Adherence Activated Monocyte Genes

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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.