Regulation of Cytokine Signaling by PIAS Protein

PIAS 蛋白对细胞因子信号传导的调节

• 批准号: 6775761
• 负责人: KE SHUAI
• 金额: $ 30.68万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6775761
• 关键词: JAK kinase; biological signal transduction; cytokine; enzyme activity; enzyme inhibitors; gel mobility shift assay; gene expression; genetic regulation; genetically modified animals; immunoprecipitation; interleukin 6; laboratory mouse; mass spectrometry; nuclear factor kappa beta; posttranslational modifications; protein binding; protein structure function; protein tyrosine kinase; western blottings

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.

描述：细胞因子在细胞生长、分化、免疫和炎症反应的调节中起重要作用。细胞因子可以激活多种信号转导途径来调节基因表达。 STAT和NF-κ B是两个重要的转录因子家族，它们被细胞因子激活。STAT和NF-kB活性的异常调节与人类疾病有关。我实验室的长期目标是研究尼古丁触发的基因激活途径的调节。我们已经鉴定并表征了一个名为皮亚斯（活化STAT的蛋白抑制剂）的蛋白质家族，其可以调节STAT响应于多种细胞因子的转录活性。最近，我们发现皮亚斯也参与了NF-κ B活性的调节。本研究计划的总体目标是使用生物化学和遗传学方法研究皮亚斯蛋白家族对精氨酸触发的基因激活途径的调节。首先，我们将研究皮亚斯蛋白家族的调节。具体来说，我们将确定和表征的干扰素诱导PIAS 1修改使用质谱分析和突变研究。PIAS 1修饰在细胞因子信号传导调节中的生物学作用将在不同水平上进行检查。其次，我们将通过鉴定和表征PIAS相关蛋白来研究PIAS介导的基因调控机制。我们将通过生物化学和突变研究来研究皮亚斯SAP结构域在PIAS介导的基因调控中的功能作用。第三，我们将继续表征PIAS 1在细胞因子信号传导中的体内作用。皮亚斯在细胞因子信号传导中的特异性和冗余性将通过遗传方法进行检查。将产生突变体PIAS 1敲入小鼠模型以检查PIAS 1 SUMO连接酶活性在细胞因子信号传导中的生理作用。这些研究将提供重要的信息，对了解尼古丁触发的基因激活途径，并将提高我们的能力，设计合理的治疗策略，采用细胞因子。