School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, United States of America.
PLoS One. 2010 Mar 4;5(3):e9459. doi: 10.1371/journal.pone.0009459.
Epstein-Barr virus (EBV) infection is associated with several human malignancies. Interferon (IFN) regulatory factor 7 (IRF-7) has several splicing variants, and at least the major splicing variant (IRF-7A) has oncogenic potential and is associated with EBV transformation processes. IRF-7C is an alternative splicing variant with only the DNA-binding domain of IRF-7. Whether IRF-7C is present under physiological conditions and its functions in viral transformation are unknown. In this report, we prove the existence of IRF-7C protein and RNA in certain cells under physiological conditions, and find that high levels of IRF-7C are associated with EBV transformation of human primary B cells in vitro as well as EBV type III latency. EBV latent membrane protein 1 (LMP-1) stimulates IRF-7C expression in B lymphocytes. IRF-7C has oncogenic potential in rodent cells and partially restores the growth properties of EBV-transformed cells under a growth-inhibition condition. A tumor array experiment has identified six primary tumor specimens with high levels of IRF-7C protein--all of them are lymphomas. Furthermore, we show that the expression of IRF-7C is apparently closely associated with other IRF-7 splicing variants. IRF-7C inhibits the function of IRF-7 in transcriptional regulation of IFN genes. These data suggest that EBV may use splicing variants of IRF-7 for its transformation process in two strategies: to use oncogenic properties of various IRF-7 splicing variants, but use one of its splicing variants (IRF-7C) to block the IFN-induction function of IRF-7 that is detrimental for viral transformation. The work provides a novel relation of host/virus interactions, and has expanded our knowledge about IRFs in EBV transformation.
EB 病毒（EBV）感染与几种人类恶性肿瘤有关。干扰素（IFN）调节因子 7（IRF-7）有几种剪接变异体，至少主要剪接变异体（IRF-7A）具有致癌潜能，并与 EBV 转化过程有关。IRF-7C 是一种具有 IRF-7 DNA 结合结构域的替代剪接变异体。在生理条件下是否存在 IRF-7C 及其在病毒转化中的功能尚不清楚。在本报告中，我们证明了在生理条件下某些细胞中存在 IRF-7C 蛋白和 RNA，并且发现高水平的 IRF-7C 与 EBV 在体外转化人原代 B 细胞以及 EBV Ⅲ型潜伏有关。EBV 潜伏膜蛋白 1（LMP-1）刺激 B 淋巴细胞中 IRF-7C 的表达。IRF-7C 在啮齿动物细胞中具有致癌潜能，并在生长抑制条件下部分恢复 EBV 转化细胞的生长特性。肿瘤阵列实验鉴定了六种具有高水平 IRF-7C 蛋白的原发性肿瘤标本 - 它们都是淋巴瘤。此外，我们表明 IRF-7C 的表达显然与其他 IRF-7 剪接变异体密切相关。IRF-7C 抑制 IFN 基因转录调节中 IRF-7 的功能。这些数据表明，EBV 可能使用 IRF-7 的剪接变异体来实现其转化过程的两种策略：利用各种 IRF-7 剪接变异体的致癌特性，但使用其剪接变异体之一（IRF-7C）来阻断 IFN 诱导的对病毒转化有害的 IRF-7 功能。该工作提供了宿主/病毒相互作用的新关系，并扩展了我们对 EBV 转化中 IRFs 的认识。
