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Molecular and Cellular Biology, May 2001, p. 3266-3279, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3266-3279.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Expression Level-Dependent Contribution of Glucocorticoid Receptor Domains for Functional Interaction with STAT5

Wolfgang Doppler,1,* Michaela Windegger,1 Claudia Soratroi,1 Jürgen Tomasi,1 Judith Lechner,1 Sandro Rusconi,2 Andrew C. B. Cato,3 Tova Almlöf,4 Johan Liden,4 Sam Okret,4 Jan-Åke Gustafsson,4 Hélène Richard-Foy,5 D. Barry Starr,6 Helmut Klocker,7 Dean Edwards,8 and Sibylle Geymayer1

Institut für Medizinische Chemie und Biochemie1 and Klinik für Urologie,7 Universität Innsbruck, A-6020 Innsbruck, Austria; Department of Biochemistry, University of Fribourg, Perolles, CH-1700 Fribourg, Switzerland2; Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany3; Department of Medical Nutrition, Karolinska Institutet, Novum, Huddinge University Hospital, S-141 86 Huddinge, Sweden4; Laboratoire de Biologie Moleculaire Eucaryote du CNRS, 31062 Toulouse, France5; Genelabs Technologies, Inc., Redwood City, California 940636; and Department of Pathology, University of Colorado School of Medicine, Denver, Colorado 802628

Received 22 December 2000/Accepted 12 February 2001

The action of the glucocorticoid receptor (GR) on beta -casein gene transcription serves as a well-studied example of a case where the action of the GR is dependent on the activity of another transcription factor, STAT5. We have investigated the domain-requirement of the GR for this synergistic response in transfection experiments employing GR mutants and CV-1 or COS-7 cells. The results were influenced by the expression levels of the GR constructs. At low expression, STAT5-dependent transactivation by mutants of the GR DNA binding domain or N-terminal transactivation domain was impaired and the antiglucocorticoid RU486 exhibited a weak agonistic activity. When the N-terminal region of the GR was exchanged with the respective domain of the progesterone receptor, STAT5-dependent transactivation was reduced at low and high expression levels. Only at high expression levels did the GR exhibit the properties of a coactivator and enhanced STAT5 activity in the absence of a functional DNA binding domain and of GR binding sites in the proximal region of the beta -casein gene promoter. Furthermore, at high GR expression levels RU486 was nearly as efficient as dexamethasone in activating transcription via the STAT5 dependent beta -casein gene promoter. The results reconcile the controversial issue regarding the DNA binding-independent action of the GR together with STAT5 and provide evidence that the mode of action of the GR depends not only on the type of the particular promoter at which it acts but also on the concentration of the GR. GR DNA binding function appears to be mandatory for beta -casein gene expression in mammary epithelial cells, since the promoter function is completely dependent on the integrity of GR binding sites in the promoter.

* Corresponding author. Mailing address: Institut für Medizinische Chemie und Biochemie, Universität Innsbruck, Fritz Pregl Str. 3, A-6020 Innsbruck, Austria. Phone: 43-512-507-3512. Fax: 43-512-507-2638. E-mail: Wolfgang.Doppler{at}uibk.ac.at.

Molecular and Cellular Biology, May 2001, p. 3266-3279, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3266-3279.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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