Papillomavirus E2 Functions: Cellular Regulation and Effectors

乳头瘤病毒 E2 功能：细胞调节和效应器

• 批准号: 8435813
• 负责人: Peter M Howley
• 金额: $ 31.56万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435813
• 关键词: Affect; Anogenital cancer; Antiviral Agents; Area; Binding; Binding Sites; Bromodomain; C-terminal; Cell Communication; Cell Line; Cells; Collaborations; Complex; DNA; DNA Binding; DNA Replication Factor; DNA biosynthesis; DNA replication origin; Development; Dimerization; Elements; Ensure; Family; Funding; Genetic Transcription; Genome; Goals; Grant; Head and Neck Cancer; Human; Human Papillomavirus; Human papillomavirus 16 E1 protein; Knowledge; Laboratories; Lesion; Life Cycle Stages; Link; Location; Maintenance; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Mitotic Chromosome; Modeling; N-terminal; Nuclear Envelope; Papillomavirus; Papillomavirus Infections; Pathway interactions; Proteins; Proteomics; Recruitment Activity; Risk; Role; Satellite Viruses; Skin Carcinoma; Trans-Activators; Transactivation; Viral; Viral Genome; base; cell growth regulation; expectation; genetic regulatory protein; helicase; inhibitor/antagonist; insight; keratinocyte; novel; protein E2, Human papilloma virus type 1; research study; small molecule; telophase; tool; transcription factor; viral DNA

DESCRIPTION (provided by applicant): The human papillomaviruses (HPVs) are causally linked to a number of human cancers. Over 100 different HPVs have been identified and many are associated with lesions that are at risk to progress to cancer. The papillomaviruses are divided into different genera based on the sequence relatedness of their genomes. Some of the alpha genus HPVs are associated with cervical cancer, other anogenital cancers, and approximately 20% of head and neck cancers. There is also suggestive but not yet compelling evidence implicating some of the beta genus HPVs in some non-melanoma skin cancers. The papillomavirus E2 gene product is conserved among papillomaviruses and functions as a major regulator of viral transcription, viral replication and genome maintenance. The E2 protein was first described in the 1980s to be a transcription factor that can activate viral transcription through E2 responsive elements located within the viral genome. E2 has additional functions however, and can serve either as a transactivator or a repressor of viral transcription depending upon the location and context of its binding sites within the viral genome. E2 is required for vira DNA replication as an auxiliary DNA replication factor that helps recruit the viral E1 helicase to the viral DNA replication origin. In addition, E2 is essential for genome maintenance in infected cells and, for some papillomaviruses, E2 functions by binding and linking the viral DNA to host cell mitotic chromosomes. In 2004 my laboratory identified the bromodomain protein Brd4 as a major E2 interacting protein and established its function as a cellular tether for the BPV E2/DNA complex on host mitotic chromosomes. In the past funding cycle, this grant focused on E2 and Brd4 and established additional roles for Brd4 in mediating various E2 functions. This grant renewal application focuses on E2. The first aim recognizes that there is a broader need for understanding Brd4 itself and will further extend our knowledge of E2 and Brd4 functions. The second is a new area for this grant, proposing a broad non-biased analysis of HPV E2 protein interactions across 20 different HPV types. As an important multifunctional regulatory protein required for several different aspects of the viral life cycle, E2 is an attractive target for the development of HPV antivirals. An ultimate goal of these experiments is to gain further insights into the cellular proteins and pathways that both regulate and mediate E2 functions, with the expectation that one or more of them might have the potential to be exploited for the identification or development of small molecule inhibitors. Such compounds would be useful tools for further studies of HPV-host cell interactions and could serve as potential leads for modeling novel antivirals to treat papillomavirus infections. PUBLIC HEALTH RELEVANCE: The human papillomaviruses (HPVs) are a family of viruses that are associated with a number of human cancers. The E2 protein is a critical regulatory protein encoded by the papillomaviruses affecting viral transcription, viral DNA replication and viral genome maintenance. The cellular factors that regulate E2 as well as the cellular factors through which E2 affects its various functions are potential targets for the development of antiviral compounds for treating HPV associated lesions.

描述（由申请人提供）：人乳头瘤病毒（HPV）与许多人类癌症有因果关系。已经确定了100多种不同的HPV，许多HPV与有癌症患有风险的病变有关。根据其基因组的序列相关性，将乳头瘤病毒分为不同的属。一些α属HPV与宫颈癌，其他肛门生殖器癌和大约20％的头颈癌有关。也有暗示性但尚未令人信服的证据，暗示了某些非黑色素瘤皮肤癌中的某些β属HPV。乳头瘤病毒E2基因产物在乳头瘤病毒中保守，并且是病毒转录，病毒复制和基因组维持的主要调节剂。 E2蛋白在1980年代首先被描述为可以通过位于病毒基因组内的E2反应元素激活病毒转录的转录因子。但是，E2具有其他功能，可以作为反式激活因子或病毒转录的阻遏物，具体取决于其在病毒基因组中的结合位点的位置和上下文。 E2是ViRA DNA复制所必需的，作为辅助DNA复制因子，有助于募集病毒E1解旋酶为病毒DNA复制起源。此外，E2对于受感染细胞的基因组维持至关重要，对于某些乳头瘤病毒，E2通过结合和将病毒DNA与宿主细胞有丝分裂染色体联系起来的功能。 2004年，我的实验室将溴结构域蛋白BRD4鉴定为主要的E2相互作用蛋白，并确立了其在宿主有丝分裂染色体上的BPV E2/DNA复合物的细胞系列的功能。在过去的融资周期中，该赠款集中在E2和BRD4上，并在中介各种E2功能中确立了BRD4的其他角色。该赠款续订申请的重点是E2。第一个目的是认识到了解BRD4本身的广泛需求，并将进一步扩展我们对E2和BRD4功能的了解。第二个是该赠款的新领域，提出了对20种不同HPV类型的HPV E2蛋白相互作用进行广泛的非偏差分析。作为病毒生命周期的几个不同方面所需的重要多功能调节蛋白，E2是HPV抗病毒药发育的有吸引力的靶标。这些实验的最终目标是获得调节和介导E2功能的细胞蛋白和途径的进一步见解，并期望其中一个或多个可能有可能利用用于识别或开发小分子抑制剂的潜力。此类化合物将是进一步研究HPV宿主细胞相互作用的有用工具，可以作为对治疗乳头瘤病毒感染的新型抗病毒药进行建模的潜在潜在客户。 公共卫生相关性：人类乳头瘤病毒（HPV）是与许多人类癌症相关的病毒家族。 E2蛋白是一种关键的调节蛋白，由影响病毒转录，病毒DNA复制和病毒基因组维持的乳头瘤病毒编码。调节E2的细胞因子以及E2影响其各种功能的细胞因子是开发用于治疗HPV相关病变的抗病毒化合物的潜在靶标。