Adherence Activated Monocyte Genes

单核细胞是免疫反应的重要组成部分。它们在组织损伤和炎症部位的附着和渗出激活了许多信号转导途径，导致诱导的趋化因子和促炎细胞因子的合成和分泌。这种诱导是通过细胞因子/趋化因子基因的粘附依赖性转录诱导及其mRNA的稳健稳定的协同作用而实现的。细胞因子mRNA的衰变部分由其3 '-非翻译区内的富含A+ U的元件（战神）控制。我们感兴趣的是ARE为什么以及如何靶向细胞因子mRNA快速衰变，涉及哪些因素，以及细胞因子mRNA衰变如何在细胞周期中调节。 免疫反应我们一直专注于ARE结合因子AUF 1，这是我们在1991年发现的，并在此后不久进行了分子克隆。迄今为止，我们的研究表明，AUF 1促进ARE指导的mRNA衰变的作用，以重塑ARE-RNA结构和成核组装的大mRNA-蛋白质复合物，靶向ARE-mRNA的细胞质信使核糖核酸酶的快速破坏。此外，这些过程受到调节控制，以响应于单核细胞粘附而发生的AUF 1磷酸化状态的变化。虽然粘附导致细胞因子mRNA、mRNA 如果在酪氨酸激酶抑制剂、或MEK激酶抑制剂、或p38 MAP激酶抑制剂存在下培养单核细胞，则稳定化被阻断。这强烈表明，衰变机制的组分作为信号转导途径的靶点来调节细胞因子mRNA的衰变。我们将处理三个主要领域。首先，我们将研究AUF 1磷酸化的变化如何影响ARE-RNA：蛋白质复合物组装。其次，我们将研究在磷酸化位点含有突变的AUF 1蛋白的衰变促进活性。最后，我们将研究决定AUF 1磷酸化状态的信号通路和机制。总之，这些研究应该为整合信号转导，mRNA结合蛋白， mRNA降解和炎症。

Monocytes are an important component of the immune response. Their attachment and extravazation at sites of tissue injury and inflammation activates a number of signal transduction pathways that lead to induced synthesis and secretion ofchemokines and proinflammatory cytokines. This induction is made possible by the concerted actions of adherence-dependent transcriptional induction of cytokine/chemokine genes and robust stabilization of their mRNAs. Decay of cytokine mRNAs is controlled in part by A+U-rich elements (AREs) within their 3'-untranslated regions. We are interested in why and how AREs target cytokine mRNAs for rapid decay, what factors are involved, and how cytokine mRNA decay is regulated during an immune response. We have focused on the ARE-binding factor AUF1, which we identified in 1991 and molecularly cloned shortly thereafter. Our studies to date indicate that AUF1 promotes ARE-directed mRNA decay by acting to remodel ARE-RNA structure and nucleating assembly of a large mRNA-protein complex that targets ARE-mRNAs for rapid destruction by cytoplasmic messenger ribonucleases. Moreover, these processes are subject to regulatory control in response to changes in AUF1 phosphorylation state that occur in response to monocyte adherence. While adherence results in robust stabilization of cytokine mRNAs, mRNA stabilization is blocked ifmonocytes are cultured in the presence of either a tyrosine kinase inhibitor, or a MEK kinase inhibitor, or a p38 MAP kinase inhibitor. This strongly suggests that components of the decay machinery serve as targets of signal transduction pathway(s) to regulate cytokine mRNA decay. We will address three major areas. First, we will examine how changes in phosphorylation of AUF1 impact ARE-RNA:protein complex assembly. Secondly, we will examine the decay-promoting activities of AUF1 proteins containing mutations in the sites ofphosphorylation. Finally, we will examine the signaling pathways and mechanisms that determine the phosphorylation state of AUF1. Together, these studies should provide novel insights into the cellular pathways that integrate signal transduction, mRNA-binding proteins, mRNA degradation, and inflammation.