Oncogenic properties of interferon regulatory factor 7

干扰素调节因子 7 的致癌特性

基本信息

批准号：
7369791
负责人：
LUWEN ZHANG
金额：
$ 21.73万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7369791
关键词：
Acquired Immunodeficiency Syndrome Affect Apoptosis B-Lymphocytes Cell Nucleus Cells Central Nervous System Lymphoma Condition DNA Binding Data Dominant-Negative Mutation EBV-associated disease Epstein-Barr Virus Infections Epstein-Barr Virus Nuclear Antigens Epstein-Barr Virus latency Epstein-Barr pathogenesis Epstein-Barr virus LMP-1 protein Family Gene Targeting Goals Growth Homologous Gene Human Human Herpesvirus 4 Human Herpesvirus 8 IRF1 gene IRF2 gene Immunocompromised Host In Vitro Individual Interferons Knowledge Life Localized Lymphoma Malignant Neoplasms Mediating Membrane Proteins Nasopharynx Carcinoma Nuclear Nuclear Translocation Numbers Oncogenic Patients Phosphorylation Play Process Property Protein Overexpression RNA Splicing Rate Regulation Research Personnel Rodent Role Serum Small Interfering RNA Stomach Carcinoma Thinking Tumor Suppressor Genes Tumor Suppressor Proteins Variant Viral Pathogenesis Work antigenic peptide transporter cell transformation in vivo insight interferon regulatory factor-7 neoplastic cell promoter transcription factor viral interferon regulatory factor

项目摘要

DESCRIPTION (provided by applicant): Interferon regulatory factor 7 (IRF-7) is implicated in the regulation of Epstein-Barr virus (EBV) latency. EBV infection is a leading cause of lymphomas especially in immunocompromised individuals and has been associated with nasopharyngeal carcinoma (NPC) and gastric carcinoma. EBV transforms primary B cells in vitro and EBV latent membrane protein 1 (LMP-1) is required for the process. LMP-1 induces the expression of IRF-7 and activates IRF-7 protein by phosphorylation and nuclear translocation. Activated IRF-7 then exerts its effect on target genes. However, little is known about the role of IRF-7 in the pathogenesis of EBV-associated diseases. Our data suggests that both expression and activation of IRF-7 are associated with EBV transformation process in vitro, and IRF-7 is highly expressed and activated in EBV-associated human central nervous system lymphoma (CNS lymphoma) in vivo. IRF-7 by itself has oncogenic potential, but it also has a cooperative effect with LMP-1 in transforming rodent cells. Furthermore, reduction of IRF-7 in EBV-transformed STAT-1-null B cells reduced the number of live cells at low serum conditions. Therefore, we hypothesize that IRF-7 may be a factor in EBV-mediated transformation process. In the proposed work, we will study in Aim 1 the mechanism of IRF-7 to transform rodent cells. Transformation domain(s) in IRF-7 will be determined. In Aim 2, we will study the mechanism of cooperative transformation between IRF-7 and LMP-1. We will examine if LMP-1-mediated nuclear translocation of IRF-7 is related to the cooperative transformation. In Aim 3, the role of IRF-7 in EBV transformation process will be determined by introducing small interfering RNA of IRF-7 or dominant negative mutant for IRF-7 transformation into EBV-transformed cells. This study should provide an insight of how IRF-7 participates in EBV transformation, and expand our knowledge about IRFs as well as the pathogenesis of EBV-associated CNS lymphoma.

描述（由申请人提供）：干扰素调节因子7（IRF-7）与Epstein-Barr病毒（EBV）潜伏期的调节有关。 EBV感染是淋巴瘤的主要原因，尤其是在免疫功能低下的个体中，并且与鼻咽癌（NPC）和胃癌有关。 EBV在体外转化原代B细胞和EBV潜在膜蛋白1（LMP-1）是该过程所必需的。 LMP-1诱导IRF-7的表达，并通过磷酸化和核易位激活IRF-7蛋白。然后，激活的IRF-7对靶基因发挥作用。然而，关于IRF-7在与EBV相关疾病的发病机理中的作用知之甚少。我们的数据表明，IRF-7的表达和激活都与体外EBV转化过程有关，而IRF-7在体内与EBV相关的人类中枢神经系统淋巴瘤（CNS淋巴瘤）中高度表达并激活。 IRF-7本身具有致癌潜力，但它在转化啮齿动物细胞中也具有与LMP-1的合作作用。此外，在EBV转化的STAT-1-NULL B细胞中IRF-7的减少减少了低血清条件下活细胞的数量。因此，我们假设IRF-7可能是EBV介导的转化过程中的一个因素。在拟议的工作中，我们将在AIM 1中研究IRF-7转化啮齿动物细胞的机制。将确定IRF-7中的转换域。在AIM 2中，我们将研究IRF-7和LMP-1之间合作转化的机制。我们将检查LMP-1介导的IRF-7的核转运是否与合作转化有关。在AIM 3中，IRF-7在EBV转化过程中的作用将通过引入IRF-7的小干扰RNA或IRF-7转化为EBV转化细胞的主要负突变体。这项研究应提供有关IRF-7如何参与EBV转化的见解，并扩展我们对IRF的知识以及与EBV相关的CNS淋巴瘤的发病机理。