Expression Level-Dependent Contribution of Glucocorticoid Receptor Domains for Functional Interaction with STAT5
| Autor: | T. Almlöf, Sibylle Geymayer, D. B. Starr, D. Edwards, J. Liden, S. Okret, M. Windegger, S. Rusconi, J. Tomasi, Helmut Klocker, Jan-Ake Gustafsson, H. Richard-Foy, Judith Lechner, Andrew C.B. Cato, C. Soratroi, Wolfgang Doppler |
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| Rok vydání: | 2001 |
| Předmět: |
Transcriptional Activation
Molecular Sequence Data Biology Cell Line Transactivation Receptors Glucocorticoid Glucocorticoid receptor Transcription (biology) Chlorocebus aethiops Coactivator Gene expression STAT5 Transcription Factor Animals Amino Acid Sequence HMGB1 Protein Promoter Regions Genetic Molecular Biology Transcription factor Transcriptional Regulation Binding Sites High Mobility Group Proteins Caseins Zinc Fingers Promoter DNA Cell Biology DNA-binding domain Milk Proteins Molecular biology DNA-Binding Proteins Amino Acid Substitution COS Cells Trans-Activators Carrier Proteins Dimerization |
| Zdroj: | Molecular and Cellular Biology. 21:3266-3279 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.21.9.3266-3279.2001 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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