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LIMD1 Is a Novel Marker Associated with IRF4 in EBV Latency and Lymphoma

LIMD1 是 EBV 潜伏期和淋巴瘤中与 IRF4 相关的新型标记物

基本信息

批准号：
9409873
负责人：
Shunbin Ning
金额：
$ 44.4万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9409873
关键词：
AIDS related cancer AIDS-Related Lymphoma Acquired Immunodeficiency Syndrome Adaptor Signaling Protein B-Lymphocytes Binding Binding Sites Biological Assay Biomedical Research CRISPR/Cas technology Carcinoma Cell Culture Techniques Cell Line Cells Cessation of life Chromosomes Clinical Consensus Data EBV-associated malignancy Elements Epithelial Epstein-Barr Virus latency Experimental Designs Gene Expression Profiling Gene Expression Regulation Genes Genetic Transcription Goals Hematologic Neoplasms Human Human Herpesvirus 4 IRF4 gene Immunoblotting Immunoprecipitation In Vitro LIM Domain LMP1 Link Lymphocyte Lymphoma Malignant Neoplasms Malignant lymphoid neoplasm Mediating Membrane Proteins Molecular Molecular Biology Molecular Profiling Multiple Myeloma Myeloproliferative disease Oncogenic Problem Solving Prognostic Marker Proteins Regulation Reporter Resources Role Series Signal Transduction Small Interfering RNA TRAF6 gene Techniques Testing Therapeutic Intervention Thinking Time Training Transcription Factor AP-1 Transcriptional Regulation Virus Writing antiretroviral therapy cancer type carcinogenesis cell transformation clinical practice diagnostic biomarker infected B cell inhibitor/antagonist interest knock-down knockout gene large cell Diffuse non-Hodgkin&apos s lymphoma latent infection leukemia/lymphoma molecular marker molecular targeted therapies novel novel marker overexpression promoter student training therapeutic target training opportunity transcription factor translational approach tumor tumorigenesis undergraduate student

项目摘要

Project Summary LIMD1 (LIM domain-containing protein 1) is deregulated in many cancers including hematological malignancies (lymphomas, leukemias, and myelomas). However, very little is known on the underlying mechanisms of its deregulation and its roles in carcinogenesis remain unclear. Epstein-Barr Virus (EBV) was the first identified human cancer virus and is now known to be associated with a large range of malignancies of lymphocytic and epithelial origin. Using high throughput expression profiling, we have identified LIMD1 as a common marker, which is associated with IRF4 in EBV-associated lymphomas and other hematological malignancies. We have confirmed this finding by immunoblotting in a panle of EBV-infected B cell lines. Further, we have identified potential conserved IRF4- and NFκB-binding motifs in the LIMD1 gene promoter. This project focuses on the transcriptional regulation of LIMD1 by IRF4 and NFκB, both activated downstream of EBV LMP1 (latent membrane protein 1) signaling, in EBV latency, and the potential contribution of LIMD1 to the EBV transformation. Our hypothesis is that IRF4 and NFκB bind to the potential binding motifs in the LIMD1 gene promoter and transcriptionally regulate LIMD1 expression in EBV-transformed cells and that LIMD1 is critical for LMP1 signaling transduction and oncogenesis. We propose to study: (1) Define the roles of IRF4 and NFκB in transcriptional regulation of LIMD1 in EBV+ cells, (2) Determine the role and mechanism of LIMD1 in LMP1 signaling transduction; (3) Determine the requirement of LIMD1 for EBV transformation; and (4) Investigate the correlation between LIMD1 and IRF4/NFκB in EBV-associated tumors. Findings from this study will identify LIMD1 as a novel molecular marker and a critical player in EBV-associated malignancies, and may identify LIMD1 as a potential therapeutic target for these malignancies.

项目概要 LIMD1（含 LIM 结构域的蛋白 1）在许多癌症中失调，包括血液学癌症恶性肿瘤（淋巴瘤、白血病和骨髓瘤）。然而，人们对其底层知之甚少其放松管制的机制及其在致癌作用中的作用仍不清楚。 EB病毒（EBV）是首次发现人类癌症病毒，现在已知与多种恶性肿瘤有关淋巴细胞和上皮起源。使用高通量表达谱分析，我们已将 LIMD1 确定为常见标志物，与 EBV 相关淋巴瘤和其他血液病中的 IRF4 相关恶性肿瘤。我们通过对一组 EBV 感染的 B 细胞系进行免疫印迹证实了这一发现。更远，我们在 LIMD1 基因启动子中发现了潜在的保守 IRF4 和 NFκB 结合基序。这个项目专注于 IRF4 和 NFκB 对 LIMD1 的转录调节，两者均在 EBV LMP1 下游激活 EBV 潜伏期中的（潜伏膜蛋白 1）信号传导，以及 LIMD1 对 EBV 的潜在贡献转变。我们的假设是 IRF4 和 NFκB 与 LIMD1 基因中的潜在结合基序结合启动子并转录调节 EBV 转化细胞中 LIMD1 的表达，并且 LIMD1 对于 LMP1 信号转导和肿瘤发生。我们建议研究：（1）定义IRF4和NFκB在 EBV+细胞中LIMD1的转录调控，（2）确定LIMD1在LMP1中的作用和机制信号转导； (3)确定LIMD1对EBV转化的要求； (4) 调查 EBV 相关肿瘤中 LIMD1 和 IRF4/NFκB 之间的相关性。这项研究的结果将确定 LIMD1 作为一种新型分子标记物，在 EBV 相关恶性肿瘤中发挥着关键作用，并且可以识别 LIMD1 作为这些恶性肿瘤的潜在治疗靶点。