IFNAR1 signaling through STAT3, PI-3 kinase and NFkB

了解干扰素-α作用的分子基础是一个重要的目标，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它作为治疗癌症模型的作用 了解细胞因子信号转导。IFNOT通过调节基因表达而产生生物学作用 通过酪氨酸磷酸化和STAT成员的激活(信号转导和 转录激活子)蛋白家族。申请人发现STAT3，一种急性白血病的转录因子 时相反应基因是干扰素信号转导和诱导干扰素生物学作用的关键元件。在……里面 此外，还发现干扰素通过激活核因子-kB(核因子-v_B)促进细胞存活。 参与PI-3K(磷脂酰肌醇-3‘-激酶)和Akt的丝氨酸激酶依赖通路，以及 统计数据3.基于这些发现，需要检验的一般假设是，干扰素_x受体整合了 信号转导通路涉及STAT3、PI-3K和NF-vJ3。在具体目标1中，STAT3作为一种 将定义PI-3K的转录因子和适配蛋白。拟议的研究将确定 STAT3中哪些特定的氨基酸残基经历了干扰素依赖的磷酸化，与 这些磷酸化事件与干扰素的生物学作用有关，哪些干扰素反应基因是STAT3- 受监管的。在具体目标2中，将确定核因子-vJ3在IFNA行动中的作用。拟议的研究将 明确PI-3K/Akt介导的磷酸化事件与阿司匹林抗细胞凋亡作用的关系 TRAF(肿瘤坏死因子受体相关因子)和NIK(核因子-vJ3-诱导激酶)在干扰素-α中的作用 诱导核因子-rJ3的激活，核因子-vJ3在干扰素基因诱导中的作用，以及IV33激酶的作用 干扰素复合体可促进核因子-kB的活化和细胞存活。尽管在干扰素_x信号转导方面取得进展 途径，但诱导干扰素不同生物学作用的机制仍然存在。 人们对此知之甚少。这项建议侧重于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。

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.