Activation of the LMP-1 Protein of Epstein-Barr Virus

Epstein-Barr 病毒 LMP-1 蛋白的激活

• 批准号: 7215749
• 负责人: JENNIFER M MARTIN
• 金额: $ 23.17万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215749
• 关键词: Address; Area; B lymphocyte immortalization; B-Cell Lymphomas; B-Lymphocytes; Biochemical; Biopsy; C-terminal; Cell Cycle Regulation; Cell Line; Cell Surface Receptors; Cells; Complex; Cytokinesis; Data; Depth; Goals; Growth; Human; Human Herpesvirus 4; In Vitro; Individual; Life Cycle Stages; Light; Link; Malignant Neoplasms; Mediating; Membrane; Membrane Microdomains; Membrane Proteins; Molecular; Nasopharynx Carcinoma; Oncogene Proteins; Play; Process; Proteins; Regulation; Research; Role; Signal Transduction; Structure; Testing; Thinking; Transmembrane Domain; Tumor Cell Line; Tumor Necrosis Factor Receptor; Work; analog; base; cell growth; cell growth regulation; cell transformation; design; in vivo; infected B cell; insight; lymphoblastoid cell line; pathogen; research study; stoichiometry; tumorigenesis

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is a human pathogen associated with a variety of cancers, including B cell lymphomas and nasopharyngeal carcinoma. EBV encodes an oncoprotein called the latent membrane protein-1 (LMP-1) whose activity is critical for B cell transformation by EBV. The ultimate goal of the proposed research is to explore the molecular and biochemical mechanisms by which LMP-1 contributes to EBV's life cycle in vitro and then to apply results to LMP-1's potential contribution to EBV's life cycle in vivo as it relates not only to the process of tumorigenesis but to the activity of EBV in latently infected B cells of healthy individuals. LMP-1 is expressed in infected primary B cells, immortalized lypmphoblastoid cell lines, and in some tumor cell lines or biopsies. LMP-1 functions as a constitutively-active cell surface receptor and activates positive growth-regulatory signals via its intracellular C-terminal signaling domain and negative growth-regulatory signals via its transmembrane domain. The studies described in this proposal are designed with the combined goals of understanding the function of LMP-1's hydrophobic transmembrane domain in the context of a) the mechanism of LMP-1's constitutive activation of cellular growth-regulatory signaling and b) signaling resulting in negative growth-regulation. Defining the mechanism of LMP-1's constitutive activation will provide insights into the control of cellular signal transduction and may be generally applicable to the molecular mechanisms involved in normal B cell growth control and in the aberrant growth of virally and nonvirally induced malignancies. Understanding the process of negative growth-regulation by LMP-1 will provide insights into the broad areas of cell cycle regulation and cytokinesis, and may shed light on the contribution of LMP-1 to EBV's life cycle in vivo, in transformed cells and in latently infected cells in healthy seropositive individuals.

描述（由申请人提供）：eb病毒（EBV）是一种与多种癌症相关的人类病原体，包括B细胞淋巴瘤和鼻咽癌。EBV编码一种称为潜伏膜蛋白-1 （LMP-1）的癌蛋白，其活性对EBV转化B细胞至关重要。本研究的最终目标是探索LMP-1在体外促进EBV生命周期的分子和生化机制，然后将结果应用于LMP-1在体内对EBV生命周期的潜在贡献，因为它不仅与肿瘤发生过程有关，而且与EBV在健康个体潜伏感染的B细胞中的活性有关。LMP-1在受感染的原代B细胞、永生化淋巴母细胞细胞系和一些肿瘤细胞系或活组织检查中表达。LMP-1作为一种组成活性的细胞表面受体，通过其胞内c端信号域激活正生长调控信号，通过其跨膜域激活负生长调控信号。本提案中描述的研究旨在了解LMP-1疏水跨膜结构域在a) LMP-1组成性激活细胞生长调节信号的机制和b)信号导致负生长调节的背景下的功能。确定LMP-1的组成激活机制将有助于深入了解细胞信号转导的控制，并可能普遍适用于正常B细胞生长控制以及病毒和非病毒诱导的恶性肿瘤异常生长的分子机制。了解LMP-1的负生长调节过程将为细胞周期调节和细胞分裂的广泛领域提供见解，并可能阐明LMP-1对EBV在体内、转化细胞和健康血清阳性个体潜伏感染细胞中的生命周期的贡献。