Identification of CCAAT/enhancer-binding proteins as exchange protein activated by cAMP-activated transcription factors that mediate the induction of the SOCS-3 gene

Stephen J Yarwood, Gillian Borland, William A. Sands, Timothy M. Palmer

    Research output: Contribution to journalArticle

    61 Citations (Scopus)

    Abstract

    The prototypical second messenger cAMP is a key regulator of immune and inflammatory responses. Its ability to inhibit interleukin (IL)-6 responses is due to induction of suppressor of cytokine signaling-3 (SOCS-3), a negative regulator of IL-6 receptor signaling. We have determined previously that SOCS-3 induction by cAMP occurs independently of cAMP-dependent protein kinase, instead requiring the recently identified cAMP sensor exchange protein activated by cAMP 1 (EPAC1). Here we present evidence to suggest that the C/EBP family of transcription factors link EPAC1 activation to SOCS-3 induction. Firstly, selective activation of EPAC in human umbilical vein endothelial cells increased C/EBP DNA binding activity and recruitment of C/EBPbeta to the SOCS-3 promoter. Secondly, knockdown of C/EBPbeta and -delta isoforms abolished both SOCS-3 induction and inhibition of IL-6 signaling in response to cAMP. Thirdly, overexpression of C/EBPalpha, -beta, or -delta potentiated EPAC-mediated accumulation of SOCS-3. Finally, these effects were not restricted to human umbilical vein endothelial cells, because similar phenomena were observed in murine embryonic fibroblasts in which C/EBPbeta or delta had been deleted. In summary, our findings constitute the first description of an EPAC-C/EBP pathway that can control cAMP-mediated changes in gene expression independently of protein kinase A.

    Original languageEnglish
    Pages (from-to)6843-6853
    Number of pages11
    JournalJournal of Biological Chemistry
    Volume283
    Issue number11
    DOIs
    Publication statusPublished - 14 Mar 2008

    Keywords

    • Animals
    • CCAAT-Enhancer-Binding Proteins
    • Cyclic AMP
    • Cyclic AMP-Dependent Protein Kinases
    • Endothelium, Vascular
    • Fibroblasts
    • Gene Expression Regulation
    • Interleukin-6
    • Mice
    • Models, Biological
    • Protein Isoforms
    • Signal Transduction
    • Suppressor of Cytokine Signaling Proteins
    • Umbilical Veins

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