Role of E7 in HPV Infections

E7 在 HPV 感染中的作用

• 批准号: 6842445
• 负责人: Laimonis A. LAIMINS
• 金额: $ 20.99万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6842445
• 关键词: amidohydrolases; antiinfective agents; cell differentiation; cell growth regulation; cell line; chromatin immunoprecipitation; communicable disease control; communicable disease transmission; cooperative study; disease /disorder etiology; human papillomavirus; human tissue; keratinocyte; laboratory mouse; laboratory rabbit; molecular pathology; monoclonal antibody; protein binding; protein protein interaction; protein structure function; sexually transmitted diseases; small interfering RNA; topical drug application; transcription factor; tumor suppressor genes; virus genetics; virus protein; women' s health

This proposal seeks continued support for our studies examining the mechanisms by which the E7 proteins of genital human papillomaviruses (HPV) contribute to the pathogenesis of viral infections, in anogenital cancers, the E6 and E7 genes of the high risk viruses are selectively retained and expressed implicating their products as oncoproteins. Epithelial cells immortalized by E6 and E7 also exhibit altered differentiation capabilities in raft cultures similar to those seen in neoplasias in vivo. The mechanisms by which these viral oncoproteins immortalize and alter the differentiation capabilities of epithelial cells involves the binding of host proteins involved in cell-cycle regulation. The E7 protein binds the retinoblastoma gene product (Rb) as well as the related p107 and p130 proteins. The binding of E7 to Rb and p107 alters the regulation of E2F mediated transcription. In the current funding period we have demonstrated an important role for E7 in the productive viral life cycle by acting to facilitate the maintenance of viral episomes. Furthermore, our recent studies have determined that the interaction between E7 and histone deacyelases (HDACs) is important for extension of life span and episomal maintenance. In this renewal application, I propose to investigate the importance of E7 interactions with Rb family members as well as HDACs in the viral life cycle and to dissect the mechanisms by which E7 blocks cell cycle exit during differentiation. We will ask the following questions: 1). What are the effects of E7-Rb binding as well as E7-HDAC interactions on the loading of transcription factors on S-phase specific promoters in undifferentiated and differentiated cells? Do the E7-HDAC complexes activate or repress E2F-inducible genes? 2). What are the effects of Rb, p130 and p107 during the differentiation dependent late phase of the viral life cycle? Does abrogation of Rb, p130 and p107 by siRNA mimic the effects of E7 on these activities. 3). What is the effect of interactions with Rb, p130 p107 and HDACs on the functions of low risk E7 protein in the viral life cycle? Are there any novel interacting partners of HPV 11 E7?

该提案寻求继续支持我们的研究，以检查生殖器人乳头瘤病毒（HPV）的E7蛋白促进病毒感染发病机制的机制，在肛门生殖器癌症中，高风险病毒的E6和E7基因被选择性保留和表达暗示他们的产品是癌蛋白。 E6和E7永生化的上皮细胞在筏培养物中也表现出改变的分化能力，类似于体内瘤形成中所见的分化能力。这些病毒癌蛋白永生化和改变上皮细胞分化能力的机制涉及与参与细胞周期调节的宿主蛋白的结合。 E7 蛋白结合视网膜母细胞瘤基因产物 (Rb) 以及相关的 p107 和 p130 蛋白。 E7 与 Rb 和 p107 的结合改变了 E2F 的调节 介导的转录。在当前的资助期间，我们通过促进病毒附加体的维持，证明了 E7 在生产性病毒生命周期中的重要作用。此外，我们最近的研究确定 E7 和组蛋白脱酰酶 (HDAC) 之间的相互作用对于延长寿命和游离维持很重要。在此更新应用中，我建议研究 E7 与 Rb 家族成员以及 HDAC 相互作用在病毒生命周期中的重要性，并剖析 E7 在分化过程中阻止细胞周期退出的机制。我们会问以下问题： 1). E7-Rb 结合以及 E7-HDAC 相互作用对未分化和分化细胞中 S 期特异性启动子上转录因子的负载有何影响？ E7-HDAC 复合物激活还是抑制 E2F 诱导基因？ 2）。 Rb、p130 和 p107 在病毒生命周期的分化依赖后期有何作用？ siRNA 消除 Rb、p130 和 p107 是否模拟了 E7 对这些活性的影响？ 3）。与 Rb、p130 p107 和 HDAC 的相互作用对病毒生命周期中低风险 E7 蛋白的功能有何影响？ HPV 11 E7 是否有任何新的相互作用伙伴？