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* Fondation pour Recherches Médicales, University of Geneva, 1211 Geneva, Switzerland; and
Department of Nutrition and Institut du Cancer, University of Montreal, Centre de Recherche L. C. Simard, Montreal H2L 4M1, Canada
1Correspondence: Fondation pour Recherches Médicales, University of Geneva, 64 avenue de la Roseraie, 1211 Geneva, Switzerland. E-mail: vanhaast{at}cmu.unige.ch
Glucose controls long-term processes in the pancreatic ß-cell such as metabolic enzymes gene expression, cell growth, and apoptosis. Such control is likely mediated via the expression of immediate-early response genes since several of these genes including c-fos are strongly induced by glucose in the ß-cell line INS-1, provided costimulation with cAMP-raising glucoincretin hormones. This study addresses the mechanism of c-fos gene activation by glucose. Glucose in the presence of chlorophenylthio-cAMP generated a low threefold induction of the c-fos/basic luciferase reporter gene, which includes only the c-fos promoter. In contrast, the c-fos/intron construct containing the first intron in addition to promoter elements showed a pronounced 16-fold induction, comparable to the increased c-fos mRNA accumulation. Similar observations were made with glucose in combination with the glucoincretins glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and pituitary adenylyl cyclase-activating peptide 38. Deletion of a 119 bp region in intron 1 that includes a transcriptional arrest site did not affect the inductive process. In contrast, a 534 bp deletion comprising a major part of the intron reduced the induction by 75%. At the promoter level, mutating the cAMP response element reduced by more than 60% the transcriptional activation whereas mutating the serum response element had no effect. Inhibitors of protein kinase A and Ca2+/calmodulin-dependent protein kinases each reduced by 50% the reporter gene activation and together fully prevented the glucose-glucoincretin effect. In conclusion, the strong induction of c-fos by glucose and glucoincretins results from Ca2+ and cAMP signaling pathways addressing both the CRE in the promoter and essential response element(s) in the first intron that are unrelated to the transcription arrest site.—Susini, S., van Haasteren, G., Li, S., Prentki, M., Schlegel, W. Essentiality of intron control in the induction of c-fos by glucose and glucoincretin peptides in INS-1 ß-cells.
Key Words: immediate-early response genes • proto-oncogenes • intragenic response element • glucagon-like peptide 1 • intracellular Ca2+
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