Biology of the papillomavirus E5 oncoprotein family

描述（由申请人提供）：高危乳头状瘤病毒是人类恶性肿瘤的关键病原体，最重要的是宫颈癌。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。最近几个月，一些研究已经确定E5蛋白的进化与E6蛋白的进化紧密相关，并且高危乳头瘤病毒的E5基因具有将其与低危病毒区分开的特征。高危型HPV-16 E5蛋白具有广泛的生物学活性，包括改变生长因子受体转换、MHC转运、内体酸化、锚定非依赖性生长和细胞间连接通讯。以前，我们已经表明，E5蛋白结合的V-ATP酶复合物的一个组成部分，并干扰内体酸化，从而提供一些洞察如何E5可能增强生长因子受体的信号转导。在目前的提案中，我们发现了E5的其他靶点，包括小窝蛋白和一种116 kDa的细胞蛋白。基于我们积累的关于E5的去污剂溶解性特性和鉴定的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这些信号平台中的蛋白质相关联。我们已经构建了一个模型，在概念上联系确定的E5目标与过多的已知E5诱导的细胞表型，并设计了基于此模型的实验。E5如何靶向筏，它如何结合特定的筏驻留蛋白，以及它如何干扰这些蛋白质的功能的具体描述是这项资助的重点。预计对E5功能的深入了解将阐明其与HPV诱导的恶性肿瘤的联系。

DESCRIPTION (provided by applicant): 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 associates with 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 it 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.