EBV Antigen and Cell Cycle Regulation

摘要： 普遍存在的人类EB病毒（EBV）已被证明与广泛的 包括伯基特淋巴瘤，鼻咽癌， 霍奇金淋巴瘤、成人T细胞淋巴瘤和淋巴组织增生性疾病 免疫功能低下的患者。在体外，EBV可以有效地转化人原代B细胞， 导致感染的原代B细胞持续增殖成转化的 类淋巴母细胞系（LCL）。EB病毒对B淋巴细胞的转化是严格的， 潜伏性在于一组选定基因表达，其中之一是爱泼斯坦-巴尔核抗原 （EBNA）3C。EBNA 3C已被证明是体外B细胞转化所必需的， 病毒的基因分析在过去的十年中，与EBNA 3C相关的功能 通过相互作用将这种重要分子与病毒和细胞转录的调节联系起来 与转录抑制因子CSL，Nm 23-H1，肿瘤抑制分子Rb和其他 细胞周期调节因子包括细胞周期蛋白A和细胞周期蛋白D1。 本研究旨在探讨EBV核心抗原3C与其受体之间的相互作用， 以及参与调节细胞增殖，细胞周期， 转录和参与维持细胞稳态的信号传导。特定的氨基 将探索这些细胞靶点c-Myc和E2 F与3C相互作用的氨基酸， 在B细胞转化和永生化方面检查功能关系。的 c-Myc和E2 F的翻译后修饰对于激活其调节性转录因子是重要的。 还将对职能进行全面调查。同时，我们将生成特定于站点的 重组EBNA 3C分子，其因在细胞内的特异性相互作用而被敲除。 EBV基因组以确定它们在原代B细胞转化中的作用。

Abstract: The ubiquitous human Epstein-Barr virus (EBV) has been shown to be linked to a wide range of human cancers which include Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, adult T-cell lymphomas and lymphoproliferative diseases in immunocompromised patients. In vitro, EBV can efficiently transform human primary B-cells in vitro resulting in continual proliferation of the infected primary B-cells into transformed lymphoblastoid cell lines (LCLs). The nascently transformed B-lymphocytes by EBV are strictly latent in that a select set of genes are expressed, one of which is Epstein-Barr nuclear antigen (EBNA)3C. EBNA3C has been shown to be essential for B cell transformation in vitro by genetic analysis of the virus. Over the last decade the functions associated with EBNA3C has linked this essential molecule to regulation of viral and cellular transcription through interaction with the transcription repressor CSL, Nm23-H1, the tumor suppressor molecule Rb and other cell cycle regulatory factors which include Cyclin A and Cyclin D1. This proposal will investigate the interactions of the essential EBV nuclear antigen 3C and the cellular factors E2F and c-Myc involved in regulation of cell proliferation, cell cycle, transcription, and signaling involved in maintenance of cellular homeostasis. The specific amino acids of these cellular targets c-Myc and E2F interacting with 3C will be explored and the functional relationships examined in terms of B cell transformation and immortalization. The post-translational modifications of c-Myc and E2F important for activation of their regulatory functions will also be fully investigated. Simultaneously, we will generate site specific recombinant EBNA3C molecules that are knocked out for the specific interactions within the EBV genome to determine their role in primary B cell transformation.