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

项目摘要 LIMD1(LIM结构域包含蛋白1)在包括血液病在内的许多癌症中被解除调控 恶性肿瘤(淋巴瘤、白血病和骨髓瘤)。然而，人们对其潜在原因知之甚少 其放松调控的机制及其在癌症发生中的作用尚不清楚。爱泼斯坦-巴尔病毒(EBV)是 最早发现人类癌症病毒，现在已知与多种恶性肿瘤有关 淋巴细胞性和上皮来源。使用高通量表达谱，我们已经确定LIMD1是一种 EBV相关淋巴瘤和其他血液病中与IRF4相关的共同标记物 恶性肿瘤。我们已经通过在一组EBV感染的B细胞系中进行免疫印迹证实了这一发现。此外， 我们已经在κ基因启动子中发现了潜在的保守的IRF4和NFIMD1B结合基序。这个项目 重点研究了EB病毒LMP1下游激活的IRF4和NFκB对LIMD1mRNA的转录调控 (潜伏膜蛋白1)信号，在EBV潜伏期，以及LIMD1对EBV的潜在贡献 转型。我们的假设是IRF4和NFLIMD1B与κ基因中潜在的结合基序结合 启动子和转录调控LIMD1在EBV转化细胞中表达 LMP1信号转导与肿瘤发生我们建议研究：(1)确定IRF4和NFκB在 LIMD1在EBV+细胞中的转录调控，(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)研究LIMD1对EBV转化的影响。 EB病毒相关肿瘤中LIMD1I和IRF4/NFκB表达的相关性这项研究的发现将确定 LIMD1作为一种新的分子标志物和EBV相关恶性肿瘤的关键角色，并可能识别 LIMD1作为治疗这些恶性肿瘤的潜在靶点。

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.