Mouse Glucocorticoid Receptor Phosphorylation Status Influences Multiple Functions of the Receptor Protein
| Autor: | Christine M. Jewell, John A. Cidlowski, Allan Munck, Madhabananda Sar, Jeffrey C. Webster, Jack E. Bodwell |
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| Rok vydání: | 1997 |
| Předmět: |
Transcription
Genetic Receptor expression Biology Transfection Biochemistry Mice Estrogen-related receptor alpha Receptors Glucocorticoid Glucocorticoid receptor Animals 5-HT5A receptor RNA Messenger Phosphorylation Glucocorticoids Molecular Biology Nuclear receptor co-repressor 1 Cell Nucleus Cell Biology Cell biology Interleukin-21 receptor COS Cells Mutagenesis Site-Directed Nuclear receptor coactivator 2 Cancer research Estrogen-related receptor gamma Half-Life |
| Zdroj: | Journal of Biological Chemistry. 272:9287-9293 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.272.14.9287 |
| Popis: | Although studies have shown that the mouse glucocorticoid receptor (mGR) contains eight phosphorylation sites (Bodwell, J. E., Ortí, E. , Coull, J. M., Pappin, D. J. C., Smith, L. I., and Swift, F. (1991) J. Biol. Chem. 266, 7549-7555), the effect of phosphorylation on receptor function is unclear. We have examined the consequences of single or multiple phosphorylation site mutations on several properties of mGR including receptor expression, ligand-dependent nuclear translocation, hormone-mediated transactivation, ligand-dependent down-regulation of mGR, and receptor protein half-life. Mutations had little effect on receptor expression, subcellular distribution, ligand-dependent nuclear translocation, or on the ability to activate hormone-mediated transcription from a complex (murine mammary tumor virus) promoter. In contrast, the phosphorylation status of the mGR had a profound effect on the ability to transactivate a minimal promoter containing simple glucocorticoid response elements after hormone administration. Similarly, ligand-dependent down-regulation by glucocorticoids of both receptor mRNA and protein was abrogated in mutants containing three or more phosphorylation site alterations. Finally, we show that the phosphorylation status of mGR has a profound effect on the stability of the glucocorticoid receptor protein. Receptors containing seven or eight mutated sites have a markedly extended half-life and do not show the ligand-dependent destabilization seen with wild type receptor. These data show that receptor phosphorylation may play a crucial role in regulating receptor levels and hence control receptor functions. |
| Databáze: | OpenAIRE |
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