Function of the Adenovirus E1B Oncogene

性状（申请人提供）：人DNA肿瘤病毒腺病毒 在人类细胞中高效复制，并将原代啮齿类动物上皮细胞 细胞这些活动的组成部分是细胞周期控制的失调 以及病毒致癌基因对程序性细胞死亡（凋亡）的抑制 E1 A和E1 B。E1 A诱导S期，这是病毒复制所必需的。 转化中DNA和细胞增殖的刺激。E1 A还诱导 细胞凋亡，它需要E1 B抑制，以维持生产性感染， 允许致癌转化。E1 A通过结合细胞周期调控因子， 并抑制细胞生长的负调节因子，其中之一是 视网膜母细胞瘤肿瘤抑制基因产物（Rb）。E1 B编码两种蛋白质 通过结合和抑制促凋亡蛋白质来阻断凋亡：55 K 结合并抑制p53肿瘤抑制蛋白; 19 K结合并抑制Bax 以及凋亡机制的其它相关促凋亡组分。我 建议将这些研究扩展到以 E1 A和E1 B调节死亡受体信号传导的机制 感染人细胞，并抑制p53依赖性 在啮齿动物细胞中，E1 B 19 K蛋白引起线粒体下游的凋亡。 最后，将对凋亡机制中已知成分的小鼠突变体进行研究。 用于建立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 实现这些目标，我们希望阐明细胞死亡的新机制， 调节以及它们如何与病毒复制和发展相关， 癌从这种方法中获得的知识将有助于开发 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.