Oncogenic properties of interferon regulatory factor 7

描述（由申请人提供）：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，特别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，EBV潜伏膜蛋白1 （LMP-1）是这一过程所必需的。LMP-1诱导IRF-7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，人们对IRF-7在ebv相关疾病发病机制中的作用知之甚少。我们的数据表明，IRF-7的表达和激活与EBV在体外的转化过程有关，并且IRF-7在EBV相关的人中枢神经系统淋巴瘤（CNS淋巴瘤）中高表达和激活。IRF-7本身具有致癌潜能，但它也与LMP-1在转化啮齿动物细胞中具有协同作用。此外，在低血清条件下，ebv转化的stat -1缺失的B细胞中IRF-7的减少减少了活细胞的数量。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。在这项工作中，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协同转化的机制。我们将研究lmp -1介导的IRF-7核易位是否与协同转化有关。在Aim 3中，IRF-7在EBV转化过程中的作用将通过将IRF-7的小干扰RNA或显性阴性突变体引入EBV转化细胞来确定。本研究旨在揭示IRF-7如何参与EBV转化，并扩大我们对irf以及EBV相关中枢淋巴瘤发病机制的认识。

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.