鼻咽癌的EBNA3C-P53蛋白质复合体结构功能研究

Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in China, and its tumourigenesis is highly associated with the infection of the Epstein-Barr virus (EBV). The tumor suppressor gene p53 is essential for the prevention of cancer development, with more than half of human cancers carrying p53 mutations. However, P53 expression is up-regulated in most NPCs, and p53 mutations are rarely found in NPCs. The mechanism of P53 inactivation in NPC is not well understood. Recent studies show that EBNA3C, an EBV-encoded nuclear protein, interacts with P53, and these two proteins form a stable complex in nucleus. EBNA3C can inhibit P53 DNA binding and repress P53-regulated transactivation. In the proposed studies, we will use X-ray crystallography to solve the crystal structure of EBNA3C-P53 complex, analyze its function, and look for sites to block the interaction between EBNA3C and P53. These studies will provide a structural framework for understanding the mechanism by which EBNA3C inactivates P53, and a basis for searching small molecules to block the interaction between EBNA3C and P53 proteins, which may lead to the development of new treatment options for NPC.

鼻咽癌是我国常见的恶性肿瘤之一，其发生、发展与EB病毒高度相关。P53抑瘤基因在肿瘤发生发展过程中发挥至关重要的作用，50%以上的肿瘤存在P53突变。但是鼻咽癌中P53突变罕见且在大多数鼻咽癌中P53表达上调，鼻咽癌中P53灭活机制尚不清楚。研究资料显示，EB病毒表达产物EBNA3C蛋白与P53蛋白结合，在宿主细胞核内形成稳定的复合体，进而抑制P53与DNA的结合及P53的转录调节功能。鉴于EBNA3C-P53相互作用在EB病毒致癌过程中的重要作用，本研究将用结构生物学的方法解析EBNA3C和P53复合体的三维结构，探讨EBNA3C-P53复合体功能，在此基础上筛选抑制EBNA3C-P53相互作用位点，为阐明EB病毒在鼻咽癌中灭活P53的分子机制，为研发阻断EBNA3C和P53结合的小分子化合物，开展新的鼻咽癌的治疗方法提供科学依据。

鼻咽癌的发生发展与EB病毒高度相关，EB病毒在鼻咽癌发病过程中的作用一直是鼻咽癌病理研究的重点和热点。大量研究表明，对抑癌基因p53功能的抑制是病毒引发或促进癌症发生发展的机制之一。EB病毒潜伏期表达的核蛋白EBNA3C可以与P53 蛋白结合并抑制P53的转录调节功能。EB病毒由潜伏期转为裂解感染期的关键因子BZLF1也可以与p53蛋白结合并抑制其转录功能，还可以通过蛋白酶体途径促进p53的泛素化降解。本研究主要采用了蛋白晶体学方法研究P53核心结构域和EBNA3C复合物、P53核心结构域和BZLF1复合物的蛋白结构，通过结构解析找到p53与EBNA3C、BZLF1的相互作用位点，筛选抑制相互作用的小分子抑制剂，为研发阻断p53与EBNA3C、BZLF1结合的小分子化合物和开展新的鼻咽癌的治疗方法提供理论依据。