EPSTEIN BARR VIRUS LMP1 MEDIATED ONCOGENICITY

描述：(根据摘要)目标是发展足够的知识 LMP1改变细胞生长的分子机制及其影响 抑制这些机制，以便为抑制剂设计筛选 可能对治疗EBV相关的恶性肿瘤有效。具体目标 目的是：(1)利用基于重组EBV的遗传学来阐明特异性的作用 LMP1氨基酸在原代B淋巴细胞生长转化中的作用焦点 将在变换效应部位1(TES1)和TES2、TES1、 跨膜结构域中的TES2和AA。(2)判断LMP1是否 通过与其他受体的相互作用来传递信号。LMP1关联 膜筏，带有细胞骨架元素，以及其他膜蛋白， 特别是TNFR，将使用遗传学、生化和 生理学方法。(3)确定N-终端的运行机制 截短IKB导致EBV转化细胞凋亡 验证抑制NFkB作为治疗靶点的有效性。(4)调查 LMP1的细胞质效应，包括LMP1的分子机制 CD40招募TRAF，修饰TRAF，激活NIK和ASK，影响NIK和ASK1 与下游的激酶相互作用，并不断发出信号或返回到 基本状态。(5)测定LMP1对B淋巴细胞和上皮细胞的影响 从LMP1、LMP1表达后RNA的变化看基因的表达 TES1、LMP1、TES2或TES1和TES2零突变的LMP1。它的重要性 NFkB、AP1、CREB或其他因子的激活将通过分析进行评估 相关启动子，如TRAF1、EGFR和CD40。LMP1TES1和LMP1TES1的作用 LMP1TES2对细胞基因转录和转化的影响 LMP1及LMP1/CD40在转基因小鼠体内的作用(六)评估政府的作用 TRAF3在LMP1、CD40和LTbetaR信号转导中的作用 TRAF3基因敲除中表达LMP1或激活CD40或LTbetaR的RNA 而不是正常的小鼠细胞或小鼠。PKN在TRAF3对细胞作用中的作用 还将对细胞骨架、膜或转录进行评估。(7) 研究线虫TRAF3同源基因在线虫神经中的作用 起作用，以便筛选可能识别相互作用的基因 新颖的TRAF函数。

DESCRIPTION: (as per abstract) The objective is to develop sufficient knowledge of the molecular mechanisms by which LMP1 alters cell growth and of the effects of inhibiting those mechanisms so as to design screens for inhibitors that might be effective in treating EBV associated malignancies. The specific goals are to: (1) Use recombinant EBV based genetics to clarify the role of specific LMP1 amino acids (aa) in primary B lymphocyte growth transformation. The focus will be on aa between transformation effector site 1 (TES1) and TES2, TES1, TES2 and aa within the transmembrane domains. (2) Determine whether LMP1 signals through interactions with other receptors. LMP1 association with membrane rafts, with cytoskeletal elements, and with other membrane proteins, particularly TNFRs, will be investigated using genetic, biochemical, and physiological approaches. (3) Determine the mechanisms by which N-terminally truncated IkB causes apoptosis of EBV transformed cells so as to better validate inhibition of NFkB as a therapeutic target. (4) Investigate the cytoplasmic effects of LMP1, including the molecular mechanisms by which LMP1 and CD40 recruit TRAFs, modify TRAFs, activate NIK and ASK, effect NIK and ASK1 interaction with downstream kinases, and continuously signal or return to a basal state. (5) Determine the effects of LMP1 on B lymphocytes and epithelial gene expression from the changes in RNAs following expression of LMP1, LMP1 TES1, LMP1 TES2, or LMP1 with null mutations in TES1 and TES2. The importance of NFkB, AP1, CREB, or other factor activations will be evaluated by analyses of relevant promoters, e.g., TRAF1, EGFR, and CD40. The effects of LMP1TES1 and LMP1TES2 on cell gene transcription and on transformation will be compared with the effects of LMP1 and LMP1/CD40 in transgenic mice. (6) Evaluate the role of TRAF3 in LMP1, CD40, and LTbetaR signaling through observing differences in RNAs with LMP1 expression or CD40 or LTbetaR activation in TRAF3 knockout versus normal mouse cells or mice. The role of PKN in TRAF3 effects on the cell cytoskeleton, membranes, or transcription will also be assessed. (7) Investigate the role of C. elegans TRAF3 homologue in C. elegans neural function so as to enable screens for interacting genes that might identify novel TRAF functions.