Protein Kinase Pathways in Cytokine-Signaling

描述（由申请人提供）：越来越多的证据表明，除了经典的ifn激活的Jak-Stat通路外，非stat通路在诱导干扰素的生物活性中也起着重要作用。我们已经提供了第一个证据，证明I型ifn激活p38 Map激酶途径，并且该信号级联的激活在I型ifn依赖性转录调节中起关键作用。我们的初步研究强烈表明，p38 MAPK的功能对于ifn反应的产生至关重要，包括ifn对人类造血的抑制作用和抗病毒状态的诱导。本提案的总体目标是确定p38通路在I型ifn信号传导中的功能作用。具体目标A的研究将确定I型ifn依赖性p38 MAPK通路的上游元件，并将定义这些元件在产生ifn应答中的作用。特异性靶B将决定p38 MAPK级联是与经典的Jak-Stat通路合作，还是独立于它来调节干扰素敏感基因的转录。在isg启动子中，p38介导的组蛋白丝氨酸磷酸化可能在I型ifn依赖性转录激活中表现出潜在的作用，也将被研究。特异性目的C将确定p38 MAPK在诱导I型ifn依赖性HBV抗病毒活性和在正常骨髓祖细胞上产生生长抑制反应中的作用。这些研究还将确定在造血谱系级联中p38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。特异性目的D将确定恶性黑色素瘤患者肿瘤细胞中的p38通路是否被ifn - α激活，以及该通路的缺陷激活是否导致黑色素瘤中ifn -耐药的发生。这种多方面的方法应该为ifn信号转化为特定生物反应的机制以及恶性细胞对干扰素生物活性产生抗性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，并促进未来基于ifn的新型治疗方法的发展。

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.