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

爱泼斯坦-巴尔病毒(EBV)是一种人类病原体，与包括B细胞在内的多种癌症有关 淋巴瘤和鼻咽癌。EBV编码一种称为潜伏期的癌蛋白 膜蛋白-1(LMP-1)，其活性在EB病毒转化B细胞过程中起关键作用。这个 拟议研究的最终目标是通过以下方式探索分子和生化机制 哪种LMP-1在EB病毒的体外生命周期中起作用，然后将结果应用于LMP-I的潜能 对EBV体内生命周期的贡献，因为它不仅与肿瘤发生过程有关，而且与 健康人潜伏感染B细胞中EB病毒的活性LMP-1在感染性疾病中表达 原代B细胞，永生化的淋巴母细胞系，以及在一些肿瘤细胞系或活检组织中。 LMP-1作为一种结构性活性的细胞表面受体，激活正向生长- 细胞内C末端信号转导结构域调控信号和负生长调控 通过其跨膜结构域传递信号。这项建议中描述的研究是用 了解LMP-I疏水跨膜结构域在血管内皮细胞中的功能 A)LMP-I对细胞生长调节的结构性激活机制 信号和b)信号导致负生长调节。定义LMP的机制-- L的结构性激活将为控制细胞信号转导和 可能普遍适用于参与正常B细胞生长控制的分子机制 以及病毒和非病毒诱导的恶性肿瘤的异常生长。了解 LMP-1的负生长调节过程将为深入了解细胞的广泛领域提供帮助 细胞周期调节和胞质分裂，并可能阐明LMP-1对EBV生命周期的贡献 在体内，在转化的细胞中，以及在健康血清阳性个体的潜伏感染细胞中。 _erp(JRMANGE S_TP--{S)[组织、城市、州] 科罗拉多大学分子、细胞和发育生物学系， 博尔德 关键人员。请参阅第11页的说明。根据需要使用续页，以如下所示的格式提供所需信息。 命名项目中的组织角色 詹妮弗·马丁，科罗拉多大学博士，MCDB首席研究员 小灵通398(4/98版)第2页E}B 在整个应用程序的底部连续编号页码。不要使用3a、3b等后缀。 CC首席调查员/项目主任(最后、第一、中间)：&gt；Martin_Jennifer M. 在每张打印页和每张续页的顶部输入首席调查员/项目主任的姓名。(有关类型规格，请参阅说明 (见第6页。) 研究补助金 目录 页码 主页.......................................................................................................................................................................................................................... 描述，

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-I'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, immortalizaed 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-I's hydrophobic transmembrane domain in the context of a) the mechanism of LMP-I's constitutive activation of cellular growth-regulatory signaling and b) signaling resulting in negative growth-regulation. Defining the mechanism of LMP- l'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. _ERP(JRMANGE S_TP--{S) {organization, city, state) >Department of Molecular, Cellular and Developmental Biology (MCDB), University of Colorado, Boulder KEY PERSONNEL. See instructions on Page 11. Use continuation pages as needed to provide the required information in the format shown below. Name Organization Role on Project Jennifer M. Martin, Ph.D. University of Colorado, MCDB Principal Investigator PHS 398 (Rev. 4/98) Page 2 E}B Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b. CC Principal Investigator/Program Director (Last, first, middle): > Martin_ Jennifer M. Type the name of the principal investigator/program director at the top of each printed page and each continuation page. (For type specifications, see instructions on page 6.) RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page .......................................................................................................................................................................................................................... Description,