Stress induced gene expression: a direct role for MAPKAP kinases in transcriptional activation of immediate early genes

N. Ronkina, M. B. Menon, J. Schwermann, J. S. C. Arthur, H. Legault, J. -B. Telliez, U. S. Kayyali, A. R. Nebreda, A. Kotlyarov, M. Gaestel

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    Immediate early gene (IEG) expression is coordinated by multiple MAP kinase signaling pathways in a signal specific manner. Stress-activated p38 alpha MAP kinase is implicated in transcriptional regulation of IEGs via MSK-mediated CREB phosphorylation. The protein kinases downstream to p38, MAPKAP kinase (MK) 2 and MK3 have been identified to regulate gene expression at the posttranscriptional levels of mRNA stability and translation. Here, we analyzed stress-induced IEG expression in MK2/3-deficient cells. Ablation of MKs causes a decrease of p38 alpha level and p38-dependent IEG expression. Unexpectedly, restoration of p38 alpha does not rescue the full-range IEG response. Instead, the catalytic activity of MKs is necessary for the major transcriptional activation of IEGs. By transcriptomics, we identified MK2-regulated genes and recognized the serum response element (SRE) as a common promoter element. We show that stress-induced phosphorylation of serum response factor (SRF) at serine residue 103 is significantly reduced and that induction of SRE-dependent reporter activity is impaired and can only be rescued by catalytically active MK2 in MK2/3-deficient cells. Hence, a new function of MKs in transcriptional activation of IEGs via the p38 alpha-MK2/3-SRF-axis is proposed which probably cooperates with MKs' role in posttranscriptional gene expression in inflammation and stress response.

    Original languageEnglish
    Pages (from-to)2503-2518
    Number of pages16
    JournalNucleic Acids Research
    Issue number7
    Publication statusPublished - Apr 2011

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