权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Biology of the papillomavirus E5 oncoprotein family

乳头瘤病毒 E5 癌蛋白家族的生物学

基本信息

批准号：
7578852
负责人：
Richard Schlegel
金额：
$ 39.06万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-01-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7578852
关键词：
Alkalinization Anchorage-Independent Growth Aneuploidy Binding Biological Biological Assay Biology C-terminal Cancer Etiology Caveolins Cell Differentiation process Cells Cervical Cessation of life Characteristics Collaborations Communication Complex Connexins Contact Inhibition Detergents Differentiation and Growth Endosomes Epidermal Growth Factor Receptor Epidermis Evolution Family Fibroblasts Gap Junctions Genes Goals Grant Growth Growth Factor Receptors Human Human papillomavirus 16 In Vitro Infection Intercellular Junctions Intracellular Membranes Knockout Mice Knowledge Laboratories Link Maintenance Malignant Neoplasms Malignant neoplasm of cervix uteri Measures Mediating Membrane Membrane Lipids Membrane Microdomains Modeling Molecular Target Monitor Mus Neoplasms Oncogene Proteins Oncogenes Oncogenic Viruses Papillomavirus Phenotype Property Protein Binding Proteins Research Personnel Risk Role Signal Pathway Signal Transduction Solubility System TERT gene TP53 gene Transgenic Mice Transplantation Tumor Suppressor Proteins Tumorigenicity Vesicle Virus Woman anticancer research base cost design high risk in vitro activity in vivo insight keratinocyte mouse model mutant programs protein function research study trafficking tumor vacuolar H+-ATPase

项目摘要

The high-risk papillomaviruses are critical etiologic agents in human malignancy, most importantly in cervical cancer. These oncogenic viruses encode the E6 and E7 proteins that have been shown to modulate cell growth.and differentiation, target the p53 and Rb tumor suppressor proteins, and induce the hTERT gene and cellular immortalization. In addition to the E6 and E7 proteins, the high-risk papillomaviruses also encode the hydrophobic, membrane-associated E5 protein. In recent months, several studies have established that the evolution of the E5 protein is tightly linked to that of the E6 protein and that the E5 genes of high-risk papillomaviruses have characteristics that separate them from those of low-risk viruses. The high-risk HPV-16 E5 protein has a wide spectrum of biological activities, ranging from alterations of growth factor receptor turnover, MHC transport, endosome acidification, anchorage-independent growth, and intercellular junction communication. Previously we have shown that the E5 protein binds a component of the V-ATPase complex and interferes with endosome acidification, thereby giving some insight into how E5 might potentiate the signaling of growth factor receptors. In the current proposal, we have discovered additional targets for E5, including caveolin and a 116 kDa cellular protein. Based upon our accumulated knowledge regarding the detergent solubility properties of E5 and the identified E5-associated proteins, we hypothesize that E5 partitions into membrane lipid rafts and associateswith proteins that are resident in these signaling platforms. We have constructed a model that conceptually links the identified E5 targets with the plethora of known E5-induced cellular phenotypes and have designed experiments based upon this model. The specific delineation of how E5 is targeted to rafts, how it binds to specific raft-resident proteins, and how is interferes with the functions of these proteins is the focus of this grant. It is anticipated that insights into E5 functions will illuminate its linkage to HPV-induced malignancy.

高危乳头瘤病毒是人类恶性肿瘤的关键病原体，最重要的是宫颈癌。癌症。这些致癌病毒编码 E6 和 E7 蛋白，已被证明可以调节细胞生长和分化，靶向 p53 和 Rb 肿瘤抑制蛋白，并诱导 hTERT 基因和细胞永生化。除了E6和E7蛋白外，高危乳头瘤病毒还编码疏水性膜相关 E5 蛋白。近几个月来，多项研究表明确定 E5 蛋白的进化与 E6 蛋白的进化紧密相关，并且 E5 基因高风险乳头瘤病毒具有与低风险病毒不同的特征。这高危 HPV-16 E5 蛋白具有广泛的生物活性，包括改变生长因子受体周转、MHC 转运、内体酸化、不依赖锚定的生长和细胞间连接通讯。之前我们已经证明 E5 蛋白结合了 V-ATP酶复合物并干扰内体酸化，从而深入了解E5如何可能会增强生长因子受体的信号传导。在当前的提案中，我们发现 E5 的其他靶标，包括小窝蛋白和 116 kDa 细胞蛋白。根据我们积累的关于 E5 的洗涤剂溶解度特性和已鉴定的 E5 相关蛋白的知识，我们假设 E5 划分成膜脂筏并与驻留在其中的蛋白质结合这些信号平台。我们构建了一个模型，在概念上将已识别的 E5 目标与大量已知的 E5 诱导的细胞表型，并基于此设计了实验模型。 E5如何靶向筏、如何与特定筏驻留蛋白结合的具体描述，如何干扰这些蛋白质的功能是本次资助的重点。预计对 E5 功能的深入了解将阐明其与 HPV 诱发的恶性肿瘤的联系。