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Molecular and Cellular Biology, July 2008, p. 4588-4597, Vol. 28, No. 14
0270-7306/08/$08.00+0     doi:10.1128/MCB.01191-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The MODY1 Gene for Hepatocyte Nuclear Factor 4{alpha} and a Feedback Loop Control COUP-TFII Expression in Pancreatic Beta Cells{triangledown}

Anaïs Perilhou,1,2 Cécile Tourrel-Cuzin,1,2 Pili Zhang,3 Ilham Kharroubi,1,2 Haiyan Wang,4 Véronique Fauveau,1,2 Donald K. Scott,3 Claes B. Wollheim,5 and Mireille Vasseur-Cognet1,2*

Department of Endocrinology, Metabolism and Cancer, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France,1 INSERM, U567, Paris, France,2 Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261,3 PRBD-Metabolic Diseases, Hoffmann-La Roche, Basel, Switzerland,4 Department of Cell Physiology and Metabolism, University Medical Centre, 1211 Geneva 4, Switzerland5

Received 4 July 2007/ Returned for modification 2 August 2007/ Accepted 18 April 2008

Pancreatic islet beta cell differentiation and function are dependent upon a group of transcription factors that maintain the expression of key genes and suppress others. Knockout mice with the heterozygous deletion of the gene for chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) or the complete disruption of the gene for hepatocyte nuclear factor 4{alpha} (HNF4{alpha}) in pancreatic beta cells have similar insulin secretion defects, leading us to hypothesize that there is transcriptional cross talk between these two nuclear receptors. Here, we demonstrate specific HNF4{alpha} activation of a reporter plasmid containing the COUP-TFII gene promoter region in transfected pancreatic beta cells. The stable association of the endogenous HNF4{alpha} with a region of the COUP-TFII gene promoter that contains a direct repeat 1 (DR-1) binding site was revealed by chromatin immunoprecipitation. Mutation experiments showed that this DR-1 site is essential for HNF4{alpha} transactivation of COUP-TFII. The dominant negative suppression of HNF4{alpha} function decreased endogenous COUP-TFII expression, and the specific inactivation of COUP-TFII by small interfering RNA caused HNF4{alpha} mRNA levels in 832/13 INS-1 cells to decrease. This positive regulation of HNF4{alpha} by COUP-TFII was confirmed by the adenovirus-mediated overexpression of human COUP-TFII (hCOUP-TFII), which increased HNF4{alpha} mRNA levels in 832/13 INS-1 cells and in mouse pancreatic islets. Finally, hCOUP-TFII overexpression showed that there is direct COUP-TFII autorepression, as COUP-TFII occupies the proximal DR-1 binding site of its own gene in vivo. Therefore, COUP-TFII may contribute to the control of insulin secretion through the complex HNF4{alpha}/maturity-onset diabetes of the young 1 (MODY1) transcription factor network operating in beta cells.

* Corresponding author. Mailing address: Institut Cochin, Department of Endocrinology, Metabolism and Cancer, Université Paris Descartes, CNRS (UMR 8104), 24 rue du Faubourg Saint Jacques, Paris 75014, France. Phone: (33) 1 44 41 24 20. Fax: (33) 1 44 41 24 21. E-mail: mireille.vasseur{at}inserm.fr

{triangledown} Published ahead of print on 12 May 2008.

Molecular and Cellular Biology, July 2008, p. 4588-4597, Vol. 28, No. 14
0270-7306/08/$08.00+0     doi:10.1128/MCB.01191-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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  • Perilhou, A., Tourrel-Cuzin, C., Kharroubi, I., Henique, C., Fauveau, V., Kitamura, T., Magnan, C., Postic, C., Prip-Buus, C., Vasseur-Cognet, M. (2008). The Transcription Factor COUP-TFII Is Negatively Regulated by Insulin and Glucose via Foxo1- and ChREBP-Controlled Pathways. Mol. Cell. Biol. 28: 6568-6579 [Abstract] [Full Text]  


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