Role of a New Polyomavirus in Merkel Cell Carcinoma

新型多瘤病毒在默克尔细胞癌中的作用

• 批准号: 8694310
• 负责人: PATRICK S. MOORE
• 金额: $ 44.18万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-13 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694310
• 关键词: Acute; Affect; Affinity; Age; Antigen Targeting; Antineoplastic Agents; Apoptosis; Biological Assay; Cancer Etiology; Cancer Research Project; Cell Death; Cell Line; Cell Proliferation; Cell division; Cells; Chronic; Clinical Trials; Complex; Cre-LoxP; Development; Diagnosis; Diagnostic; Diagnostic tests; Eastern Cooperative Oncology Group; Epigenetic Process; Fractionation; Gene Expression Profile; Generations; Genes; Grant; Herpesviridae; Human; Human Herpesvirus 8; Human Virus; In Vitro; Infection; Investigation; Kaposi Sarcoma; Lead; Light; Link; Malignant Neoplasms; Maps; Measures; Mediating; Merkel Cells; Merkel cell carcinoma; Messenger RNA; Methods; Molecular; Mouse, Founder, Transgenic; Oncogene Proteins; Oncogenes; Oncogenic; Ontology; Pathway interactions; Pattern; Phosphorylation; Phosphorylation Site; Phosphotransferases; Polyomavirus; Polyomavirus Infections; Polyribosomes; Preclinical Drug Evaluation; Process; Protein Biosynthesis; Proteins; Publishing; Reagent; Regulation; Research; Ribosomes; Rodent; Role; Signal Transduction; Site; Skin; Skin Cancer; Small T Antigen; Speed; Tamoxifen; Testing; Therapy Clinical Trials; Toxic effect; Transgenic Mice; Transgenic Organisms; Translations; Tumor Suppressor Proteins; Viral; Viral Cancer; Viral Proteins; Virus; cancer cell; cancer therapy; cell transformation; cytotoxicity; digital; improved; in vivo; insight; mRNA Expression; mouse model; neoplastic cell; novel; novel diagnostics; protein degradation; protein expression; public health relevance; tumor; tumorigenesis; ubiquitin-protein ligase

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.

描述（由申请方提供）：本次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了默克尔细胞多瘤病毒（MCV或MCPyV）作为MCC的克隆整合感染。它是第七种人类癌症病毒，也是我们小组发现的第二种（除了卡波西肉瘤疱疹病毒，KSHV或HHV 8）。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蛋白质的细胞伴侣、病毒癌蛋白敲除和确定MCV感染的诊断测定的研究。总之，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。 MCV作为一种新的癌症病毒，可以用来发现新的致病癌症途径。我们发现MCV癌蛋白，小T（sT）抗原，靶向细胞蛋白质调节激活病毒和细胞癌蛋白。它是一种新的病毒试剂，现在可用于研究表观遗传蛋白质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降解决定子调节，2）了解MCV如何使4 E-BP 1失活，导致失调的帽依赖性翻译和细胞转化，3）鉴定由MCV激活的细胞致癌途径，4）检查MCV诱导的肿瘤发生的转基因小鼠模型。该提案描述了MCV用于驱动癌细胞增殖的新分子机制，然后将这些发现应用于生物体水平。这些研究将揭示表观遗传癌细胞信号传导，并可能加速新癌症疗法的开发和测试。