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The transcriptional regulation and cell-specific expression of the MAPK-activated protein kinase MK5

Abstract

The mitogen-activated protein kinase (MAPK) cascades regulate important cellular processes, including growth, differentiation, apoptosis, embryogenesis, motility and gene expression. Although MAPKs mostly appear to be constitutively expressed, the transcript levels of some MAPK-encoding genes increase upon treatment with specific stimuli. This applies to the MAPKactivated protein kinases MK2 and MK3. By contrast, the transcriptional regulation of the related MK5 has not yet been studied. The MK5 promoters of mouse, rat and human contain a plethora of putative transcription factor sites, and the spatio-temporal expression of MK5 suggests inducible transcription of the gene. We examined the transcription pattern of MK5 in different tissues, and studied the kinetics of MK5 expression at the transcriptional and/or translation level in PC12 cells exposed to arsenite, forskolin, KCl, lipopolysaccharide, spermine NONOate, retinoic acid, serum, phorbol ester, temperature shock, and vanadate. Cells exposed to forskolin display a transient increase in MK5 mRNA, despite their unaltered MK5 protein levels. The MK5 promoters of human, mouse and rat contain a cAMP-responsive element that binds the cAMPresponsive element-binding protein (CREB) in vitro. Luciferase reporter constructs containing an 850-base pair human MK5 promoter fragment encompassing the CRE showed a basal activity that was 10-fold higher than the corresponding construct in which the CRE motif was deleted. siRNA-mediated depletion of CREB had no effect on the endogenous MK5 protein levels. Several binding motifs for heat shock factor are dispersed in the mouse and rat promoter, and temperature shock transiently enhanced the MK5 transcript levels. None of the other tested stimuli had an effect on the MK5 mRNA or protein levels. Our results indicate an inducible regulation of MK5 transcription in response to specific stimuli. However, the MK5 protein levels remained unaffected by all the stimuli tested. There is still no explanation for the discrepancy between the increased mRNA and unchanged MK5 protein levels.

Abbreviations

bp:

base pairs

CRE:

cAMP-response element

CREB:

CREbinding protein

HSF:

heat shock factor

LPS:

lipopolysaccharide

MAPK:

mitogenactivated protein kinase

miRNA:

microRNA

MK:

MAPK-activated protein kinase

MNK:

MAPK-interacting kinases

MSK:

mitogen- and stress-activated kinases

PKA:

protein kinase A or cAMP-dependent protein kinase

RA:

retinoic acid

RSK:

ribosomal S6 kinase

siRNA:

small interfering RNA

TPA:

tetradecanoyl phorbol acetate

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Correspondence to Ugo Moens.

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Key words

  • Mitogen-activated protein kinase-activated protein kinase
  • MK5
  • Promoter
  • CREB
  • Heat-shock
  • Oxidative stress