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J. Biol. Chem., Vol. 280, Issue 9, 7976-7984, March 4, 2005

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Essential Interaction of Egr-1 at an Islet-specific Response Element for Basal and Gastrin-dependent Glucagon Gene Transactivation in Pancreatic -Cells^*

Stéphane Leung-Theung-Long, Emmanuelle Roulet¶, Pascal Clerc, Chantal Escrieut, Sophie Marchal-Victorion||, Beate Ritz-Laser¶, Jacques Philippe¶, Lucien Pradayrol, Catherine Seva, Daniel Fourmy, and Marlène Dufresne**

From the Inserm U531, IFR31, Hospital Rangueil, 31059 Toulouse Cedex 9, France, and the ^¶Diabetes Unit, University Hospital Geneva, 1211 Geneva 14, Switzerland

The peptide hormone gastrin is secreted from G cells of the gastric antrum and is the main inducer of gastric acid secretion via activation of its receptor the cholecystokinin 2 (CCK2) receptor. Both gastrin and CCK2 receptors are also transiently detected in the fetal pancreas and believed to exert growth/differentiation effects during endocrine pancreatic development. We demonstrated previously that whereas gastrin expression is extinguished in adult pancreas, CCK2 receptors are present in human glucagon-producing cells where their activation stimulates glucagon secretion. Based on these findings, we investigate in the present study whether gastrin regulates glucagon gene expression. To this aim, the CCK2 receptor was stably expressed into a glucagon-producing pancreatic islet cell line, and a glucagon-reporter fusion gene was transiently transfected in this new cellular model. We report that gastrin stimulates glucagon gene expression in glucagon-producing pancreatic cells. By using progressively 5'-increased sequences of the glucagon gene, gastrin responsiveness was located within the minimal promoter. Moreover, we clearly identified early growth response protein 1 (Egr-1) as an essential transcription factor interacting with the islet cell-specific G4 element. Egr-1 was shown to be essential for basal and gastrin-dependent glucagon gene transactivation. Furthermore, our results demonstrate that the MEK1/ERK1/2 pathway couples the CCK2 receptor to nuclearization and DNA binding of Egr-1. In conclusion, our data provide new information concerning the transcriptional regulation of the glucagon gene. Moreover they open new working hypothesis with reference to a potential role of gastrin in glucagon-producing pancreatic cells.

Received for publication, July 6, 2004 , and in revised form, December 3, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY842856.

^* This work was supported in part by Association pour la Recherche sur le Cancer Grants 4430 and 4514 and by Génopôle of Toulouse Grant ur531-257-8RB06. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of support from the Ligue contre le Cancer (région Midi-Pyrénées), University of Toulouse (ATUPS), and the Solvay-Pharma/Club Français du Pancréas.

^|| Recipient of support from the Ligue contre le Cancer (Tarn et Garonne).

^** To whom correspondence should be addressed: IFR31, Institut Louis Bugnard, INSERM U531, BP 84225, 31432 Toulouse, Cedex 4, France. Tel.: 33-5-6132-2405; Fax: 33-5-6132-2403; E-mail: dufresne{at}toulouse.inserm.fr.

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