Function of the Adenovirus E1B Oncogene

腺病毒 E1B 癌基因的功能

• 批准号: 6512695
• 负责人: Eileen P. White
• 金额: $ 30.39万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6512695
• 关键词: Adenoviridae; BCL2 gene /protein; Bax gene /protein; apoptosis; cysteine endopeptidases; cytochrome c; cytokine receptors; host organism interaction; laboratory mouse; microorganism culture; mitochondria; nuclease; oncogenes; oncoproteins; p53 gene /protein; tumor necrosis factor alpha; viral carcinogenesis; virus genetics; virus protein; virus replication

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.

描述（由申请人提供）：人DNA肿瘤病毒腺病毒 在人类细胞中有效地复制并转化主要的啮齿动物上皮 细胞。这些活动不可或缺的是细胞周期控制的管制 病毒癌基因对程序性细胞死亡（凋亡）的抑制作用 E1A和E1B。 E1a诱导S期，这是复制病毒所必需的 DNA和在转化中细胞增殖的刺激。 E1a也引起 凋亡需要E1B抑制维持生产感染和 允许致癌转化。 E1a通过与 并抑制细胞生长的阴性调节剂，其中之一是 视网膜细胞瘤肿瘤抑制基因产物（RB）。 E1B编码两个蛋白质 通过结合并抑制促凋亡蛋白来阻断凋亡：55K 结合并抑制p53肿瘤抑制蛋白； 19k结合并抑制Bax 以及凋亡机制的其他相关促凋亡组件。我 提议将这些研究扩展到集中的两个特定领域 E1A和E1B对死亡受体信号传导的调节机制 人类细胞的感染以及抑制p53的机制 啮齿动物细胞中E1B 19K蛋白的线粒体下游凋亡。 最后，凋亡机械上已知成分的小鼠突变体将是 用于在 病毒感染和转化中的细胞死亡信号通路。经过 执行这些目标，我们希望阐明细胞死亡的新型机制 调节及其与病毒复制的关系以及 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。