the development of colitis into colorectal cancer will be explored in the cell and animal model. The development of the project is expected to discover a novel ubiquitination regulator of the NF-kB pathway, which could broaden our view of its regulation network and provide new clues and ideas for colon cancer targeted therapy.

NF-kB信号通路是细胞内关键的免疫调节信号通路，参与调控多种重要生物学功能，与免疫、炎症、肿瘤发生密切相关。NF-kB信号通路的翻译后修饰调节一直是当前生命科学领域的热点问题，然而具体机制目前仍不清楚。在前期研究中发现一种新型泛素结合酶UBE2W对于NF-kB信号通路的激活具有负调控作用。本项目将利用已建立的稳定表达UBE2W及其基因沉默的细胞模型，通过免疫共沉淀、体外激酶实验等生物学手段，深入研究UBE2W及其相互作用蛋白质对NF-kB信号通路活性和功能的调控作用，分析其对NF-kB信号通路内重要蛋白质的泛素化调节功能，阐明其作用的分子机制及分子调控网络，并利用结肠炎和结肠癌动物模型，在动物整体水平探讨UBE2W在结肠炎→结肠癌的发生发展中发挥的作用。本项目研究有望发现一种新型NF-kB信号通路的泛素化调控分子，为NF-kB信号通路的翻译后修饰研究，结肠癌的靶向治疗提供新的线索和思路。