Role of PLZF in regulating the Interferon response

干扰素途径在脊椎动物对病原体的免疫防御中是必不可少的。根据细胞类型和环境的不同，IFN既可以保护细胞，也可以提醒细胞注意病毒、细菌和其他免疫攻击，并促进细胞抗病毒状态、减少增殖或诱导细胞凋亡。基于这些特性，干扰素已被用于临床治疗各种疾病，包括病毒感染、免疫调节疾病以及包括肾癌在内的血液和实体肿瘤。然而，决定干扰素治疗结果的因素仍有待确定。我们已经确定了干扰素刺激基因的一个子集，其持续表达被发现与肾细胞癌细胞株对干扰素的抗病毒敏感性增强相关。其中许多基因被发现具有转录抑制因子原肌细胞锌指蛋白(PLZF)的结合位点。PLZF首先在急性早幼粒细胞白血病患者的一个亚群中被发现，并参与维持雄性小鼠的红系干细胞和精原干细胞。PLZF此前并未与干扰素反应有关。因此，我们研究了干扰素刺激基因的表达，发现免疫相关基因的表达增加依赖于PLZF的表达。PLZF还被发现与干扰素刺激基因的启动子中的结合部位直接相关，这需要组蛋白去乙酰化。因此，我们发现了PLZF在增强干扰素相关基因表达方面的新功能。我们建议检验这一假设，即PLZF是干扰素反应的重要组成部分。作为推论，我们还将测试PLZF的表达是否与肾癌的干扰素应答有关。这些研究将确定PLZF在干扰素应答中的作用，并确定其在预测治疗应用中干扰素应答的有效性。

The Interferon (IFN) pathway is essential for immune defense against pathogens in vertebrates. IFNs both protect and alert cells about viral, bacterial, and other immune assaults and promote a cellular antiviral state, reduce proliferation, or induce apoptosis depending on the cell type and environment. Based on these properties, IFNs have been used clinically against a variety of diseases including viral infections, immunomodulatory disorders and hematologic and solid tumors including renal cell carcinoma. However, the factors determining outcome of IFN treatment, remain to be determined. We have identified a subset of interferon stimulated genes whose sustained expression was found to correlate with heightened antiviral sensitivity of renal cell carcinoma cell lines to IFN. Many of these genes were found to have binding sites for the transcriptional repressor promyleocytic zinc finger protein (PLZF). PLZF was first identified in a subset of Acute Promyelocytic Leukemia patients and is involved in maintenance of erythroid lineage stem cells and spermatogonial stem cells in male mice. PLZF has not previously been implicated in the IFN response. Accordingly, we investigated the expression of interferon stimulated genes and showed that increased expression of immune related genes depends on PLZF expression. PLZF was also found to directly associate with binding sites in promoters of interferon stimulated genes and that this requires histone deacetylation. Thus, we uncovered a novel function for PLZF in enhancement of IFN associated gene expression. We propose to test the hypothesis that PLZF is an essential component of the IFN response. As a corollary, we will also test whether PLZF expression can be linked to IFN responsiveness in renal cell carcinoma. These studies will establish the role of PLZF in the IFN response and define its utility in predicting IFN responsiveness in therapeutic applications.