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Research article

MSKs are required for the transcription of the nuclear orphan receptors Nur77, Nurr1 and Nor1 downstream of MAPK signalling

Joanne Darragh, Ana Soloaga, Victoria A. Beardmore, Andrew D. Wingate, Giselle R. Wiggin, Mark Peggie, J. Simon C. Arthur
Biochemical Journal Sep 05, 2005, 390 (3) 749-759; DOI: 10.1042/BJ20050196
Joanne Darragh
MRC Protein Phosphorylation Unit, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Ana Soloaga
MRC Protein Phosphorylation Unit, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Victoria A. Beardmore
MRC Protein Phosphorylation Unit, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Andrew D. Wingate
MRC Protein Phosphorylation Unit, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Giselle R. Wiggin
MRC Protein Phosphorylation Unit, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Mark Peggie
MRC Protein Phosphorylation Unit, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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J. Simon C. Arthur
MRC Protein Phosphorylation Unit, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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  • For correspondence: j.s.c.arthur@dundee.ac.uk
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Abstract

MSK (mitogen- and stress-activated protein kinase) 1 and MSK2 are kinases activated downstream of either the ERK (extracellular-signal-regulated kinase) 1/2 or p38 MAPK (mitogen-activated protein kinase) pathways in vivo and are required for the phosphorylation of CREB (cAMP response element-binding protein) and histone H3. Here we show that the MSKs are involved in regulating the transcription of the immediate early gene Nur77. Stimulation of mouse embryonic fibroblasts with PMA, EGF (epidermal growth factor), TNF (tumour necrosis factor) or anisomycin resulted in induction of the Nur77 mRNA. The induction of Nur77 by TNF and anisomycin was abolished in MSK1/2 double-knockout cells, whereas induction was significantly reduced in response to PMA or EGF. The MSK responsive elements were mapped to two AP (activator protein)-1-like elements in the Nur77 promoter. The induction of Nur77 was also blocked by A-CREB, suggesting that MSKs control Nur77 transcription by phosphorylating CREB bound to the two AP-1-like elements. Consistent with the decrease in Nur77 mRNA levels in the MSK1/2-knockout cells, it was also found that MSKs were required for the induction of Nur77 protein by PMA and TNF. MSKs were also found to be required for the transcription of two genes related to Nur77, Nurr1 and Nor1, which were also transcribed in a CREB- or ATF1 (activating transcription factor-1)-dependent manner. Downstream of anisomycin signalling, a second ERK-dependent pathway, independent of MSK and CREB, was also required for the transcription of Nurr1 and Nor1.

  • extracellular-signal-regulated kinase (ERK)
  • mitogen- and stress-activated protein kinase (MSK)
  • Nur77
  • Nurr1
  • Nor1
  • p38

Abbreviations: AP-1, activator protein-1; ATF1, activating transcription factor-1; CRE, cAMP response element; CREB, CRE-binding protein; DMEM, Dulbecco's modified Eagle's medium; EGF, epidermal growth factor; ERK, extracellular-signal-regulated kinase; MAPK, mitogen-activated protein kinase; MSK, mitogen- and stress-activated protein kinase; MEF, murine embryonic fibroblast; MEF2D, myocyte-enhancer-binding factor 2D; NGF, nerve growth factor; NGFI-B, NGF-induced B factor; NBRE, NGFI-B response element; PKA, protein kinase A; PKI, PKA inhibitor; TCR, T-cell receptor; TNF, tumour necrosis factor α

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September 2005

Volume: 390 Issue: 3

Biochemical Journal: 390 (3)
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MSKs are required for the transcription of the nuclear orphan receptors Nur77, Nurr1 and Nor1 downstream of MAPK signalling
Joanne Darragh, Ana Soloaga, Victoria A. Beardmore, Andrew D. Wingate, Giselle R. Wiggin, Mark Peggie, J. Simon C. Arthur
Biochemical Journal Sep 2005, 390 (3) 749-759; DOI: 10.1042/BJ20050196
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MSKs are required for the transcription of the nuclear orphan receptors Nur77, Nurr1 and Nor1 downstream of MAPK signalling
Joanne Darragh, Ana Soloaga, Victoria A. Beardmore, Andrew D. Wingate, Giselle R. Wiggin, Mark Peggie, J. Simon C. Arthur
Biochemical Journal Sep 2005, 390 (3) 749-759; DOI: 10.1042/BJ20050196

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Keywords

extracellular-signal-regulated kinase (ERK)
mitogen- and stress-activated protein kinase (MSK)
Nur77
Nurr1
Nor1
p38

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