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| The EMBO Journal
(1999) 18, 4969–4980, doi:10.1093/emboj/18.18.4969 |
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| The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism |
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| Reinhard Winzen1, 4, Michael Kracht1, 4, Birgit Ritter1, Arno Wilhelm1, Chyi-Ying A. Chen2, Ann-Bin Shyu2, Monika Müller3, Matthias Gaestel3, Klaus Resch1 and Helmut Holtmann1 |
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1 Institute of Molecular Pharmacology, Medical School Hannover, D-30623 Hannover, Germany 2 Department of Biochemistry and Molecular Biology, The University of Texas Houston Health Science Center, Medical School, Houston, TX 77030, USA 3 Innovationskolleg Zellspezialisierung, Martin-Luther-Universität, D-06099 Halle, Germany 4 R.Winzen and M.Kracht contributed equally to this work To whom correspondence should be addressed Helmut Holtmann, holtmann.helmut@mh-hannover.de Received 23 March 1999; Revised 20 July 1999; Accepted 20 July 1999. |
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| Abstract |
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Stabilization of mRNAs contributes to the strong and rapid induction of genes in the inflammatory response. The signaling mechanisms involved were investigated using a tetracycline-controlled expression system to determine the half-lives of interleukin (IL)-6 and IL-8 mRNAs. Transcript stability was low in untreated HeLa cells, but increased in cells expressing a constitutively active form of the MAP kinase kinase kinase MEKK1. Destabilization and signal-induced stabilization was transferred to the stable  -globin mRNA by a 161-nucleotide fragment of IL-8 mRNA which contains an AU-rich region, as well as by defined AU-rich elements (AREs) of the c-fos and GM-CSF mRNAs. Of the different MEKK1-activated signaling pathways, no significant effects on mRNA degradation were observed for the SAPK/JNK, extracellular regulated kinase and NF- B pathways. Selective activation of the p38 MAP kinase (=SAPK2) pathway by MAP kinase kinase 6 induced mRNA stabilization. A dominant-negative mutant of p38 MAP kinase interfered with MEKK1 and also IL-1-induced stabilization. Furthermore, an active form of the p38 MAP kinase-activated protein kinase (MAPKAP K2 or MK2) induced mRNA stabilization, whereas a negative interfering MK2 mutant interfered with MAP kinase kinase 6-induced stabilization. These findings indicate that the p38 MAP kinase pathway contributes to cytokine/stress-induced gene expression by stabilizing mRNAs through an MK2-dependent, ARE-targeted mechanism. |
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| Keywords: cytokines, kinase cascade, MAPKAP kinase-2, mRNA degradation, signal transduction |
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