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Molecular and Cellular Biology, November 1998, p. 6305-6315, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Glucocorticoid Receptor, C/EBP, HNF3, and Protein Kinase A Coordinately Activate the Glucocorticoid Response Unit of the Carbamoylphosphate Synthetase I Gene

Vincent M. Christoffels,1 Thierry Grange,2 Klaus H. Kaestner,3 Timothy J. Cole,4 Gretchen J. Darlington,5 Colleen M. Croniger,6 and Wouter H. Lamers1,*

Department of Anatomy and Embryology, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands1; Institut Jaques Monod du CNRS, Université Paris 7, 75251 Paris Cedex 05, France2; Department of Genetics, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104-61453; Baker Medical Research Institute, Prahran, 3181 Victoria, Australia4; Department of Pathology and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 770305; and Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 441066

Received 20 March 1998/Returned for modification 28 April 1998/Accepted 5 August 1998

A single far-upstream enhancer is sufficient to confer hepatocyte-specific, glucocorticoid- and cyclic AMP-inducible periportal expression to the carbamoylphosphate synthetase I (CPS) gene. To identify the mechanism of hormone-dependent activation, the composition and function of the enhancer have been analyzed. DNase I protection and gel mobility shift assays revealed the presence of a cyclic AMP response element, a glucocorticoid response element (GRE), and several sites for the liver-enriched transcription factor families HNF3 and C/EBP. The in vivo relevance of the transcription factors interacting with the enhancer in the regulation of CPS expression in the liver was assessed by the analysis of knockout mice. A strong reduction of CPS mRNA levels was observed in glucocorticoid receptor- and C/EBPalpha -deficient mice, whereas the CPS mRNA was normally expressed in C/EBPbeta knockout mice and in HNF3alpha and -gamma double-knockout mice. (The role of HNFbeta could not be assessed, because the corresponding knockout mice die at embryonic day 10). In hepatoma cells, most of the activity of the enhancer is contained within a 103-bp fragment, which depends for its activity on the simultaneous occupation of the GRE, HNF3, and C/EBP sites, thus meeting the requirement of a glucocorticoid response unit. In fibroblast-like CHO cells, on the other hand, the GRE in the CPS enhancer does not cooperate with the C/EBP and HNF3 elements in transactivation of the CPS promoter. In both hepatoma and CHO cells, stimulation of expression by cyclic AMP depends mainly on the integrity of the glucocorticoid pathway, demonstrating cross talk between this pathway and the cyclic AMP (protein kinase A) pathway.

* Corresponding author. Mailing address: Department of Anatomy and Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Phone: 31 20 5664927. Fax: 31 20 6976177. E-mail: w.h.lamers{at}amc.uva.nl.

Molecular and Cellular Biology, November 1998, p. 6305-6315, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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