Role of a New Polyomavirus in Merkel Cell Carcinoma

描述（由申请人提供）：此更新支持对导致大多数默克尔细胞癌（MCC）的最新人类癌症病毒的研究。我们在2008年通过数字转录组减法发现默克尔细胞多瘤病毒（MCV或MCPyV）是一种MCC的克隆整合感染。这是我们小组发现的第七种人类癌症病毒，也是第二种人类癌症病毒（除了卡波西肉瘤疱疹病毒，KSHV或HHV8）。我们最初的资助非常成功，发表了超过35项关于MCV mRNA和蛋白质表达模式、MCV复制、MCV蛋白的细胞伴侣、病毒癌蛋白敲除以及确定MCV感染的诊断分析的研究。综上所述，这些研究表明，MCV是大多数MCC的感染原因。这些发现也直接导致了诊断和治疗MCC的新方法（ECOG临床试验2612）。在短短五年内，这项研究从根本上改善了这种难治性癌症的诊断和治疗前景。作为一种新的癌症病毒，MCV可以用来发现新的癌症病原学途径。我们发现MCV癌蛋白，小T （sT）抗原，靶向细胞蛋白调控来激活病毒和细胞癌蛋白。它是一种新的病毒试剂，现在可以用来研究表观遗传蛋白翻译如何促进癌细胞增殖。我们更新的目的是：1)鉴定和表征MCV大T （LT）和细胞癌蛋白的磷酸化调控；2)了解MCV如何失活4E-BP1，导致帽依赖翻译和细胞转化失调；3)鉴定MCV激活的细胞致癌途径；4)检验MCV诱导肿瘤发生的转基因小鼠模型。该建议描述了MCV驱动癌细胞增殖的新分子机制，并将这些发现应用于组织水平。这些研究将揭示表观遗传癌细胞信号，并可能加快新的癌症治疗方法的开发和测试。

DESCRIPTION (provided by applicant): This renewal supports investigation into the newest human cancer virus causing most Merkel cell carcinoma (MCC). We found Merkel cell polyomavirus (MCV or MCPyV) in 2008 by digital transcriptome subtraction as a clonally integrated infection of MCC. It is the seventh human cancer virus and the second discovered by our group (in addition to Kaposi's sarcoma Herpes virus, KSHV or HHV8). Our initial grant was highly successful, with over 35 studies published on MCV mRNA and protein expression patterns, MCV replication, cellular partners to MCV proteins, viral oncoprotein knockdown and diagnostic assays to determine MCV infection. Taken together, these studies show that MCV is the infectious cause for most MCC. These findings also led directly to new methods to diagnose and treat MCC (ECOG clinical trial 2612). In just five years, this research has radically improved prospects for diagnosis and treatment of this intractable cancer. As a new cancer virus, MCV can be exploited to uncover new etiologic cancer pathways. We find that an MCV oncoprotein, small T (sT) antigen, targets cellular protein regulation to activate both viral and cellular oncoproteins. It is a new viral reagent that now can be used to investigate how epigenetic protein translation contributes to cancer cell proliferation. The aims of our renewal are: 1) to identify and characterize phosphodegron regulation of MCV large T (LT) and cellular oncoproteins, 2) to understand how MCV inactivates 4E-BP1, leading to dysregulated cap-dependent translation and cell transformation, 3) to identify the cellular oncogenic pathways that are activated by MCV and 4) to examine a transgenic mouse model for MCV-induced tumorigenesis. This proposal characterizes novel molecular mechanisms used by MCV to drive cancer cell proliferation and then applies these findings at the organismal level. These investigations will shed light on epigenetic cancer cell signaling and may speed development and testing of new cancer therapies.