REGULATION OF CYTOKINE mRNA STABILITY BY ARE-BINDING PROTEINS HuR AND TRISTETRAPROLINE IN MACROPHAGES
Date Issued
2005
Date
2005
Author(s)
Huang, Ya-Ling
DOI
zh-TW
Abstract
Messenger RNA stability is one of the key mechanisms that eukaryotic cells regulate gene expression and influence cell growth and differentiation. AU-rich elements (AREs) present in the 3’ untranslated regions of mRNAs from many protooncogenes, cytokines, and growth factors may be targets for rapid degradation. HuR, a ubiquitous expressed member of the ELAV family of RNA binding proteins, selectively binds to AREs and stabililizes ARE-containing mRNAs in transiently transfected cells. Tristetraproline (TTP) is an immediate-early gene that could bind to AREs and trigger RNA destabilization. To investigate the regulation of stability of ARE-containing mRNAs, we performed experiments on the expression and regulation of half-life of TNFα and IL-1β mRNAs in LPS-stimulated macrophages. Electrophoretic mobility shift assays showed that the LPS-induced destabilization factor TTP could bind to TNFα ARE much better than that of IL-1β ARE. HuR was found to interact with TNFα ARE to stabilize its RNA. Interestingly, LPS-induced stability of IL-1β mRNA was p38 signaling pathway-dependent while that of TNFα mRNA was p38 signaling pathway-independent. Activation of p38 pathway resulted in the phosphorylation of TTP and decrease of its RNA-binding activity. Contrary to ARE of TNFα, p38 signal could reverse the inhibitory activity of TTP on IL-1β ARE. Our results indicate that TTP could respond to p38 signal to modulate the expression of specific ARE-containing mRNAs such as IL-1β.
Subjects
細胞激素
穩定性
RNA結合蛋白
cytokine
stability
RNA binding protein
Type
other
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