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

Abstract

R.Winzen and M.Kracht contributed equally to this workStabilization 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.

Insulin-like growth factor-I induces cyclooxygenase-2 expression via PI3K, MAPK and PKC signaling pathways in human ovarian cancer cells☆

“…We found that the p38 selective inhibitor SB203580 suppressed IGF-I-induced activation of COX-2 promoter activity and mRNA stabilization. This is consistent with previous findings showing that p38 MAPK was involved in COX-2 transcription presumably through increasing AP-1 activity (41,(45)(46)(47), and that p38 MAPK regulated COX-2 mRNA stabilization by its downstream kinase MK-2 (9,36,48).…”

Post‐transcriptional regulation of gene expression by degradation of messenger RNAs

“…Several examples point to stabilization of otherwise labile mRNAs under conditions promoting induction, which contributes to a rapid increase in their amounts. Phorbol ester treatment increased the half-life of GM-CSF mRNA (Shaw and Kamen, 1986;Bickel et al, 1990); stabilization of mRNAs also contributes to the strong and rapid induction of genes in the inflammatory response (Winzen et al, 1999); and activation of the leukocyte integrin lymphocyte-function-associated antigen-1 (LFA-1) promotes the induction of urokinase plasminogen activator receptor in the T-cell membrane through the stabilization of its ARE-containing mRNA (Wang et al, 1998).…”

“…The affinity of recombinant p37 AUF1 for the ARE motif is closely correlated with its potential to destabilize the mRNA . Inhibition of the p38 pathway stabilizes the AREcontaining mRNAs (Winzen et al, 1999;Lasa et al, 2000), inactivating AUF1 protein (Sirenko et al, 1997), which suggests that p38 is involved in the AUF1 activity. In conclusion, the efficiency of ARE-dependent mRNA turnover is compromised in cells containing low levels of endogenous p37 AUF1 and p40 AUF1 (Ross et al, 1991;Buzby et al, 1996) or following sequestration of AUF1 by treatment with hemin (Loflin et al, 1999).…”

AgC10, a mucin from Trypanosoma cruzi, destabilizes TNF and cyclooxygenase‐2 mRNA by inhibiting mitogen‐activated protein kinase p38

“…Our results show that AgC10 destabilizes TNF and COX-2 mRNA by inhibiting activation of p38 mitogen-activated protein kinase (MAPK) and its substrate MAPK-activated protein kinase-2 (MAPKAP-K2). Macrophage stimulation with LPS activates these kinases, which have been previously described as important regulators of TNF and COX-2 mRNA stability [15,16]. These results represent a previously undescribed mechanism in which a parasite surface molecule is able to avoid the release of proinflammatory mediators that play a crucial role in the elimination of T. cruzi.…”

“…In turn, p38 phosphorylates and activates MAPKAP-K2 [20]. This signal transduction cascade is required for the expression of several proinflammatory genes, including TNF and COX-2, and exerts its effects, at least in part, through mRNA stability [15,16]. To test if AgC10 affects p38 activation, we performed Western blot analysis of activated macrophages using anti-phosphorylated p38 antibody that recognizes the phosphorylated and active forms of this kinase.…”