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

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 β‐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‐κB 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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