Function of the Adenovirus E1B Oncogene

描述(申请人提供)：人类DNA肿瘤病毒腺病毒 在人类细胞中高效复制并转化为原代啮齿动物上皮 细胞。这些活动的一个组成部分是解除对细胞周期控制的管制 以及病毒癌基因对细胞程序性死亡(细胞凋亡)的抑制 E1A和E1B。E1a诱导病毒复制所需的S期 DNA和刺激细胞在转化中的增殖。E1a还诱导 它需要E1B来抑制细胞凋亡以维持生产性感染和 允许致癌转化。E1a通过结合细胞周期来解除对细胞周期的调控 抑制细胞生长的负面调节因素，其中之一是 视网膜母细胞瘤肿瘤抑制基因产物(Rb)。E1B编码两种蛋白质 通过结合和抑制促凋亡蛋白来阻断细胞凋亡：55k 结合并抑制P53抑癌蛋白；19K结合并抑制Bax 以及凋亡机制中其他相关的促凋亡成分。我 建议将这些研究扩展到两个特定领域，主要围绕 E1a和E1B对死亡受体信号的调控机制 人细胞感染及其抑制P53依赖的机制 啮齿动物细胞中E1B 19K蛋白诱导线粒体下游的细胞凋亡。 最后，突变的小鼠的已知成分上的凋亡机制将是 用来确定这些基因产物的需求和排序 病毒感染和转化中的细胞死亡信号通路。通过 为了实现这些目标，我们希望阐明细胞死亡的新机制 监管以及它们与病毒复制和发展的关系 癌症。从这种方法中获得的知识将在开发中有用 新的抗病毒和抗癌疗法。

DESCRIPTION (provided by applicant): The human DNA tumor virus adenovirus replicates productively in human cells and transforms primary rodent epithelial cells. Integral to these activities is the deregulation of cell cycle control and the inhibition of programmed cell death (apoptosis) by the viral oncogenes E1A and E1B. E1A induces S-phase, which is required for replication of viral DNA and stimulation of cell proliferation in transformation. E1A also induces apoptosis that it requires E1B to inhibit to sustain productive infection and permit oncogenic transformation. E1A deregulates the cell cycle by binding to and inhibiting negative regulators of cell growth, one of which is the retinoblastoma tumor suppressor gene product (Rb). E1B encodes two proteins that block apoptosis by binding to and inhibiting pro-apoptotic proteins: 55K binds and inhibits the p53 tumor suppressor protein; 19K binds and inhibits Bax and other related pro-apoptotic components of the apoptotic machinery. I propose to extend these studies in two specific areas that center around the mechanism of modulation of death receptor signaling by E1A and E1B during infection of human cells, and the mechanism of inhibition of p53-dependent apoptosis downstream of mitochondria by the E1B 19K protein in rodent cells. Finally, mice mutant for known components on the apoptotic machinery will be utilized to establish the requirement and ordering of these gene products in cell death signaling pathways in viral infection and transformation. By executing these aims we hope to illuminate novel mechanisms of cell death regulation and how they relate to virus replication and the development of cancer. Knowledge gained from this approach will be useful in the development of new anti-viral and anti-cancer regimens.