Extracellular signal-regulated kinase mitogen-activated protein kinase-dependent SOCS-3 gene induction requires c-Jun, signal transducer and activator of transcription 3, and specificity protein 3 transcription factors

Jolanta Wiejak, Julia Dunlop, Shan Gao, Gillian Borland, Stephen J Yarwood

    Research output: Contribution to journalArticle

    13 Citations (Scopus)

    Abstract

    SOCS-3 gene induction by cAMP-elevating agents or the protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), in primary HUVECs was found to require PKCη- and PKCε-dependent extracellular signal-regulated kinase (ERK) activation. The minimal, ERK-responsive element of the SOCS-3 promoter was localized to a region spanning nucleotides -107 to the transcription start site and contains conserved binding sites for AP-1 and SP1/SP3 transcription factors, as well as proximal and distal signal transducer and activator of transcription (pSTAT and dSTAT) binding elements. All three classes of transcription factor were activated in response to ERK activation. Moreover, representative protein components of each of these transcription factor binding sites, namely c-Jun, STAT3, and SP3, were found to undergo ERK-dependent phosphorylation within their respective transactivation domains. Mutational analysis demonstrated an absolute requirement for the SP1/SP3 binding element in controlling basal transcriptional activity of the minimal SOCS-3 promoter. In addition AP-1, pSTAT, and SP1/SP3 binding sites were required for ERK-dependent, PMA-stimulated SOCS-3 gene activation. The dSTAT site seems to be important for supporting activity of the AP-1 site, because combined deletion of both sites completely blocks transcriptional activation of SOCS-3 by PMA. Together these results describe novel, ERK-dependent regulation of transcriptional activity that requires codependent activation of multiple transcription factors within the same region of the SOCS-3 gene promoter.

    Original languageEnglish
    Pages (from-to)657-668
    Number of pages12
    JournalMolecular Pharmacology
    Volume81
    Issue number5
    DOIs
    Publication statusPublished - May 2012

    Keywords

    • Animals
    • Binding Sites
    • CCAAT-Enhancer-Binding Protein-beta
    • Cells, Cultured
    • Endothelial Cells
    • Extracellular Signal-Regulated MAP Kinases
    • Extracellular Space
    • Humans
    • Mice
    • Promoter Regions, Genetic
    • Protein Kinase C
    • Proto-Oncogene Proteins c-jun
    • STAT3 Transcription Factor
    • Signal Transduction
    • Sp3 Transcription Factor
    • Suppressor of Cytokine Signaling Proteins

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