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：
8840705
负责人：
Jianxin You
金额：
$ 5.74万
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 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8840705
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 Health 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 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，宫颈癌是全球女性中第二常见的癌症，占女性癌症死亡率的 15%。乳头瘤病毒通过将其基因组维持为受感染细胞中的附加体来建立持续感染。在与宿主上皮分化程序紧密相关的HPV生命周期中，E2确保病毒基因组在早期感染的基底上皮细胞中建立、复制和维持。在上皮分化过程中，E2 还有助于严格调控病毒癌基因转录，为病毒生命周期的成功完成创造有利的环境。 E2 表达缺失会导致病毒癌基因表达失调，并在机制上与 HPV 阳性病变的恶性进展相关。我们之前的工作将细胞蛋白 Brd4（含溴结构域蛋白 4）确定为 E2 的新型受体。 Brd4-E2 相互作用在病毒附加体维持、病毒转录激活和病毒癌基因抑制中发挥作用。我们的研究表明，Brd4 在基底上皮层中高度表达，支持其在病毒生命周期早期阶段的 E2 功能中的作用。然而，人们对 Brd4 如何调节 E2 的多种功能知之甚少，也不清楚这种病毒-宿主相互作用如何促进分化依赖性 HPV 生命周期。该拨款申请旨在识别和表征调节 E2-Brd4 功能的其他细胞成分，确定 Brd4 如何促进 E2 转录调节，并研究上皮分化期间 E2-Brd4 相互作用对 HPV 生命周期的功能影响。 HPV 感染是最常见的性传播媒介，影响着 50-80% 的人口。这项研究将加深对调节 HPV 生命周期和恶性进展的分子机制的了解。这项研究中确定的新机制将为开发新化合物提供一个出发点，以消除病毒与宿主的相互作用并治愈 HPV 持续感染。对 E2-Brd4 相互作用如何抑制导致 HPV 相关疾病致瘤性质的病毒癌基因的机制见解将为新的治疗策略提供有希望的线索。这项研究将为其他附加型 DNA 肿瘤病毒提供范例，包括卡波西肉瘤相关疱疹病毒和 Epstein-Barr 病毒，这两种病毒也以 Brd4 为目标。