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Originally published In Press as doi:10.1074/jbc.M206006200 on November 5, 2002

J. Biol. Chem., Vol. 278, Issue 2, 1380-1387, January 10, 2003
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Transcriptional Activation of the Proglucagon Gene by Lithium and beta -Catenin in Intestinal Endocrine L Cells*

Zuyao NiDagger , Younes Anini§, Xianjun Fang||, Gordon Mills||, Patricia L Brubaker§**Dagger Dagger , and Tianru JinDagger **§§¶¶||||

From the Dagger  Division of Cell & Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 2M1, Canada, the Departments of § Physiology, ** Medicine, §§ Laboratory Medicine and Pathobiology, and the ¶¶ Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and the || Department of Molecular Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

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-3beta , a key mediator in the Wnt signaling pathway. We show here that lithium, an inhibitor of GSK-3beta , 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 beta -catenin, a downstream effector of GSK-3beta activities, activated the proglucagon gene promoter without a CRE. Furthermore, forskolin and 8-Br-cAMP phosphorylated GSK-3beta at serine 9 in intestinal proglucagon-producing cells, and both lithium and forskolin induced the accumulation of free beta -catenin in these cell lines. These observations indicate that the proglucagon gene is among the targets of the Wnt signaling pathway.

* This work was supported in part by Canadian Institutes of Health Research (CIHR) Grant MOP36398 (to T. J.) and grants from the Canadian Diabetes Association (CDA) (to P. L. B. and T. J.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Canadian Diabetes Association postdoctoral fellowship (in the name of Margaret Francis).

Dagger Dagger Supported by the Canada Research Chair Program.

|||| To whom correspondence should be addressed: Rm. 421, 67 College St., Toronto General Research Inst., University Health Network, Toronto, Ontario M5G 2M1, Canada. Tel.: 416-340-4800 (ext. 4768); Fax: 416-340-3453; E-mail: tianru.jin@utoronto.ca.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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