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首页> 外文学位 >Role of IRF4 in the Regulation of Cellular Interferon Stimulated Genes and KSHV Lytic Gene Expression in Primary Effusion Lymphoma.
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Role of IRF4 in the Regulation of Cellular Interferon Stimulated Genes and KSHV Lytic Gene Expression in Primary Effusion Lymphoma.

机译：IRF4在原发性积液性淋巴瘤的细胞干扰素刺激基因和KSHV裂解基因表达调控中的作用。

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摘要

The interferon regulatory factors (IRF) are a family of transcription factors that control intrinsic cellular responses to viral infections. The regulation of target gene expression by IRF proteins is mediated by binding to interferon-stimulated response elements (ISRE) DNA motifs located in the 5' regulatory region of Interferon-stimulated genes (ISGs). Interferon regulatory factor 4 (IRF4), a hematopoietic-specific transcription factor, is a potential dual regulator of ISRE-mediated gene expression although its transcriptional signature is still poorly understood. Primary effusion lymphoma (PEL), a rare B-cell malignancy is characterized by the expression of high level of cellular IRF4, a disrupted B-cell transcriptional program, and latent infection with Kaposi's sarcoma-associated herpesvirus (KSHV). The goal of this study is to elucidate the ability of IRF4 to alter the transcriptional expression of ISRE and ISRE-like sequence regulated genes in the absence of B-cell specific binding partners. Small-scale gene expression assays showed that IRF4 is capable of differentially regulating the expression of ISRE-responsive genes. The positive regulation of IRF4 target genes (ISG60 and Cig5) was shown to be in response to direct binding of IRF4 to chromatin regions corresponding to ISRE-motifs located at the 5' promoter regulator regions of ISG60 and Cig5. To understand the role of IRF4 beyond cellular gene expression, we tested KSHV-encoded latency associated genes that modulated IRF4-mediated gene expression. We identified the viral FLICE inhibitory protein (vFLIP) as an enhancer of IRF4-mediated ISG induction and showed that this function is dependent on the activation of NF-ƒUB. Finally, we examined the role of IRF4 in the regulation of lytic gene expression. The replicator and transcription activator (RTA) protein, is a sequence specific transcription factor that regulates the expression of a subset of early genes through binding ISRE-like motifs on their promoters. Studies aimed at understanding the consequences of IRF4 expression in PEL cells showed that IRF4 acts as a negative regulator of lytic gene expression by inhibiting RTA expression and RTA-mediated gene transactivation. These data support a model in which IRF4 mediates an antiviral cellular response, inhibiting lytic replication of KSHV while contributing to the transformative effects of KSHV by promoting viral latency.
机译：干扰素调节因子（IRF）是一类转录因子，可控制细胞对病毒感染的内在反应。 IRF蛋白对靶基因表达的调节是通过与位于干扰素刺激基因（ISGs）5'调控区的干扰素刺激响应元件（ISRE）DNA基序结合而介导的。干扰素调节因子4（IRF4），一种造血特异性转录因子，是ISRE介导的基因表达的潜在双重调节因子，尽管其转录特征仍知之甚少。原发性渗出性淋巴瘤（PEL）是一种罕见的B细胞恶性肿瘤，其特征在于高水平的细胞IRF4表达，B细胞转录程序被破坏以及卡波西氏肉瘤相关疱疹病毒（KSHV）的潜在感染。这项研究的目的是阐明在没有B细胞特异性结合伴侣的情况下IRF4改变ISRE和ISRE样序列调控基因的转录表达的能力。小型基因表达分析表明，IRF4能够差异调节ISRE反应基因的表达。 IRF4靶基因（ISG60和Cig5）的正向调节被证明是对IRF4与对应于位于ISG60和Cig5的5'启动子调节子区域的ISRE基序的染色质区域的直接结合作出反应。为了了解IRF4在细胞基因表达之外的作用，我们测试了KSHV编码的潜伏期相关基因，该基因调节IRF4介导的基因表达。我们确定病毒FLICE抑制蛋白（vFLIP）是IRF4介导的ISG诱导的增强子，并表明该功能取决于NF-ƒUB的激活。最后，我们研究了IRF4在裂解基因表达调控中的作用。复制子和转录激活因子（RTA）蛋白是一种序列特异性转录因子，可通过在其启动子上结合ISRE样基序来调节早期基因子集的表达。旨在了解IRF4在PEL细胞中表达的后果的研究表明，IRF4通过抑制RTA表达和RTA介导的基因反式激活而充当裂解基因表达的负调节剂。这些数据支持IRF4介导抗病毒细胞应答，抑制KSHV的裂解复制，同时通过促进病毒潜伏期促进KSHV的转化作用的模型。

著录项

  • 作者

    Rueda, Adriana Forero.;

  • 作者单位

    University of Pittsburgh.;

  • 授予单位 University of Pittsburgh.;
  • 学科 Biology Virology.;Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 212 p.
  • 总页数 212
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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