FUNCTION OF THE EBV EBNA 1 PROTEIN IN B CELL LYMPHOMA

描述：（申请人的描述） 拟议研究的目的是确定直接贡献 EB病毒（EBV）EBNA-1蛋白与EBV相关淋巴瘤的关系。 尽管EBNA-1间接地促进了EBV的致瘤潜力， 通过其病毒基因组维护功能，一些观察结果支持 EBNA-1在肿瘤发生中的直接作用。 具体地：i）EBNA-1是一种 具有靶向细胞基因潜能的转录调节因子 表达，这是一种机制，使EBNA-1影响细胞 ii）Akata中EBNA-1表达的丧失 伯基特淋巴瘤（BL）细胞具有较低的致瘤潜力; 和iii）活性表达的EBNA-1转基因使小鼠易患B细胞 肿瘤的 以BL为模型系统，申请人将解决 EBNA-1对肿瘤发生的贡献集中在两个定义 这种肿瘤的特征：EBV感染，其中EBNA-1是唯一已知的 病毒蛋白表达和c-myc表达失调 原癌基因 为了实现这一目标，申请人提出了三项建议。 明确的目标。 目的1：确定EBNA-1在肿瘤中的致瘤潜力。 EBV阴性BL细胞背景;为此，EBNA-1将稳定表达 在EBV阴性的Akata和其他BL细胞中， 这些细胞相对于它们的EBV阳性和EBV阴性对应物 将被检测。 目标2：确定EBNA-1对 EBV的致癌潜力;具体而言，申请人将确定 EBNA-1在EB病毒介导的c-myc表达失调中的作用及其与肿瘤细胞增殖的关系 EBNA-1抑制c-myc诱导的细胞凋亡的能力。 此外，他将 评估EBNA-1补充c-myc功能的潜力， 共转化测定。 目的3：鉴定EBNA-1应答细胞基因 并评估其对致瘤潜力的贡献;使用诱导型 EBNA-1表达系统和代表性差异分析， 申请人将鉴定被激活或抑制的细胞基因， EBNA-1，然后将描绘由EBNA-1编码的蛋白质的功能。 这些基因与肿瘤发生有关。

DESCRIPTION: (Applicant's Description) The objective of the proposed research is to define the direct contribution of the Epstein-Barr virus (EBV) EBNA-1 protein to EBV-associated lymphoma. Although EBNA-1 indirectly contributes to the tumorigenic potential of EBV through its viral genome maintenance function, several observations support a direct role of EBNA-1 in tumorigenesis. Specifically: i) EBNA-1 is a transcriptional regulator with the potential to target cellular gene expression, a mechanism that would enable EBNA-1 to influence cellular processes important to tumorigenesis; ii) loss of EBNA-1 expression in Akata Burkitt lymphoma (BL) cells is associated with lower tumorigenic potential; and iii) actively expressed EBNA-1 transgenes predispose mice to B-cell tumors. Using BL as a model system, the applicant will address the contribution of EBNA-1 to tumorigenesis focusing on the two defining features of this tumor: EBV infection in which EBNA-1 is the only known viral protein expressed and the deregulated expression of the c-myc proto-oncogene. To fulfill the objective, the applicant proposes three specific aims. Aim 1: Determine the tumorigenic potential of EBNA-1 in an EBV-negative BL-cell background; to do this, EBNA-1 will be stably expressed in EBV-negative Akata and other BL cells, and the tumorigenic potential of these cells relative to their EBV-positive and EBV-negative counterparts will be assayed. Aim 2: Define direct contributions of EBNA-1 to the oncogenic potential of EBV; specifically, the applicant will determine the role of EBNA-1 in EBV-mediated deregulation of c-myc expression and the ability of EBNA-1 to inhibit c-myc-induced apoptosis. Additionally, he will assess the potential of EBNA-1 to complement c-myc function in co-transformation assays. Aim 3: Identify EBNA-1 responsive cellular genes and evaluate their contribution to tumorigenic potential; using an inducible EBNA-1 expression system and representational difference analysis, the applicant will identify cellular genes that are activated or repressed by EBNA-1 and will then delineate the functions of the proteins encoded by these genes with respect to tumorigenesis.