Interferon regulatory factor 7 (IRF-7) is implicated in the regulation of Epstein-Barr virus (EBV) latency. EBV infection is a leading cause of lymphomas especially in immunocompromised individuals and has been associated with nasopharyngeal carcinoma (NPC) and gastric carcinoma. EBV transforms primary B cells in vitro and EBV latent membrane protein 1 (LMP-1) is required for the process. LMP-1 induces the expression of IRF-7 and activates IRF-7 protein by phosphorylation and nuclear translocation. Activated IRF-7 then exerts its effect on target genes. However, little is known about the role of IRF-7 in the pathogenesis of EBV-associated diseases. Our data suggests that both expression and activation of IRF-7 are associated with EBV transformation process in vitro, and IRF-7 is highly expressed and activated in EBV-associated human central nervous system lymphoma (CNS lymphoma) in vivo. IRF-7 by itself has oncogenic potential, but it also has a cooperative effect with LMP-1 in transforming rodent cells. Furthermore, reduction of IRF-7 in EBV-transformed STAT-1-null B cells reduced the number of live cells at low serum conditions. Therefore, we hypothesize that IRF-7 may be a factor in EBV-mediated transformation process. In the proposed work, we will study in Aim 1 the mechanism of IRF-7 to transform rodent cells. Transformation domain(s) in IRF-7 will be determined.
In Aim 2, we will study the mechanism of cooperative transformation between IRF-7 and LMP-1. We will examine if LMP-1-mediated nuclear translocation of IRF-7 is related to the cooperative transformation.
In Aim 3, the role of IRF-7 in EBV transformation process will be determined by introducing small interfering RNA of IRF-7 or dominant negative mutant for IRF-7 transformation into EBV-transformed cells. This study should provide an insight of how IRF-7 participates in EBV transformation, and expand our knowledge about IRFs as well as the pathogenesis of EBV-associated CNS lymphoma.
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