Protein Kinase Pathways in Cytokine-Signaling

描述(申请人提供)：有越来越多的证据表明，除了经典的干扰素激活的Jak-Stat途径外，非Stat途径在诱导干扰素的生物活性方面发挥着重要作用。我们首次提出了I型干扰素激活p38MAPK通路的证据，并且该信号级联的激活在I型干扰素依赖的转录调控中起着关键作用。我们的初步研究有力地表明，p38MAPK的功能对于产生干扰素应答是必不可少的，包括IFN对人类造血的抑制作用和抗病毒状态的诱导。这项建议的总体目标是确定p38通路在I型干扰素信号中的功能作用。特定目标A的研究将确定I型干扰素依赖的p38MAPK途径的上游元件，并将确定这些元件在产生干扰素应答中的作用。具体目标B将确定p38MAPK级联信号通路是否与经典的Jak-Stat途径协同作用，或独立于该通路而调节干扰素敏感基因的转录。P38介导组蛋白丝氨酸磷酸化在ISGs的启动子中可能在I型干扰素依赖的转录激活中发挥的潜在作用也将被检测。具体目的C将确定p38MAPK在诱导I型干扰素依赖的抗病毒活性和对正常骨髓祖细胞产生生长抑制反应中的作用。这些研究还将确定p38在造血谱系级联中被I型IFN激活的阶段，并将剖析p38下游介导造血抑制的途径。具体目的D将确定恶性黑色素瘤患者肿瘤细胞中的p38通路是否被干扰素α激活，以及该通路的激活缺陷是否与黑色素瘤干扰素耐药的发生有关。这一多方面的方法应该为干扰素信号转化为特定生物反应的机制以及肿瘤细胞对干扰素生物活性产生抵抗力的机制提供重要的见解。了解这些机制可能具有重要的翻译意义，并有助于未来基于干扰素的新型治疗方法的开发。

DESCRIPTION (provided by applicant): There is accumulating evidence that in addition to the classic IFN-activated Jak-Stat pathway, non-Stat pathways play important roles in the induction of the biological activities of interferons. We have provided the first evidence that Type I IFNs activate the p38 Map kinase pathway and that activation of this signaling cascade plays a critical role in Type I IFN-dependent transcriptional regulation. Our preliminary studies strongly suggest that the function of p38 MAPK is essential for the generation of IFN-responses, including the suppressive effects of IFNs on human hematopoiesis and the induction of an antiviral state. The overall goal of this proposal is to define the functional role of the p38 pathway in Type I IFN-signaling. The studies of specific aim A will identify upstream elements of the Type I IFN-dependent p38 MAPK pathway and will define the roles of such elements in the generation of IFN-responses. Specific aim B will determine whether the p38 MAPK cascade cooperates with the classic Jak-Stat pathway, or acts independently of it to regulate transcription of interferon-sensitive genes. The potential role that p38-mediated histone serine phosphorylation in the promoters of ISGs may exhibit in Type I IFN-dependent transcriptional activation, will be also examined. Specific aim C will define the role of p38 MAPK in the induction of Type I IFN-dependent antiviral activities against HBV and the generation of growth inhibitory responses on normal bone marrow progenitors. These studies will also identify the stage in the hematopoietic lineage cascade at which p38 is activated by Type I IFNs and will dissect the pathways downstream of p38 that mediate hematopoietic suppression. Specific aim D will determine whether the p38 pathway is activated by IFNalpha in tumor cells from patients suffering from malignant melanoma, and whether defective activation of this pathway accounts for the development of IFN-resistance in melanoma. This multifaceted approach should provide important insights on the mechanisms by which IFN-signals translate to specific biological responses, as well as on the mechanisms by which malignant cells develop resistance to the biological activities of interferons. Understanding such mechanisms may have important translational implications and facilitate the development of novel IFN-based therapeutic approaches in the future.