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

超出所提供的空间。当人们考虑 IFN 在癌症、病毒性肝炎和多发性硬化症中的治疗潜力及其作为了解细胞因子信号转导的模型的作用时，了解干扰素 α (IFN_) 作用的分子基础是一个重要目标。 IFNot 通过酪氨酸磷酸化和 STAT（信号转导和转录激活剂）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（急性期反应基因的转录因子）是IFN信号传导和IFN生物作用诱导的关键元件。此外，还发现IFN通过涉及PI-3K（磷脂酰肌醇-3'激酶）和Akt以及STAT3的丝氨酸激酶依赖性途径激活NF-KB（核因子-v_B），从而促进细胞存活。基于这些发现，需要测试的一般假设是 IFN_x 受体整合了涉及 STAT3、PI-3K 和 NF-vJ3 的信号通路。在具体目标 1 中，将定义 STAT3 作为转录因子和 PI-3K 接头蛋白的作用。拟议的研究将确定 STAT3 中哪些特定氨基酸残基经历 IFN 依赖性磷酸化、这些磷酸化事件与 IFN 生物学作用的关系，以及哪些 IFN 响应基因受 STAT3 调节。在具体目标 2 中，将定义 NF-vJ3 在 IFNa 作用中的作用。拟议的研究将确定 PI-3K/Akt 介导的磷酸化事件与 IFN 抗凋亡作用之间的关系、TRAF（TNF 受体相关因子）和 NIK（NF-vJ3 诱导激酶）在 IFN 诱导的 NF-rJ3 激活中的作用、NF-vJ3 在 IFN 基因诱导中的作用以及 Iv33 的作用 IFN 中的激酶复合物促进 NF-KB 激活和细胞存活。尽管 IFN_x 信号通路取得了进展，但诱导 IFN_x 不同生物作用的机制仍然知之甚少。该提案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。表演网站==========================================章节结束===============================================