Molecular Biology of Oncogenic Papillomaviruses

 描述（由申请人提供）：人乳头瘤病毒（HPV）与许多人类癌症存在因果关系。已经鉴定了超过140种不同的HPV，其中一个子集，称为高风险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也与其他肛门生殖器癌和约20%的口咽癌相关。目前基于VLP的疫苗只能预防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异很大;在美国，年轻女性的疫苗接种率目前仅为30%左右。尽管有针对HPV 16和HPV 18（约占宫颈癌的70%）的基于VLP的预防性疫苗，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。全世界每年诊断出50万例新的宫颈癌病例，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尚未得到满足。两种病毒致癌基因E6和E7驱动HPV相关的致癌作用。扰乱HPV相关恶性肿瘤中E6和E7的功能（或其表达）为治疗开发提供了潜力。在我的实验室的研究一直集中在乳头瘤病毒近40年，并作出了重大贡献，我们目前的理解这些乳头瘤病毒-宿主细胞相互作用的致癌性的分子机制的关键方面。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癌蛋白的细胞相互作用，以及控制病毒癌基因表达的E2调节蛋白，以确定可以作为治疗靶点的细胞靶点和途径。近25年前我的实验室发现的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（E6 AP）通过泛素介导的蛋白水解靶向p53失活。HPV阳性细胞中E6或E6 AP的抑制导致p53稳定， 在E7诱导的致癌应激引起的细胞凋亡或衰老中的作用。因此，我的最高优先级是靶向E6/E6 AP介导的p53蛋白水解。尽管在我的实验室里发现了E6 AP和这种泛素化途径超过20年，但令人惊讶的是，人们对它的调控或参与其调控的其他基因的身份知之甚少。正在进行的研究 在我的实验室中，主要集中在（1）鉴定参与E6介导的p53泛素化的基因和途径，以及（2）鉴定在HPV阳性癌症中稳定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.