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This version published online on July 21, 2005
Molecular Endocrinology, doi:10.1210/me.2004-0497
A more recent version of this article appeared on December 1, 2005
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Submitted on December 8, 2004
Accepted on July 13, 2005

The Glucose-6-Phosphatase Catalytic Subunit Gene Promoter Contains Both Positive and Negative Glucocorticoid Response Elements

Beth T. Vander Kooi, Hiroshi Onuma, James K. Oeser, Christina A. Svitek, Shelley R. Allen, Craig W. Vander Kooi, Walter J. Chazin, and Richard M. O'Brien*

Department of Molecular Physiology and Biophysics, Department of Biochemistry, Center for Structural Biology, and Department of Physics, Schools of Medicine and Arts and Science, Vanderbilt University, Nashville, Tennessee 37232

* To whom correspondence should be addressed. E-mail: richard.obrien{at}vanderbilt.edu.

Glucose-6-phosphatase catalyzes the final step in the gluconeogenic and glycogenolytic pathways. Glucocorticoids stimulate glucose-6-phosphatase catalytic subunit (G6Pase) gene transcription and studies performed in H4IIE hepatoma cells demonstrate the presence of a glucocorticoid response unit (GRU) in the proximal G6Pase promoter. In vitro DNase I footprinting analyses show that the glucocorticoid receptor (GR) binds to three glucocorticoid response elements (GREs) in the -231 to -129 promoter region and transfection results indicate all three contribute to glucocorticoid induction of G6Pase gene transcription. Furthermore, binding sites for HNF-1, HNF-4, CRE binding factors and FKHR (FOXO1a) are required for the full glucocorticoid response. Chromatin immunoprecipitation assays show that dexamethasone treatment stimulates GR and FKHR binding to the endogenous G6Pase promoter. Surprisingly, although glucocorticoids stimulate G6Pase gene transcription, DNase I footprinting and transfection analyses demonstrate the presence of a negative GRE and an associated negative accessory factor element in the -271 to -225 promoter region, which inhibit the glucocorticoid response. This appears to be the first report of a promoter that contains both positive and negative GREs, which function within the same cellular environment. We hypothesize that targeted signaling to the negative accessory element within the GRU may provide tight regulation of the glucocorticoid stimulation.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR
Ligands:   Dexamethasone



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