Journal
NUCLEIC ACIDS RESEARCH
Volume 39, Issue 7, Pages 2503-2518Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkq1178
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Funding
- Deutsche Forschungsgemeinschaft
- Hannover Medical School
- MRC [MC_U127081014] Funding Source: UKRI
- Medical Research Council [MC_U127081014] Funding Source: researchfish
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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.
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