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

doi:10.1128/MCB.21.9.3266-3279.2001

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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 wherethe action of the GR is dependent on the activity of another transcriptionfactor, STAT5. We have investigated the domain-requirement ofthe GR for this synergistic response in transfection experimentsemploying GR mutants and CV-1 or COS-7 cells. The results wereinfluenced by the expression levels of the GR constructs. At lowexpression, STAT5-dependent transactivation by mutants of theGR DNA binding domain or N-terminal transactivation domain wasimpaired and the antiglucocorticoid RU486 exhibited a weak agonisticactivity. When the N-terminal region of the GR was exchanged withthe respective domain of the progesterone receptor, STAT5-dependenttransactivation was reduced at low and high expression levels.Only at high expression levels did the GR exhibit the propertiesof a coactivator and enhanced STAT5 activity in the absence ofa functional DNA binding domain and of GR binding sites in theproximal region of the $beta$ -casein gene promoter. Furthermore, athigh GR expression levels RU486 was nearly as efficient as dexamethasonein activating transcription via the STAT5 dependent $beta$ -casein genepromoter. The results reconcile the controversial issue regardingthe DNA binding-independent action of the GR together with STAT5and provide evidence that the mode of action of the GR dependsnot only on the type of the particular promoter at which it actsbut also on the concentration of the GR. GR DNA binding functionappears to be mandatory for $beta$ -casein gene expression in mammaryepithelial cells, since the promoter function is completely dependenton the integrity of GR binding sites in thepromoter.

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

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