Molecular Biology of Oncogenic Papillomaviruses

 描述(申请人提供)：人乳头瘤病毒(HPV)与许多人类癌症有因果关系。目前已发现140多种不同的HPV，其中一部分被称为高危HPV，与癌症有关。几乎所有的宫颈癌病例都可归因于HPV感染。这些高危HPV还与其他肛门生殖道癌和大约20%的口咽癌有关。目前以VLP为基础的疫苗只预防14种高危HPV类型中的2种感染，年轻女性的疫苗接种率在各国之间差别很大；在美国，年轻女性的疫苗接种率目前只有30%左右。尽管基于VLP的针对HPV16和HPV18(约占宫颈癌的70%)的预防性疫苗已经问世，但仍需要针对HPV相关癌症和导致这些癌症的持续感染的治疗选择。由于全世界每年新诊断的宫颈癌病例有50万例，而且由于目前的疫苗对数百万已经感染的妇女没有治疗益处，因此对治疗方案的需求尚未得到满足。两个病毒癌基因，E6和E7，驱动HPV相关的癌症发生。在HPV相关的恶性肿瘤中干扰E6和E7的功能(或其表达)为治疗开发提供了潜力。近40年来，我的实验室一直专注于乳头瘤病毒的研究，并为我们目前理解这些乳头瘤病毒与宿主细胞相互作用的致癌分子机制的关键方面做出了重要贡献。这个OIA应用程序基于我的愿景，即翻译我们所知道的并继续了解这些相互作用，以确定治疗HPV阳性癌症和癌前病变的治疗靶点。我建议继续使用无偏见的方法来了解更多关于病毒E6和E7癌蛋白以及控制病毒癌基因表达的E2调节蛋白的细胞相互作用，目的是确定可以作为治疗靶点的细胞靶点和途径。我的实验室在近25年前发现的E6和E7的主要转化活性是P53和视网膜母细胞瘤家族蛋白的失活。E6通过劫持细胞泛素连接酶E6相关蛋白(E6AP)，通过泛素介导的蛋白降解来靶向P53的失活。抑制HPV阳性细胞中的E6或E6AP导致P53稳定 在E7诱导的致癌应激引起的细胞凋亡或衰老过程中。因此，我的首要任务是针对E6/E6AP介导的P53蛋白水解酶。尽管我的实验室在20多年的时间里发现了E6AP和这种泛素化途径，但令人惊讶的是，人们对其调控或参与其调控的其他基因的识别知之甚少。正在进行的研究 我的实验室专注于(1)识别参与E6介导的P53泛素化的基因和途径，以及(2)在HPV阳性的癌症中识别稳定P53的小分子。

 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.