The protein kinase C inhibitor, Ro-31-7459, is a potent activator of ERK and JNK MAP kinases in HUVECs and yet inhibits cyclic AMP-stimulated SOCS-3 gene induction through inactivation of the transcription factor c-Jun

Wiejak, J., Dunlop, J. , Stoyle, C., Lappin, G., McIlroy, A., Pediani, J. D. , Gao, S. and Yarwood, S. J. (2012) The protein kinase C inhibitor, Ro-31-7459, is a potent activator of ERK and JNK MAP kinases in HUVECs and yet inhibits cyclic AMP-stimulated SOCS-3 gene induction through inactivation of the transcription factor c-Jun. Cellular Signalling, 24(8), pp. 1690-1699. (doi:10.1016/j.cellsig.2012.04.016)

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Publisher's URL: http://dx.doi.org/10.1016/j.cellsig.2012.04.016

Abstract

Induction of the suppressor of cytokine signalling 3 (SOCS-3) gene is vital to the normal control of inflammatory signalling. In order to understand these processes we investigated the role of the proto-oncogene component of the AP-1 transcription factor complex, c-Jun, in the regulation of SOCS-3 gene induction. We found that cyclic AMP stimulation of HUVECs promoted phosphorylation and activation of JNK MAP kinase and its substrate c-Jun. The JNK responsive element of the human SOCS-3 promoter mapped to a putative AP-1 site within 1000 bp of the transcription start site. The PKC inhibitors, GF-109203X, Gö-6983 and Ro-317549, were all found to inhibit AP-1 transcriptional activity, transcriptional activation of this minimal SOCS-3 promoter and SOCS-3 gene induction in HUVECs. Interestingly, Ro-317549 treatment was also found to promote PKC-dependent activation of ERK and JNK MAP kinases and promote JNK-dependent hyper-phosphorylation of c-Jun, whereas GF-109203X and Gö-6983 had little effect. Despite this, all three PKC inhibitors were found to be effective inhibitors of c-Jun DNA-binding activity. The JNK-dependent hyper-phosphorylation of c-Jun in response to Ro-317549 treatment of HUVECs does therefore not interfere with its ability to inhibit c-Jun activity and acts as an effective inhibitor of c-Jun-dependent SOCS-3 gene induction.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Pediani, Dr John and Yarwood, Dr Stephen and Wiejak, Dr Jolanta and Dunlop, Mrs Julia
Authors: Wiejak, J., Dunlop, J., Stoyle, C., Lappin, G., McIlroy, A., Pediani, J. D., Gao, S., and Yarwood, S. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Cellular Signalling
Publisher:Elsevier
ISSN:0898-6568
ISSN (Online):1873-3913
Published Online:25 April 2012
Copyright Holders:Copyright © 2012 Elsevier Inc.
First Published:First published in Cellular Signalling 24(8):1690-1699
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
528251The Role of EPAC1-regulated Protein Kinase C Isoforms in Mediating C/EBPdelta -dependent, Anti-inflammatory Actions of Cyclic AMP in Vascular Endothelial CellsStephen YarwoodBritish Heart Foundation (BHF)PG/10/026/28303RI MOLECULAR CELL & 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/08/125/26415RI CARDIOVASCULAR & MEDICAL SCIENCES