Protein Kinase Pathways in Cytokine-Signaling

描述（由申请人提供）：有越来越多的证据表明，除了经典的IFN-激活的Jak-Stat途径外，非Stat途径在诱导干扰素的生物活性中发挥重要作用。我们已经提供了第一个证据表明，I型干扰素激活p38地图激酶途径，激活这种信号级联在I型干扰素依赖性转录调控中起着关键作用。我们的初步研究强烈表明，p38 MAPK的功能是必不可少的IFN-应答的产生，包括IFN对人造血的抑制作用和诱导的抗病毒状态。该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。特定目标A的研究将鉴定I型IFN依赖性p38 MAPK途径的上游元件，并将确定这些元件在IFN应答产生中的作用。特异性目的B将决定p38 MAPK级联是否与经典的Jak-Stat途径合作，或独立于其发挥作用以调节干扰素敏感基因的转录。p38介导的组蛋白丝氨酸磷酸化在ISG启动子中可能在I型IFN依赖性转录激活中表现出的潜在作用也将被研究。具体目标C将定义p38 MAPK在诱导I型IFN依赖性抗HBV抗病毒活性和在正常骨髓祖细胞上产生生长抑制应答中的作用。这些研究还将确定造血谱系级联中p38被I型IFN激活的阶段，并将剖析介导造血抑制的p38下游途径。具体目标D将确定来自患有恶性黑素瘤的患者的肿瘤细胞中的p38途径是否被IFN α激活，以及该途径的缺陷性激活是否导致黑素瘤中IFN抗性的发展。这种多方面的方法应提供重要的见解的机制，IFN-信号转化为特定的生物反应，以及恶性细胞产生耐药性的干扰素的生物活性的机制。了解这些机制可能具有重要的翻译意义，并促进新的IFN为基础的治疗方法在未来的发展。

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.