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: 6572560
• 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/6572560
• 关键词: apoptosis; biological signal transduction; cell proliferation; chimeric proteins; cytokine receptors; immunoprecipitation; interferon alpha; interferon inducers; nuclear factor kappa beta; nucleic acid probes; nucleic acid purification; phosphatidylinositol 3 kinase; phosphorylation; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Understanding the molecular basis of interferon-alpha (IFNalpha) 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. IFNalpha 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-kB) 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 IFNalpha receptor integrates signaling pathways involving STAT3, PI-3K and NF-kB. 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-kB 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-kB-inducing kinase) in IFNinduced NF-kB activation, the role of NF-kB in gene induction by IFN, and the role of the IkB kinase complex in IFN promoted NF-kB activation and cell survival. Despite advances made on the IFNalpha signaling pathway, the mechanisms that underlie the induction of the different biological actions of IFNalpha remain poorly understood. This proposal focuses on characterizing the molecular basis of signaling pathways as they relate to IFN action on cell proliferation and survival.

描述（由申请人提供）：当人们考虑干扰素在癌症、病毒性肝炎和多发性硬化症中的治疗潜力以及其作为理解细胞因子信号转导的模型的作用时，理解干扰素-α（IFN α）作用的分子基础是一个重要的目标。IFN α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，从而发挥其生物学作用。申请人发现，STAT 3是急性期反应基因的转录因子，是IFN信号传导和诱导IFN生物学作用的关键元件。此外，还发现IFN通过经由涉及PI-3 K（磷脂酰肌醇-3 '激酶）和Akt以及STAT 3的丝氨酸激酶依赖性途径激活NF-kB（核因子-kB）来促进细胞存活。基于这些发现，有待检验的一般假设是IFN α受体整合了涉及STAT 3、PI-3 K和NF-kB的信号通路。在具体目标1中，将定义STAT 3作为PI-3 K的转录因子和衔接蛋白的作用。这些研究将确定STAT 3中哪些特定的氨基酸残基经历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应答基因受STAT 3调节。在具体目标2中，将定义NF-kB在IFNa作用中的作用。这些研究将确定PI-3 K/Akt介导的磷酸化事件与IFN的抗凋亡作用之间的关系，TRAFs（TNF受体相关因子）和NIK（NF-kB诱导激酶）在IFN诱导的NF-kB活化中的作用，NF-kB在IFN诱导的基因诱导中的作用，以及IkB激酶复合物在IFN促进NF-kB活化和细胞存活中的作用。尽管在IFN α信号通路方面取得了进展，但对IFN α诱导不同生物学作用的机制仍然知之甚少。该建议的重点是表征信号通路的分子基础，因为它们与IFN对细胞增殖和存活的作用有关。