Inhibition of the TNF Apoptotic Pathway by HPV 16 E6

HPV 16 E6 对 TNF 凋亡途径的抑制

• 批准号: 6681391
• 负责人: PENELOPE J DUERKSEN-HUGHES
• 金额: $ 28.84万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6681391
• 关键词: CD95 molecule; SDS polyacrylamide gel electrophoresis; apoptosis; biological signal transduction; cervix neoplasms; cysteine endopeptidases; flow cytometry; genetic strain; host organism interaction; human papillomavirus; human tissue; immunoprecipitation; in situ hybridization; neoplasm /cancer genetics; oncogenes; oncogenic virus; protein protein interaction; receptor binding; site directed mutagenesis; tumor necrosis factor alpha; virus related neoplasm /cancer

DESCRIPTION (PROVIDED BY APPLICANT): High-risk strains of human papillomavirus (HPV), such as HPV 16, are causative agents in most cases of human cervical carcinoma. Worldwide, this disease is responsible for approximately 370,000 newly diagnosed cases each year, with about a 50% mortality rate. HPV 16, as well as other "high risk" strains, codes for two oncogenes, E6 and E7. E7 functions by binding to and inactivating Rb, while E6 is best known for its ability to mediate the rapid degradation of p53. The accumulating evidence, however, indicates that this is not the only function of E6, and indeed, cannot completely explain its transforming potential. Previous work in our laboratory has shown that transfection of the E6 gene from HPV 16 into a number of cell lines, derived from two species and several tissue types, protects them from TNF-triggered apoptosis in a p53-independent manner. E6 was then shown to bind to TNF R1, resulting in impaired transmission of the apoptotic signal. Recently, we have found that E6 binds to FADD as well as to TNF R1, and can block apoptosis mediated by Fas as well as that mediated by TNF R1. This project integrates a variety of biochemical, genetic and cell biological approaches designed to achieve our overall goal of understanding the interactions of E6 with host apoptotic pathways at a molecular level, and of laying the groundwork for future novel therapeutic interventions. Specifically, four specific aims will address the following questions.1) What region(s) of TNF R1 are required for binding to E6? 2) What is the biological significance of E6-mediated protection from TNF in the contexts of virus survival and oncogenicity? 3) How generalized is the protection from apoptotic stimuli provided by HPV 16 E6? 4) What molecules can block this protective ability? The ability of papillomavirus-encoded proteins to interact with key regulators in receptor-triggered apoptotic pathways has not previously been described, and may contribute to the ability of the virus to evade the host immune system and/or to transform cells. A more complete understanding of such interactions will, therefore, enhance efforts to develop novel and effective preventive and therapeutic approaches to papillomavirus infection.

描述（由申请人提供）：在大多数人类宫颈癌的情况下，人乳头瘤病毒（HPV）的高风险菌株，例如HPV 16。在全球范围内，这种疾病每年造成大约370,000例新诊断的病例，死亡率约为50％。 HPV 16以及其他“高风险”菌株，编码两个肿瘤基因E6和E7。 E7通过与RB结合并灭活RB的功能，而E6以介导p53快速降解的能力而闻名。然而，积累的证据表明，这不是E6的唯一功能，实际上无法完全解释其转变潜力。我们实验室中的先前工作表明，将E6基因从HPV 16转染为多种细胞系，源自两种物种和几种组织类型，可保护它们免受p53的非依赖性方式的TNF触发的凋亡。 然后显示E6与TNF R1结合，从而导致凋亡信号的传播受损。 最近，我们发现E6与FADD和TNF R1结合，并且可以阻止FAS介导的凋亡以及TNF R1介导的凋亡。该项目整合了各种生化，遗传和细胞生物学方法，旨在实现我们在分子水平上与宿主凋亡途径相互作用的总体目标，并为未来的新型治疗干预奠定了基础。 具体而言，四个具体目标将解决以下问题。1）与E6结合需要哪个区域TNF R1？ 2）在病毒生存和致癌性的背景下，E6介导的TNF保护抗TNF的生物学意义是什么？ 3）HPV 16 E6提供的凋亡刺激的保护有多普遍？ 4）哪些分子可以阻止这种保护能力？先前尚未描述乳头瘤病毒编码蛋白与受体触发的凋亡途径中关键调节剂相互作用的能力，并且可能有助于病毒逃避宿主免疫系统和/或转化细胞的能力。因此，对这种相互作用的更完整的理解将加强​​开发新颖有效的预防和治疗方法来感染乳头状病毒感染的努力。