Mechanism of Brd4-mediated papillomavirus host interactions

Brd4介导的乳头瘤病毒宿主相互作用的机制

基本信息

批准号：
8598663
负责人：
Jianxin You
金额：
$ 5.78万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-18 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8598663
关键词：
Accounting Antiviral Agents Applications Grants Binding Biological Bromodomain Cell Cycle Cell Cycle Progression Cell Proliferation Cell division Cell physiology Cells Chromatin Chromatin Remodeling Factor Competitive Binding Complex DNA Tumor Viruses DNA biosynthesis Development Devices Disease Elongation Factor Ensure Environment Episome Epithelial Epithelial Cells Epithelium Event Female Genes Genetic Transcription Genome HPV-High Risk Human Human Herpesvirus 4 Human Herpesvirus 8 Human Papillomavirus Human papilloma virus infection Immunohistochemistry In Situ Hybridization Infection Learning Lesion Life Cycle Stages Link Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of cervix uteri Mediating Methylcellulose Mitotic Chromosome Molecular Nature Papillomavirus Phase Play Population Proteins Proteomics RNA Interference RNA Polymerase II Recruitment Activity Regulation Repression Research Risk Factors Role Sexually Transmitted Agents Structure System Therapeutic Time Transcription Elongation Transcriptional Activation Transcriptional Regulation Viral Viral Genome Viral Oncogene Woman Work cancer cell carcinogenesis gene repression insight mortality novel novel therapeutics prevent programs promoter public health relevance receptor research study tumorigenesis tumorigenic viral DNA virus episome maintenance virus host interaction

项目摘要

DESCRIPTION (provided by applicant): High-risk human papillomavirus (HPV) infection is the primary risk factor for cervical cancer, which is the second most prevalent cancer in women worldwide causing 15% of female cancer mortality. Papillomaviruses establish persistent infection by maintaining their genomes as episomes in infected cells. In the HPV life cycle that is tightly linked to the differentiation program of host epithelium, E2 ensures that the viral genome is established, replicated and maintained in the early-infected basal epithelial cells. During epithelium differentiation, E2 also contributes to the tight regulation of the viral oncogene transcription to create a conducive environment for successful completion of the viral life cycle. Loss of E2 expression leads to dysregulated viral oncogene expression and has been mechanistically linked to malignant progression of HPV positive lesions. Our previous work identified the cellular protein Brd4 (bromodomain-containing protein 4) as a novel receptor for E2. Brd4-E2 interaction functions in viral episome maintenance, viral transcriptional activation and repression of the viral oncogenes. Our studies established that Brd4 is highly expressed in the basal epithelial layer, supporting its role in E2 functions during the early phase of the viral life cycle. However, little is known about how Brd4 regulates the multiple functions of E2, nor is it clear how this virus-host interaction contributes to the differentiation- dependent HPV life cycle. This grant application aims to identify and characterize additional cellular components that regulate the E2-Brd4 functions, to determine how Brd4 contributes to E2 transcriptional regulation, and to investigate the functional impact of E2-Brd4 interactions in the HPV life cycle during epithelium differentiation. Infection by the HPV is the most common sexually transmitted agent, afflicting 50-80% of the population. This research will provide greater understanding of the molecular mechanisms that regulate the HPV life cycle and malignant progression. The new mechanisms identified in this study will provide a point of departure for developing new compounds to abrogate the virus-host interaction and cure HPV persistent infections. Mechanistic insights into how E2-Brd4 interactions repress the viral oncogenes that account for the tumorigenic nature of HPV-associated diseases will offer promising leads for novel therapeutic strategies. This study will provide a paradigm for other episomal DNA tumor viruses, including Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus, both of which also target Brd4.

描述（由申请人提供）：高危人乳头瘤病毒（HPV）感染是宫颈癌的主要危险因素，宫颈癌是全世界第二大最普遍的癌症，导致15％的女性癌症死亡率。乳头瘤病毒通过将其基因组保持为感染细胞中的偶发来建立持续的感染。在与宿主上皮的分化程序紧密相关的HPV生命周期中，E2确保在早期感染的基底上皮细胞中建立，复制和维持病毒基因组。在上皮分化过程中，E2还有助于严格调节病毒癌基因转录，以创造成功完成病毒生命周期的有利环境。 E2表达的丧失导致病毒癌基因表达失调，并与HPV阳性病变的恶性进展有关。我们以前的工作将细胞蛋白BRD4（含溴脱域的蛋白4）确定为E2的新型受体。 BRD4-E2的相互作用在病毒围绕谱系维持，病毒转录激活和病毒癌基因的抑制中的功能。我们的研究确定，BRD4在基础上皮层中高度表达，在病毒生命周期的早期阶段支持其在E2功能中的作用。然而，关于BRD4如何调节E2的多个功能的了解知之甚少，也不清楚这种病毒宿主相互作用如何有助于分化依赖性的HPV生命周期。该赠款应用旨在识别和表征调节E2-BRD4功能的其他细胞成分，以确定BRD4如何对E2转录调控贡献，并研究上皮差异过程中HPV寿命中E2-BRD4相互作用的功能影响。 HPV感染是最常见的性传播药物，遭受了50-80％的人口。这项研究将对调节HPV生命周期和恶性进展的分子机制有更深入的了解。这项研究中确定的新机制将为开发新化合物的出发点，以消除病毒宿主相互作用并治愈HPV持续感染。关于E2-BRD4相互作用的机理洞察力如何压制病毒性癌基因，这些病毒性肿瘤基因是HPV相关疾病的肿瘤性质，将为新的治疗策略提供有希望的潜在客户。这项研究将为其他偶发DNA肿瘤病毒提供一个范式，包括卡波西肉瘤相关的疱疹病毒和爱泼斯坦 - 巴尔病毒，这两个病毒也靶向BRD4。