Regulation of Cytokine Signaling by PIAS Protein

描述：细胞因子在调节细胞生长、分化、免疫和炎症反应中发挥重要作用。细胞因子可以激活多条信号转导通路来调节基因表达。STATS和NF-kB是由细胞因子激活的两个重要的转录因子家族。STAT和NF-kB活性的异常调节与人类疾病有关。我的实验室的长期目标是研究细胞因子触发的基因激活途径的调节。我们已经鉴定并鉴定了一个名为PIAS(Protein Inhibitor Of Actiated STATS)的蛋白质家族，它可以调节STATs对多种细胞因子的转录活性。最近，我们发现PIAS也参与了对NF-kB活性的调节。这项研究提案的总体目标是利用生化和遗传学方法研究PIAS蛋白家族对细胞因子触发的基因激活途径的调节。首先，我们将研究PIAS蛋白家族的调控。具体地说，我们将使用质谱分析和突变研究来鉴定和表征细胞因子诱导的PIAS1修饰。PIAS1修饰在细胞因子信号调节中的生物学作用将在不同的水平上进行检测。其次，我们将通过对PIAS相关蛋白的鉴定和鉴定来研究PIAS介导的基因调控机制。我们将通过生化和突变研究来研究PIAS SAP结构域在PIAS介导的基因调控中的功能作用。第三，我们将继续研究PIAS1在细胞因子信号转导中的体内作用。PIAS在细胞因子信号传递中的特异性和冗余性将通过遗传学方法进行检验。将建立突变的PIAS1敲门小鼠模型，以检测PIAS1相扑连接酶活性在细胞因子信号转导中的生理作用。这些研究将为理解细胞因子触发的基因激活途径提供重要信息，并将提高我们利用细胞因子设计合理治疗策略的能力。

Description: Cytokines play important roles in the regulation of cell growth, differentiation, immune and inflammatory responses. Cytokines can activate multiple signal transduction pathways to regulate gene expression. STATs and NF-kB are two important families of transcription factors that are activated by cytokines. Abnormal regulation of STAT and NF-kB activities has been associated with human diseases. The long-term goal of my laboratory is to study the regulation of cytokine-triggered gene activation pathways. We have identified and characterized a family of proteins named PIAS (protein inhibitor of activated STATs), which can regulate the transcriptional activity of STATs in response to a variety of cytokines. Most recently, we found that PIAS is also involved in the regulation of NF-kB activity. The overall goal of this research proposal is to study the regulation of cytokine-triggered gene activation pathways by the PIAS family of proteins using biochemical and genetic approaches. First, we will study the regulation of the PIAS protein family. Specifically, we will identify and characterize cytokine-induced PIAS1 modification using mass spectrometry analysis and mutational studies. The biological role of PIAS1 modification in the regulation of cytokine signaling will be examined at various levels. Second, we will study the mechanism of PIAS-mediated gene regulation through the identification and characterization of PIAS-associated proteins. We will examine the functional role of the PIAS SAP domain in PIAS-mediated gene regulation using biochemical and mutational studies. Third, we will continue characterizing the in vivo role of PIAS1 in cytokine signaling. The specificity and redundancy of PIAS in cytokine signaling will be examined by genetic approaches. A mutant PIAS1 knockin mouse model will be generated to examine the physiological role of PIAS1 SUMO ligase activity in cytokine signaling. These studies will provide important information on the understanding of the cytokine-triggered gene activation pathways and will enhance our ability to design rational therapeutic strategies employing cytokines.