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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：
7771629
负责人：
Richard Schlegel
金额：
$ 39.53万
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/7771629
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.

高危型乳头瘤病毒是人类恶性肿瘤的重要病原体，尤其是宫颈癌。癌这些致癌病毒编码的E6和E7蛋白已被证明可以调节细胞凋亡。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，高危乳头瘤病毒还编码疏水性膜相关E5蛋白。近几个月来，一些研究 E5蛋白的进化与E6蛋白的进化紧密相连，高风险的乳头状瘤病毒具有将它们与低风险病毒区分开的特征。的高危型HPV-16 E5蛋白具有广泛的生物学活性，因子受体周转，MHC转运，内体酸化，锚定非依赖性生长，细胞间连接通讯以前我们已经表明，E5蛋白结合的一个组成部分， V-ATP酶复合物，并干扰内体酸化，从而对E5 可能会增强生长因子受体的信号传导。在目前的提案中，我们发现 E5的其他靶点，包括小窝蛋白和116 kDa细胞蛋白。根据我们积累的关于E5的去污剂溶解特性和鉴定的E5相关蛋白的知识，我们假设E5分配到膜脂筏中，并与驻留在膜脂筏中的蛋白质结合，这些信号平台。我们已经构建了一个模型，在概念上将已识别的E5靶点与过多的已知E5诱导的细胞表型，并基于此设计了实验模型E5如何靶向筏的具体描述，它如何与特定的筏驻留蛋白结合，以及它是如何干扰这些蛋白质的功能的，是这项资助的重点。预计各国对E5功能的深入了解将阐明其与HPV诱导的恶性肿瘤的联系。