Role of PLZF in regulating the Interferon response

PLZF 在调节干扰素反应中的作用

• 批准号: nhmrc : 436814
• 负责人: Prof Bryan Williams
• 金额: $ 35.45万
• 依托单位: Monash University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/role-plzf-regulating-interferon-response/76303
• 关键词: Role; PLZF; regulating; Interferon; response

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.

干扰素（IFN）途径是脊椎动物对病原体的免疫防御所必需的。IFN保护和警告细胞关于病毒，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，这取决于细胞类型和环境。基于这些性质，IFN已在临床上用于对抗多种疾病，包括病毒感染、免疫调节病症和血液肿瘤和实体肿瘤，包括肾细胞癌。然而，决定IFN治疗结果的因素仍有待确定。我们已经确定了一个子集的干扰素刺激的基因，其持续表达被发现与肾细胞癌细胞系对干扰素的抗病毒敏感性提高。这些基因中的许多被发现有转录抑制因子前髓细胞锌指蛋白（PLZF）的结合位点。PLZF首先在急性早幼粒细胞白血病患者的亚群中被鉴定，并且参与雄性小鼠中红系干细胞和精原干细胞的维持。PLZF以前未涉及IFN应答。因此，我们研究了干扰素刺激基因的表达，并表明免疫相关基因的表达增加取决于PLZF表达。还发现PLZF与干扰素刺激基因的启动子中的结合位点直接相关，并且这需要组蛋白脱乙酰化。因此，我们发现了PLZF在增强IFN相关基因表达中的新功能。我们建议测试的假设，PLZF是IFN反应的一个重要组成部分。作为一个推论，我们也将测试是否PLZF表达可以连接到肾细胞癌的IFN反应。这些研究将确立PLZF在IFN应答中的作用，并确定其在治疗应用中预测IFN应答的效用。