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

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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.