The pancreatic islet hormone glucagon stimulates hepatic glucose production and thus maintains blood glucose levels in the fasting state. Transcription factors of the Foxa [Fox (forkhead box) subclass A; also known as HNF-3 (hepatocyte nuclear factor-3)] family are required for cell-specific activation of the glucagon gene in pancreatic islet α-cells. However, their action on the glucagon gene is poorly understood. In the present study, comparative sequence analysis and molecular characterization using protein–DNA binding and transient transfection assays revealed that the well-characterized Foxa-binding site in the G2 enhancer element of the rat glucagon gene is not conserved in humans and that the human G2 sequence lacks basal enhancer activity. A novel Foxa site was identified that is conserved in rats, mice and humans. It mediates activation of the glucagon gene by Foxa proteins and confers cell-specific promoter activity in glucagon-producing pancreatic islet α-cell lines. In contrast with previously identified Foxa-binding sites in the glucagon promoter, which bind nuclear Foxa2, the novel Foxa site was found to bind preferentially Foxa1 in nuclear extracts of a glucagon-producing pancreatic islet α-cell line, offering a mechanism that explains the decrease in glucagon gene expression in Foxa1-deficient mice. This site is located just upstream of the TATA box (between −30 and −50), suggesting a role for Foxa proteins in addition to direct transcriptional activation, such as a role in opening the chromatin at the start site of transcription of the glucagon gene.
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Research Article|
July 26 2005
Characterization of a novel Foxa (hepatocyte nuclear factor-3) site in the glucagon promoter that is conserved between rodents and humans
Sanjeev K. Sharma;
Sanjeev K. Sharma
1Department of Molecular Pharmacology, University of Göttingen, D-37099 Göttingen, Germany
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Ulrike Leinemann;
Ulrike Leinemann
1Department of Molecular Pharmacology, University of Göttingen, D-37099 Göttingen, Germany
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Regine Ratke;
Regine Ratke
1Department of Molecular Pharmacology, University of Göttingen, D-37099 Göttingen, Germany
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Elke Oetjen;
Elke Oetjen
1Department of Molecular Pharmacology, University of Göttingen, D-37099 Göttingen, Germany
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Roland Blume;
Roland Blume
1Department of Molecular Pharmacology, University of Göttingen, D-37099 Göttingen, Germany
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Corinna Dickel;
Corinna Dickel
1Department of Molecular Pharmacology, University of Göttingen, D-37099 Göttingen, Germany
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Willhart Knepel
Willhart Knepel
1
1Department of Molecular Pharmacology, University of Göttingen, D-37099 Göttingen, Germany
1To whom correspondence should be addressed (email wknepel@med.uni-goettingen.de).
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Publisher: Portland Press Ltd
Received:
February 24 2005
Revision Received:
March 31 2005
Accepted:
April 14 2005
Accepted Manuscript online:
April 14 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 389 (3): 831–841.
Article history
Received:
February 24 2005
Revision Received:
March 31 2005
Accepted:
April 14 2005
Accepted Manuscript online:
April 14 2005
Citation
Sanjeev K. Sharma, Ulrike Leinemann, Regine Ratke, Elke Oetjen, Roland Blume, Corinna Dickel, Willhart Knepel; Characterization of a novel Foxa (hepatocyte nuclear factor-3) site in the glucagon promoter that is conserved between rodents and humans. Biochem J 1 August 2005; 389 (3): 831–841. doi: https://doi.org/10.1042/BJ20050334
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