Oncogenic properties of interferon regulatory factor 7

干扰素调节因子 7 的致癌特性

• 批准号: 7844530
• 负责人: LUWEN ZHANG
• 金额: $ 2.57万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7844530
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Apoptosis; B-Lymphocytes; Cell Nucleus; Cells; Central Nervous System Lymphoma; 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; Lymphoma; Malignant Neoplasms; Mediating; Membrane Proteins; Nasopharynx Carcinoma; Nuclear; Nuclear Translocation; Oncogenic; Patients; Phosphorylation; Play; Process; Property; RNA Splicing; Regulation; Research Personnel; Rodent; Role; Serum; Small Interfering RNA; Stomach Carcinoma; Tumor Suppressor Genes; Tumor Suppressor Proteins; Variant; Viral Pathogenesis; Work; antigenic peptide transporter; cell transformation; in vivo; insight; interferon regulatory factor-7; neoplastic cell; overexpression; promoter; transcription factor; viral interferon regulatory factor

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（由申请方提供）：干扰素调节因子7（IRF-7）参与EB病毒（EBV）潜伏期的调节。 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）和胃癌相关。 EBV在体外转化原代B细胞，该过程需要EBV潜伏膜蛋白1（LMP-1）。 LMP-1诱导IRF-7的表达，并通过磷酸化和核转位激活IRF-7蛋白。 激活的IRF-7然后对靶基因发挥作用。 然而，关于IRF-7在EBV相关疾病的发病机制中的作用知之甚少。 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，并且IRF-7在体内EBV相关的人中枢神经系统淋巴瘤（CNS淋巴瘤）中高度表达和激活。IRF-7本身具有致癌潜力，但它在转化啮齿动物细胞中也与LMP-1具有协同作用。 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的活细胞数量。 因此，我们推测IRF-7可能是EBV介导的转化过程中的一个因子。 在本研究中，我们将在目的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。 目的二是研究IRF-7与LMP-1之间的协同转化机制。 我们将研究LMP-1介导的IRF-7核转位是否与协同转化有关。 在目的3中，通过将IRF-7的小干扰RNA或IRF-7转化的显性阴性突变体引入EBV转化细胞中来确定IRF-7在EBV转化过程中的作用。 这项研究将提供一个深入了解IRF-7如何参与EBV转化，并扩大我们的知识IRF以及EBV相关的中枢神经系统淋巴瘤的发病机制。