Stress induced gene expression: a direct role for MAPKAP kinases in transcriptional activation of immediate early genes.
Immediate early gene (IEG) expression is coordinated by multiple MAP kinase signaling pathways in a signal specific manner. Stress-activated p38α 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 p38α level and p38-dependent IEG expression. Unexpectedly, restoration of p38α 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 p38α-MK2/3-SRF-axis is proposed which probably cooperates with MKs' role in posttranscriptional gene expression in inflammation and stress response.
Institute of Biochemistry, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
N
N
Ronkina
M B
MB
Menon
J
J
Schwermann
J S C
JS
Arthur
H
H
Legault
J-B
JB
Telliez
U S
US
Kayyali
A R
AR
Nebreda
A
A
Kotlyarov
M
M
Gaestel
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D002467:Cell Nucleus / Q000201:enzymology; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D017781:Genes, Immediate-Early; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D026362:Serum Response Factor / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics; D015533:Transcriptional Activation; D014466:Ultraviolet Rays; D000099190:MAP-Kinase-Activated Kinase 2
D000841:Anisomycin; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048308:Mitogen-Activated Protein Kinase 14; D017346:Protein Serine-Threonine Kinases; D026362:Serum Response Factor; D000099190:MAP-Kinase-Activated Kinase 2; C098416:MAP-kinase-activated kinase 3