Transcriptional activation of the proglucagon gene by lithium and β-catenin in intestinal endocrine L cells

Zuyao Ni, Younes Anini, Xianjun Fang, Gordon Mills, Patricia L. Brubaker, Tianru Jin

    Research output: Contribution to journalArticle

    62 Scopus citations

    Abstract

    The proglucagon gene encodes several peptide hormones that regulate blood glucose homeostasis, growth of the small intestine, and satiety. Among them, glucagon-like peptide 1 (GLP-1) lowers blood glucose levels in patients with diabetes and inhibits eating and drinking in fasted rats. Although proglucagon transcription and GLP-1 synthesis were shown to be activated by forskolin and other protein kinase A (PKA) activators, deleting or mutating the cAMP-response element (CRE) only moderately attenuates the proglucagon gene promoter in response to PKA activation. Therefore, PKA may activate proglucagon transcription via a mechanism independent of the CRE motif. Recently, PKA was shown to phosphorylate and inactivate GSK-3β, a key mediator in the Wnt signaling pathway. We show here that lithium, an inhibitor of GSK-3β, activates proglucagon gene transcription and stimulates GLP-1 synthesis in an intestinal endocrine L cell line, GLUTag. The activation was also observed in primary fetal rat intestinal cell (FRIC) cultures, but not in a pancreatic A cell line. Co-transfection of β-catenin, a downstream effector of GSK-3β activities, activated the proglucagon gene promoter without a CRE. Furthermore, forskolin and 8-Br-cAMP phosphorylated GSK-3β at serine 9 in intestinal proglucagon-producing cells, and both lithium and forskolin induced the accumulation of free β-catenin in these cell lines. These observations indicate that the proglucagon gene is among the targets of the Wnt signaling pathway.

    Original languageEnglish (US)
    Pages (from-to)1380-1387
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume278
    Issue number2
    DOIs
    StatePublished - Jan 10 2003

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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