Journal
CELLULAR SIGNALLING
Volume 24, Issue 8, Pages 1690-1699Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2012.04.016
Keywords
MAP kinases; Cyclic AMP; SOCS-3; Transcription; c-Jun; Protein kinase C
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Funding
- British Heart Foundation [PG/10/026/28303, PG/08/125/26415]
- Biotechnology and Biological Sciences Research Council [BB/D015324/1] Funding Source: researchfish
- British Heart Foundation [PG/10/26/28303, PG/08/125/26415] Funding Source: researchfish
- BBSRC [BB/D015324/1] Funding Source: UKRI
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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, GE-109203X, Go-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 INK MAP kinases and promote JNK-dependent hyper-phosphorylation of c-Jun, whereas GF-109203X and Go-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. (C) 2012 Elsevier Inc. All rights reserved.
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