Epstein-Barr virus latent membrane protein 1 induces cellular MicroRNA miR-146a, a modulator of lymphocyte signaling pathways
Epstein-Barr virus latent membrane protein 1 induces cellular MicroRNA miR-146a, a modulator of lymphocyte signaling pathways
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DOI：
10.1128/jvi.02136-07
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发表时间：
2008-02-01
影响因子：
5.4
通讯作者：
Flemington, Erik K.
中科院分区：
文献类型：
--
作者：
Cameron, Jennifer E.;Yin, Qinyan;Flemington, Erik K.
EB病毒（EBV）编码的潜伏膜蛋白1（LMP 1）是肿瘤坏死因子受体家族的功能同源物，并通过激活核因子κ B（NF-κ B）而显著促进EBV的致癌潜力。MicroRNA（miRNAs）是一类参与细胞过程（如生长、发育和凋亡）调节的小RNA分子，并且最近已与癌症表型相关联。通过miRNA微阵列分析，我们证明了LMP 1失调了几种细胞miRNA的表达，包括其中最高度调节的miR-146 a。定量逆转录-PCR分析证实了LMP 1诱导的miR-146 a表达。对EBV潜伏期III型和I型细胞系中的miR-146 a表达的分析揭示了miR-146 a在III型（其表达LMP 1）中而不是在I型细胞系中的大量表达。报道基因研究表明，LMP 1主要通过miR-146 a启动子中的两个NF-κ B结合位点诱导miR-146 a，并鉴定了Oct-1位点在赋予基础表达和诱导表达中的作用。对用表达miR-146 a的逆转录病毒转导的Akata细胞中表达的细胞mRNA进行阵列分析，鉴定出受miR-146 a直接或间接调控的基因，包括一组受miR-146 a抑制的干扰素应答基因。由于已知miR-146 a由激活干扰素应答途径的试剂（包括LMP 1）诱导，因此这些结果表明miR-146 a在负反馈环中起作用以调节干扰素应答的强度和/或持续时间。
The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is a functional homologue of the tumor necrosis factor receptor family and contributes substantially to the oncogenic potential of EBV through activation of nuclear factor kappa B (NF-kappa B). MicroRNAs (miRNAs) are a class of small RNA molecules that are involved in the regulation of cellular processes such as growth, development, and apoptosis and have recently been linked to cancer phenotypes. Through miRNA microarray analysis, we demonstrate that LMP1 dysregulates the expression of several cellular miRNAs, including the most highly regulated of these, miR-146a. Quantitative reverse transcription-PCR analysis confirmed induced expression of miR-146a by LMP1. Analysis of miR-146a expression in EBV latency type III and type I cell lines revealed substantial expression of miR-146a in type III (which express LMP1) but not in type I cell lines. Reporter studies demonstrated that LMP1 induces miR-146a predominantly through two NF-kappa B binding sites in the miR-146a promoter and identified a role for an Oct-1 site in conferring basal and induced expression. Array analysis of cellular mRNAs expressed in Akata cells transduced with an miR-146a-expres sing retrovirus identified genes that are directly or indirectly regulated by miR-146a, including a group of interferon-responsive genes that are inhibited by miR-146a. Since miR-146a is known to be induced by agents that activate the interferon response pathway (including LMP1), these results suggest that miR-146a functions in a negative feedback loop to modulate the intensity and/or duration of the interferon response.