Activation of protein kinase Cα by EPAC1 is required for the ERK- and CCAAT/enhancer-binding protein β-dependent induction of the SOCS-3 gene by cyclic AMP in COS1 cells

Borland, G., Bird, R. J., Palmer, T. M. and Yarwood, S. J. (2009) Activation of protein kinase Cα by EPAC1 is required for the ERK- and CCAAT/enhancer-binding protein β-dependent induction of the SOCS-3 gene by cyclic AMP in COS1 cells. Journal of Biological Chemistry, 284(26), pp. 17391-17403. (doi:10.1074/jbc.M109.015370)

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Publisher's URL: http://dx.doi.org/10.1074/jbc.M109.015370

Abstract

We recently found that induction of the anti-inflammatory SOCS-3 gene by cyclic AMP occurs through novel cyclic AMP-dependent protein kinase-independent mechanisms involving activation of CCAAT/enhancer-binding protein (C/EBP) transcription factors, notably C/EBPβ, by the cyclic AMP GEF EPAC1 and the Rap1 GTPase. In this study we show that down-regulation of phospholipase (PL) Cϵ with small interfering RNA or blockade of PLC activity with chemical inhibitors ablates exchange protein directly activated by cyclic AMP (EPAC)-dependent induction of SOCS-3 in COS1 cells. Consistent with this, stimulation of cells with 1-oleoyl-2-acetyl-sn-glycerol and phorbol 12-myristate 13-acetate, both cell-permeable analogues of the PLC product diacylglycerol, are sufficient to induce SOCS-3 expression in a Ca2+-dependent manner. Moreover, the diacylglycerol- and Ca2+-dependent protein kinase C (PKC) isoform PKCα becomes activated following cyclic AMP elevation or EPAC stimulation. Conversely, down-regulation of PKC activity with chemical inhibitors or small interfering RNA-mediated depletion of PKCα or -δ blocks EPAC-dependent SOCS-3 induction. Using the MEK inhibitor U0126, we found that activation of ERK MAPKs is essential for SOCS-3 induction by either cyclic AMP or PKC. C/EBPβ is known to be phosphorylated and activated by ERK. Accordingly, we found ERK activation to be essential for cyclic AMP-dependent C/EBP activation and C/EBPβ-dependent SOCS-3 induction by cyclic AMP and PKC. Moreover, overexpression of a mutant form of C/EBPβ (T235A), which lacks the ERK phosphorylation site, blocks SOCS-3 induction by cyclic AMP and PKC in a dominant-negative manner. Together, these results indicate that EPAC mediates novel regulatory cross-talk between the cyclic AMP and PKC signaling pathways leading to ERK- and C/EBPβ-dependent induction of the SOCS-3 gene.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Yarwood, Dr Stephen and Palmer, Dr Tim and Borland, Dr Gillian
Authors: Borland, G., Bird, R. J., Palmer, T. M., and Yarwood, S. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Biological Chemistry
Journal Abbr.:J Biol Chem.
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN:0021-9258
ISSN (Online):1083-351X
Published Online:07 May 2009
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
419071The EPAC-C/EBP pathway - a new route for the control of gene expression by cyclic AMPStephen YarwoodBiotechnology and Biological Sciences Research Council (BBSRC)BB/D015324/1Institute of Molecular Cell and Systems Biology
498581EPAC1 and ERK-dependent activation of C/EBP transcription factors: a new cyclic AMP-activated anti-inflammatory gene expression module in vascular endothelial cellsTimothy PalmerBritish Heart Foundation (BHF)PG/08/125/26415Institute of Cardiovascular and Medical Sciences