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J. Biol. Chem., Vol. 280, Issue 40, 33873-33884, October 7, 2005

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Glucocorticoids Regulate Transcription of the Gene for Phosphoenolpyruvate Carboxykinase in the Liver via an Extended Glucocorticoid Regulatory Unit^*

Hanoch Cassuto, Karen Kochan, Kaushik Chakravarty, Hannah Cohen, Barak Blum, Yael Olswang, Parvin Hakimi, Chuan Xu, Duna Massillon, Richard W. Hanson*, and Lea Reshef1

From the Department of Developmental Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, 91120 Israel and the Departments of Biochemistry and Nutrition, Case Western Reserve University, Cleveland, Ohio 44106-4935

The hepatic transcriptional regulation by glucocorticoids of the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C) gene is coordinated by interactions of specific transcription factors at the glucocorticoid regulatory unit (GRU). We propose an extended GRU that consists of four accessory sites, two proximal AF1 and AF2 sites and their distal counterpart dAF1 (–993) and a new site, dAF2 (–1365); together, these four sites form a palindrome. Sequencing and gel shift binding assays of hepatic nuclear proteins interacting with these sites indicated similarity of dAF1 and dAF2 sites to the GRU proximal AF1 and AF2 sites. Chromatin immunoprecipitation assays demonstrated that glucocorticoids enhanced the binding of FOXO1 and peroxisome proliferator-activated receptor- to AF2 and dAF2 sites and not to dAF1 site but enhanced the binding of hepatic nuclear transcription factor-4 only to the dAF1 site. Insulin inhibited the binding of these factors to their respective sites but intensified the binding of phosphorylated FOXO1. Transient transfections in HepG2 human hepatoma cells showed that glucocorticoid receptor interacts with several non-steroid nuclear receptors, yielding a synergistic response of the PEPCK-C gene promoter to glucocorticoids. The synergistic stimulation by glucocorticoid receptor together with peroxisome proliferator-activated receptor- or hepatic nuclear transcription factor-4 requires all four accessory sites, i.e. a mutation of each of these markedly affects the synergistic response. Mice with a targeted mutation of the dAF1 site confirmed this requirement. This mutation inhibited the full response of hepatic PEPCK-C gene to diabetes by reducing PEPCK-C mRNA level by 3.5-fold and the level of circulating glucose by 25%.

Received for publication, April 15, 2005 , and in revised form, July 15, 2005.

^* This research was supported by United States-Israel Binational Science Foundation Grant 1999346 and by a grant from the Ministry of Health of Israel (to L. R.) and by National Institutes of Health Grant DK22541 (to R. W. H.). 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.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, Hebrew University-Hadassah Medical School, P. O. Box 12272, Jerusalem 91120, Israel. Tel.: 972-2-6758291; Fax: 972-2-6757379; E-mail: reshef{at}cc.huji.ac.il.

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