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

Jolanta Wiejak, Julia Dunlop, Chloe Stoyle, Gillian Lappin, Anna McIlroy, John D. Pediani, Shan Gao, Stephen J Yarwood

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    5 Citations (Scopus)

    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 1000bp 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.

    Original languageEnglish
    Pages (from-to)1690-1699
    Number of pages10
    JournalCellular Signalling
    Volume24
    Issue number8
    DOIs
    Publication statusPublished - Aug 2012

    Keywords

    • Cyclic AMP
    • Enzyme Activation
    • Extracellular Signal-Regulated MAP Kinases
    • Human Umbilical Vein Endothelial Cells
    • Humans
    • Indoles
    • JNK Mitogen-Activated Protein Kinases
    • Maleimides
    • Protein Kinase C
    • Protein Kinase Inhibitors
    • Proto-Oncogene Proteins c-jun
    • Suppressor of Cytokine Signaling Proteins
    • Transcriptional Activation

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