Molecular Biology of Oncogenic Papillomaviruses

致癌乳头瘤病毒的分子生物学

• 批准号: 10057232
• 负责人: Peter M Howley
• 金额: $ 101.7万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057232
• 关键词: Anogenital cancer; Apoptosis; Cell Communication; Cells; Country; Development; Eye; Genes; Goals; Human; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Human papillomavirus 18; Infection prevention; Knowledge; Laboratories; Learning; Link; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mediating; Molecular; Molecular Biology; Oncogenic; Oncoproteins; Papillomavirus; Pathway interactions; Preventive vaccine; Protein Family; Proteins; Proteolysis; Regulation; Research; Retinoblastoma; Stress; TP53 gene; Therapeutic; Translating; Ubiquitin-mediated Proteolysis Pathway; United States; Vaccination; Vaccines; Viral; Viral Oncogene; Vision; Woman; base; cancer diagnosis; carcinogenesis; cellular targeting; chronic infection; genetic regulatory protein; high risk; malignant oropharynx neoplasm; public health relevance; senescence; small molecule; therapeutic development; therapeutic target; ubiquitin ligase; virtual; young woman

 DESCRIPTION (provided by applicant): The human papillomaviruses (HPVs) are causally linked to a number of human cancers. Over 140 different HPVs have been identified and a subset of them, referred to as the high-risk HPVs, is associated with cancer. Virtually all cases of cervical cancer are attributable to infection by HPV. These high-risk HPVs are also associated with other anogenital cancers and with approximately 20% of oropharyngeal cancers. The current VLP-based vaccines prevent infection by only 2 of the 14 high-risk HPV types and vaccination rates in young women vary greatly among countries; in the United States the rate of vaccination among young women is presently only about 30%. Despite the availability of VLP-based preventive vaccines against HPV16 and HPV18 (that account for roughly 70% of cervical cancers), there is a need for therapeutic options to target HPV-associated cancers and the persistent infections that give rise to these cancers. With 500,000 new cases of cervical cancer diagnosed worldwide annually and since current vaccines having no therapeutic benefit for the millions of already infected women, there is an unmet need for the therapeutic options. Two viral oncogenes, E6 and E7, drive HPV-associated carcinogenesis. Perturbing the functions of E6 and E7 (or their expression) in HPV-associated malignancies provides the potential for therapeutic development. Research in my laboratory has been focused on the papillomaviruses for nearly 40 years and has contributed significantly to critical aspects of our current understanding of the molecular mechanisms underlying the oncogenicity of these papillomavirus-host cell interactions. This OIA application is based on my vision to translate what we know and continue to learn about these interactions to identify therapeutic targets for treating HPV-positive cancers and precancers. I propose to continue using unbiased approaches to learn more about the cellular interactions of the viral E6 and E7 oncoproteins, as well as of the E2 regulatory protein that controls viral oncogene expression, with the goal of identifying cellular targets and pathways that could serve as therapeutic targets. Major transforming activities of E6 and E7 that were discovered in my laboratory nearly 25 years ago are the inactivation of p53 and the retinoblastoma family proteins. E6 targets p53 inactivation through ubiquitin-mediated proteolysis by hijacking the cellular ubiquitin ligase E6-associated protein (E6AP). Inhibition of E6 or E6AP in HPV-positive cells leads to p53 stabilization resulting in apoptosis or senescence due to E7-induced oncogenic stress. Therefore my highest priority is targeting E6/E6AP mediated proteolysis of p53. Despite the discovery of E6AP and this ubiquitylation pathway in my laboratory over 20 years, surprisingly little has been learned about its regulation or the identity of other genes that are involved in its regulation. Ongoing research in my laboratory is focused on (1) identifying genes and pathways involved in E6-mediated ubiquitylation of p53 and (2) identifying small molecules that stabilize p53 in HPV-positive cancers.

 描述（由适用提供）：人类乳头瘤病毒（HPV）有时与许多人类癌症有关。已经确定了超过140种不同的HPV，其中一部分（称为高风险HPV）与癌症有关。实际上，所有宫颈癌病例都归因于HPV感染。这些高风险的HPV也与其他肛门生殖器癌和大约20％的口咽癌有关。目前，基于VLP的疫苗只能通过14种高风险的HPV类型中的2种和年轻女性的疫苗发生疫苗的感染差异很大。在美国，年轻妇女的疫苗速率仅占30％。尽管基于VLP的预防性疫苗针对HPV16和HPV18（占宫颈癌的70％），但需要治疗方案来靶向与HPV相关的癌症，并且持续的感染引起了这些癌症。每年在全球范围内诊断出500,000例新的宫颈癌病例，并且由于目前的疫苗对数百万已感染的妇女没有治疗益处，因此对治疗选择的需求未满足。两个病毒癌基因E6和E7驱动与HPV相关的癌变。 E6和E7（或其表达）在与HPV相关的恶性肿瘤中的扰动为治疗发育提供了潜力。我的实验室的研究一直集中在乳头瘤病毒上已有近40年了，并且对我们目前对这些乳头瘤病毒 - 宿主相互作用的致癌性基础的分子机制的理解做出了重大贡献。该OIA应用是基于我的愿景来翻译我们所知道的，并继续了解这些相互作用，以识别治疗HPV阳性癌症和预科剂的治疗靶标。我建议继续使用无偏的方法来了解有关病毒E6和E7癌蛋白的细胞相互作用，以及控制病毒性癌基因表达的E2调节蛋白，目的是识别可以用作治疗靶标的细胞靶标和途径。大约25年前，我的实验室中发现的E6和E7的主要转化活动是p53和视网膜母细胞瘤家族蛋白的失活。通过劫持细胞泛素连接酶E6相关蛋白（E6AP），E6通过泛素介导的蛋白水解靶向p53。 HPV阳性细胞中E6或E6AP的抑制导致p53稳定，从而导致稳定 由于E7诱导的致癌应激而引起的凋亡或感应。因此，我的最高优先级是针对p53的E6/E6AP介导的蛋白水解。尽管在我的实验室中发现了E6AP和这种泛素化途径20年来，但对其调节的调节或其他基因的身份几乎没有什么令人惊讶的了解。正在进行的研究 在我的实验室中，集中于（1）识别p53介导的泛素化涉及的基因和途径，以及（2）识别稳定HPV阳性癌症p53的小分子。