Temporal regulation of the essential Epstein-Barr virus oncoprotein LMP1

EB 病毒必需癌蛋白 LMP1 的时间调控

基本信息

批准号：
8594953
负责人：
Alexander Matthew Price
金额：
$ 3.25万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8594953
关键词：
3&apos Untranslated Regions Address Adult Apoptosis Attenuated B-Lymphocytes Binding Binding Sites Biological Assay Blast Cell Cancer Etiology Cell Line Cell Survival Cells Cytotoxic T-Lymphocytes Data EBV-associated malignancy Early Promoters Electrophoretic Mobility Shift Assay Ensure Epstein-Barr Virus Infections Epstein-Barr Virus latency Epstein-Barr pathogenesis Event Excision Family Gene Targeting Genes Genetic Genetic Transcription Genome Goals Growth HIV Infections Half-Life Herpesviridae Homologous Gene Human Human Herpesvirus 4 Immune Immune response Immunosuppression In Vitro Individual Infection Integration Host Factors Knowledge LMP1 Luciferases Malignant Neoplasms Mediating Membrane Proteins Messenger RNA MicroRNAs Modeling Molecular Mutate Nuclear Antigens Oncogene Proteins Oncogenic Organ Transplantation Pathogenesis Phenotype Population Porifera Proliferating Proteins Publishing Regulation Research Role Seeds Signal Pathway Signal Transduction Signaling Protein TNFRSF5 gene Technology Testing Therapeutic Therapeutic Intervention Time Trans-Activators Transcript Tumor Necrosis Factor Receptor Up-Regulation Viral Viral Genes Virus Virus Latency Work base c-myc Genes cell growth cell transformation infected B cell lymphoblastoid cell line mRNA Stability novel outcome forecast promoter proto-oncogene protein Spi-1 public health relevance research study transcription factor virus host interaction

项目摘要

DESCRIPTION (provided by applicant): Epstein-Barr virus has long been known to induce NFkB signaling through its latency associated membrane protein, LMP1. Recently our lab has challenged the dogma that NFkB signaling is constitutive at all times throughout infection by demonstrating that LMP1 protein and signaling do not accumulate to meaningful levels until around two weeks after infection. Transcriptional profiling of both EBV-infected cell lines and EBV-infected B blasts early after infection has revealed that transcription of the LMP1 gene increases 15-fold, the mRNA half-life increases 2-fold, and the total mRNA increases 50-fold compared to early times after infection. The LMP1 promoter is controlled by viral genes such as Epstein-Barr Nuclear Antigen (EBNA) 2 as well as EBNA-3C and the host transcription factor PU.1, ATF4, and IRF7. Since the transcriptional activity of PU.1, ATF4, and IRF7 is repressed early after infection, it is possible that these or other trans-acting factors are not present to transcriptionally activate LMP1 to high levels early after infection. To address the change in LMP1 mRNA stability, published work has demonstrated that a Myc-induced miRNA, miR17, has a negative effect on LMP1 expression in EBV-infected lymphoblastoid cell lines. Furthermore, miR17 is expressed at higher levels early after infection when LMP1 is expressed poorly. To investigate these hypotheses I propose to study the transformation of B cells by EBV in the absence of negative regulation by miR17 as well as further characterize the promoter activity of LMP1 early after infection. The goal of this project is to characterize how EBV dynamically controls the expression of its own transcripts using host factors and how temporal regulation of LMP1 effects B cell transformation.

描述（由申请人提供）：长期以来，已知Epstein-Barr病毒通过其潜伏期相关的膜蛋白LMP1诱导NFKB信号传导。最近，我们的实验室挑战了教条，即NFKB信号在整个感染过程中始终是构成性的，它证明了直到感染后两周左右，LMP1蛋白和信号直到有意义的水平才积累到有意义的水平。感染后早期的EBV感染细胞系和EBV感染的B爆炸的转录分析表明，LMP1基因的转录增加了15倍，mRNA半寿命增加了2倍，总mRNA增加了50倍。感染后的早期。 LMP1启动子由病毒基因控制，例如Epstein-Barr核抗原（EBNA）2以及EBNA-3C和宿主转录因子PU.1，ATF4和IRF7。由于PU.1，ATF4和IRF7的转录活性在感染后尽早抑制，因此这些或其他反式作用因子可能不存在转录在感染后早期将LMP1激活至高水平。为了解决LMP1 mRNA稳定性的变化，已发表的工作表明，MYC诱导的miRNA MiRNA，对EBV感染的淋巴细胞细胞系中的LMP1表达有负面影响。此外，当LMP1表达较差时，MIR17在感染后早期在较高水平上表达。为了研究这些假设，我建议在没有MiR17负面调控的情况下研究EBV对B细胞的转化，并进一步表征感染后早期LMP1的启动子活性。该项目的目的是表征EBV如何使用宿主因子动态控制其自己的成绩单的表达，以及LMP1的时间调节如何影响B细胞转换。