IFNAR1 signaling through STAT3, PI-3 kinase and NFkB

超出所提供的空间。当人们考虑干扰素- α (IFN_)在癌症、病毒性肝炎和多发性硬化症中的治疗潜力以及它作为理解细胞因子信号转导模型的作用时，了解干扰素- α (IFN_)作用的分子基础是一个重要的目标。IFNot通过酪氨酸磷酸化和STAT（信号转导和转录激活因子）蛋白家族成员的激活来调节基因表达，从而引发其生物学作用。申请人发现STAT3是急性期反应基因的转录因子，是IFN信号传导和诱导IFN生物作用的关键因素。此外，研究还发现IFN通过丝氨酸激酶依赖通路激活NF-KB（核因子- v_b），包括PI-3K（磷脂酰肌醇-3’激酶）和Akt以及STAT3，从而促进细胞存活。基于这些发现，需要验证的一般假设是IFN_x受体整合了包括STAT3、PI-3K和NF-vJ3在内的信号通路。在Specific Aim 1中，将定义STAT3作为转录因子和PI-3K适配蛋白的作用。拟议的研究将确定STAT3中哪些特定氨基酸残基发生IFN依赖性磷酸化，这些磷酸化事件与IFN的生物作用的关系，以及哪些IFN应答基因受STAT3调控。在特异性目标2中，将定义NF-vJ3在IFNa作用中的作用。拟开展的研究将明确PI-3K/ akt介导的磷酸化事件与IFN抗凋亡作用之间的关系，TNF受体相关因子（TRAFs）和NF-vJ3诱导激酶（NIK）在IFN诱导的NF-rJ3活化中的作用，NF-vJ3在IFN基因诱导中的作用，IFN中Iv33激酶复合物促进NF-KB活化和细胞存活的作用。尽管在IFN_x信号通路上取得了进展，但诱导IFN_x不同生物作用的机制仍然知之甚少。这一建议的重点是表征信号通路的分子基础，因为它们与1FN对细胞增殖和存活的作用有关。网站性能 ======================================== 节结束 ===========================================

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===========================================