IFNAR1 signaling through STAT3, PI-3 kinase and NFkB

通过 STAT3、PI-3 激酶和 NFkB 的 IFNAR1 信号传导

• 批准号: 6837165
• 负责人: LAWRENCE MARC PFEFFER
• 金额: $ 30.33万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-02 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6837165
• 关键词: IFNAR1; signaling; through; STAT3; PI

EXCEED THE SPACE PROVIDED. Understanding the molecular basis of interferon-alpha (IFN_) action is an important goal when one considers IFN's therapeutic potential in cancer, viral hepatitis, and multiple sclerosis, as well as its role as a model for understanding cytokine signal transduction. IFNot elicits its biological actions by regulating gene expression through the tyrosine phosphorylation and activation of members of the STAT (signal transducers and activators of transcription) protein family. The applicant found that STAT3, a transcription factor for acute phase response genes, is a critical element in IFN signaling and induction of IFN's biological actions. In addition, it was also found that IFN promotes cell survival by activating NF-KB (nuclear factor-v_B) through a serine kinase-dependent pathway involving PI-3K (phosphatidylinositol-3' kinase) and Akt, as well as STAT3. Based on these findings, the general hypothesis to be tested is that the IFN_x receptor integrates signaling pathways involving STAT3, PI-3K and NF-vJ3. In Specific Aim 1, the role of STAT3 as a transcription factor and an adapter protein for PI-3K will be defined. The proposed studies will determine which specific amino acid residues in STAT3 undergo IFN-dependent phosphorylation, the relationship of these phosphorylation events to the biologic actions of IFN, and which IFN-responsive genes are STAT3- regulated. In Specific Aim 2, the role of NF-vJ3 in IFNa action will be defined. The proposed studies will define the relationship between PI-3K/Akt-mediated phosphorylation events and the anti-apoptotic action of IFN, the roles of TRAFs (TNF receptor-associated factors) and NIK (NF-vJ3-inducing kinase) in IFN- induced NF-rJ3 activation, the role of NF-vJ3 in gene induction by IFN, and the role of the Iv33 kinase complex in IFN promoted NF-KB activation and cell survival. Despite advances made on the IFN_x signaling pathway, the mechanisms that underlie the induction of the different biological actions of IFN_x remain poorly understood. This proposal focuses on characterizing the molecular basis of signaling pathways as they relate to 1FN action on cell proliferation and survival. PERFORMANCE SITE ========================================Section End===========================================

超过提供的空间。当人们认为IFN在癌症中的治疗潜力，病毒性肝炎和多发性硬化症及其作为理解细胞因子信号传递的模型时，了解干扰素-α（IFN_）作用的分子基础是一个重要目标。 IFNOT通过通过酪氨酸磷酸化和STAT（转录信号换能器和转录的激活剂）蛋白家族的激活来调节基因表达来引起其生物学作用。申请人发现，STAT3是急性相响应基因的转录因子，是IFN信号传导和IFN生物学作用诱导的关键要素。此外，还发现，IFN通过丝氨酸激酶依赖性途径激活NF-KB（核因子-V_B），涉及PI-3K（磷脂酰氨基糖醇-3'激酶）和AKT以及STAT3以及STAT3。基于这些发现，要检验的一般假设是IFN_X受体整合了涉及STAT3，PI-3K和NF-VJ3的信号通路。在特定的目标1中，将定义STAT3作为转录因子和适配蛋白的作用。拟议的研究将确定STAT3中哪些特异性氨基酸残基经历IFN依赖性磷酸化，这些磷酸化事件与IFN的生物学作用的关系，以及哪些IFN响应基因受到STAT3的调节。在特定的目标2中，将定义NF-VJ3在IFNA作用中的作用。拟议的研究将定义PI-3K/AKT介导的磷酸化事件与IFN的抗凋亡作用，TRAF（TNF受体相关因子）的作用，NF-VJ3诱导NIK（NF-VJ3诱导的NIK）在IFN诱导的NF-RJ3活化中的作用，以及nf-rj3活化的作用，即nf-rj3活化的作用，nf-33 inf-33 IFN中的激酶复合物促进了NF-KB激活和细胞存活。尽管在IFN_X信号通路上取得了进步，但诱导IFN_X的不同生物学作用的基础的机制仍然很熟悉。该建议的重点是表征信号通路的分子基础，因为它们与细胞增殖和生存的1FN作用相关。表演站点=============================================================================================