Papillomavirus E2 Functions: Cellular Regulation and Effectors
乳头瘤病毒 E2 功能:细胞调节和效应器
基本信息
- 批准号:8435813
- 负责人:
- 金额:$ 31.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AffectAnogenital cancerAntiviral AgentsAreaBindingBinding SitesBromodomainC-terminalCell CommunicationCell LineCellsCollaborationsComplexDNADNA BindingDNA Replication FactorDNA biosynthesisDNA replication originDevelopmentDimerizationElementsEnsureFamilyFundingGenetic TranscriptionGenomeGoalsGrantHead and Neck CancerHumanHuman PapillomavirusHuman papillomavirus 16 E1 proteinKnowledgeLaboratoriesLesionLife Cycle StagesLinkLocationMaintenanceMalignant NeoplasmsMalignant neoplasm of cervix uteriMass Spectrum AnalysisMediatingMediator of activation proteinMitotic ChromosomeModelingN-terminalNuclear EnvelopePapillomavirusPapillomavirus InfectionsPathway interactionsProteinsProteomicsRecruitment ActivityRiskRoleSatellite VirusesSkin CarcinomaTrans-ActivatorsTransactivationViralViral Genomebasecell growth regulationexpectationgenetic regulatory proteinhelicaseinhibitor/antagonistinsightkeratinocytenovelprotein E2, Human papilloma virus type 1research studysmall moleculetelophasetooltranscription factorviral DNA
项目摘要
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)与许多人类癌症存在因果关系。已经鉴定出超过100种不同的HPV,其中许多与有进展为癌症风险的病变相关。乳头瘤病毒根据其基因组的序列相关性分为不同的属。一些α属HPV与宫颈癌、其他肛门生殖器癌以及约20%的头颈癌相关。也有提示性但尚未令人信服的证据表明,一些β属HPV与一些非黑色素瘤皮肤癌有关。乳头瘤病毒E2基因产物在乳头瘤病毒中是保守的,并且作为病毒转录、病毒复制和基因组维持的主要调节因子发挥功能。E2蛋白在20世纪80年代首次被描述为转录因子,其可以通过位于病毒基因组内的E2响应元件激活病毒转录。然而,E2具有额外的功能,并且可以作为病毒转录的反式激活因子或阻遏因子,这取决于其结合位点在病毒基因组内的位置和背景。E2是病毒DNA复制所需的辅助DNA复制因子,有助于将病毒E1解旋酶募集到病毒DNA复制起点。此外,E2对于感染细胞中的基因组维持是必不可少的,并且对于一些乳头瘤病毒,E2通过将病毒DNA结合和连接到宿主细胞有丝分裂染色体来发挥功能。2004年,我的实验室鉴定了溴结构域蛋白Brd 4作为主要的E2相互作用蛋白,并确定了其作为宿主有丝分裂染色体上BPV E2/DNA复合物的细胞系链的功能。在上一个供资周期,这笔赠款侧重于E2和Brd 4,并为Brd 4在调解各种E2职能方面发挥了额外作用。这一补助金更新申请侧重于E2。第一个目标是认识到,有一个更广泛的需要了解Brd 4本身,并将进一步扩大我们的知识E2和Brd 4的功能。第二个是该资助的一个新领域,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无偏见分析。作为病毒生命周期几个不同方面所需的重要多功能调节蛋白,E2是开发HPV抗病毒药物的有吸引力的靶点。这些实验的最终目标是进一步了解调节和介导E2功能的细胞蛋白质和途径,期望其中一种或多种可能具有用于鉴定或开发小分子抑制剂的潜力。这些化合物将是进一步研究HPV-宿主细胞相互作用的有用工具,并可作为模拟治疗乳头瘤病毒感染的新型抗病毒药物的潜在线索。
公共卫生相关性:人乳头瘤病毒(HPV)是与许多人类癌症相关的病毒家族。E2蛋白是由乳头瘤病毒编码的影响病毒转录、病毒DNA复制和病毒基因组维持的关键调节蛋白。调节E2的细胞因子以及E2通过其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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Peter M Howley其他文献
Peter M Howley的其他文献
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{{ truncateString('Peter M Howley', 18)}}的其他基金
Molecular Biology of Oncogenic Papillomaviruses
致癌乳头瘤病毒的分子生物学
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10322439 - 财政年份:2016
- 资助金额:
$ 31.56万 - 项目类别:
Molecular Biology of Oncogenic Papillomaviruses
致癌乳头瘤病毒的分子生物学
- 批准号:
10057232 - 财政年份:2016
- 资助金额:
$ 31.56万 - 项目类别:
Molecular Biology of Oncogenic Papillomaviruses
致癌乳头瘤病毒的分子生物学
- 批准号:
8952443 - 财政年份:2016
- 资助金额:
$ 31.56万 - 项目类别:
Small Molecule Screen Targeting p53 proteolysis in HPV positive cancers
针对 HPV 阳性癌症中 p53 蛋白水解的小分子筛选
- 批准号:
8641680 - 财政年份:2013
- 资助金额:
$ 31.56万 - 项目类别:
Small Molecule Screen Targeting p53 proteolysis in HPV positive cancers
针对 HPV 阳性癌症中 p53 蛋白水解的小分子筛选
- 批准号:
8489916 - 财政年份:2013
- 资助金额:
$ 31.56万 - 项目类别:
Papillomavirus E2 Growth Suppression Mechanisms
乳头瘤病毒 E2 生长抑制机制
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Papillomavirus E2 Growth Suppression Mechanisms
乳头瘤病毒 E2 生长抑制机制
- 批准号:
7647591 - 财政年份:2009
- 资助金额:
$ 31.56万 - 项目类别:
Mechanistic Analysis of Papillimavirus E2 Functions
乳头状病毒E2功能的机制分析
- 批准号:
7105179 - 财政年份:2006
- 资助金额:
$ 31.56万 - 项目类别:
Mechanistic Analysis of Papillimavirus E2 Functions
乳头状病毒E2功能的机制分析
- 批准号:
7909331 - 财政年份:2006
- 资助金额:
$ 31.56万 - 项目类别:
Mechanistic Analysis of Papillimavirus E2 Functions
乳头状病毒E2功能的机制分析
- 批准号:
7772357 - 财政年份:2006
- 资助金额:
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