This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Charmandari, E. Articles by Kino, T. Search for Related Content PubMed PubMed Citation Articles by Charmandari, E. Articles by Kino, T.

The Human Glucocorticoid Receptor (hGR) ß Isoform Suppresses the Transcriptional Activity of hGR by Interfering with Formation of Active Coactivator Complexes

Pediatric and Reproductive Endocrinology Branch (E.C., G.P.C., T.I., A.V., T.K.), National Institute of Child Health and Human Development, and Diabetes Branch (N.B.), National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Evangelia Charmandari, MD, Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Building 10, Room 9D42, Bethesda, Maryland 20892-1583. E-mail: charmane{at}mail.nih.gov.

The human glucocorticoid receptor (hGR) ß, a splicing variant of the classic receptor hGR, functions as a dominant-negative inhibitor of hGR. We explored the mechanism(s) underlying this effect of hGRß by evaluating the interactions of this isoform with known steroid receptor coactivators. We found that hGRß suppressed the transcriptional activity of both activation function (AF)-1 and AF-2 of hGR, indicating that hGRß may exert its dominant-negative effect by affecting the function of coactivators that are attracted to these transactivation domains. hGRß bound to one of the p160 coactivators, the glucocorticoid receptor-interacting protein 1 (GRIP1) via its preserved AF-1 but not via its defective AF-2 in vitro. In a chromatin immunoprecipitation assay, hGRß prevented coprecipitation of GRIP1 with hGR tethered to glucocorticoid response elements of the endogenous tyrosine aminotransferase promoter, whereas deletion of the AF-1 of hGRß abolished this effect. In further experiments, overexpression of GRIP1 attenuated the suppressive effect of hGRß on hGR-mediated transactivation of the mouse mammary tumor virus promoter. Competition for binding to glucocorticoid response elements or heterodimerization with hGR via the D loop dimerization interface occurred, but they were not necessary for the suppressive effect of hGRß on the transcriptional activity of hGR. Our findings suggest that hGRß suppresses the transcriptional activity of hGR by competing with hGR for binding to GRIP1, and possibly other p160 coactivators, through its preserved AF-1. These findings suggest that participation of hGRß in the formation of a coactivator complex renders this complex ineffective.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR

Coregulators:   GRIP1

Ligands:   Dexamethasone

This article has been cited by other articles:

				I. V. Glybina, A. Kennedy, P. Ashton, G. W. Abrams, and R. Iezzi Photoreceptor Neuroprotection in RCS Rats via Low-Dose Intravitreal Sustained-Delivery of Fluocinolone Acetonide Invest. Ophthalmol. Vis. Sci., October 1, 2009; 50(10): 4847 - 4857. [Abstract] [Full Text] [PDF]

				E. Charmandari, T. Ichijo, W. Jubiz, S. Baid, K. Zachman, G. P. Chrousos, and T. Kino A Novel Point Mutation in the Amino Terminal Domain of the Human Glucocorticoid Receptor (hGR) Gene Enhancing hGR-Mediated Gene Expression J. Clin. Endocrinol. Metab., December 1, 2008; 93(12): 4963 - 4968. [Abstract] [Full Text] [PDF]

				K. Kamiyama, N. Matsuda, S. Yamamoto, K.-i. Takano, Y. Takano, H. Yamazaki, S.-i. Kageyama, H. Yokoo, T. Nagata, N. Hatakeyama, et al. Modulation of glucocorticoid receptor expression, inflammation, and cell apoptosis in septic guinea pig lungs using methylprednisolone Am J Physiol Lung Cell Mol Physiol, December 1, 2008; 295(6): L998 - L1006. [Abstract] [Full Text] [PDF]

				A. Nehme and J. Edelman Dexamethasone Inhibits High Glucose-, TNF-{alpha}-, and IL-1{beta}-Induced Secretion of Inflammatory and Angiogenic Mediators from Retinal Microvascular Pericytes Invest. Ophthalmol. Vis. Sci., May 1, 2008; 49(5): 2030 - 2038. [Abstract] [Full Text] [PDF]

				M. J. M. Schaaf, D. Champagne, I. H. C. van Laanen, D. C. W. A. van Wijk, A. H. Meijer, O. C. Meijer, H. P. Spaink, and M. K. Richardson Discovery of a Functional Glucocorticoid Receptor {beta}-Isoform in Zebrafish Endocrinology, April 1, 2008; 149(4): 1591 - 1599. [Abstract] [Full Text] [PDF]

				L.-b. Li, D. Y. M. Leung, M. J. Strand, and E. Goleva ATF2 impairs glucocorticoid receptor mediated transactivation in human CD8+ T cells Blood, September 1, 2007; 110(5): 1570 - 1577. [Abstract] [Full Text] [PDF]

				T. Kino, T. Ichijo, N. D. Amin, S. Kesavapany, Y. Wang, N. Kim, S. Rao, A. Player, Y.-L. Zheng, M. J. Garabedian, et al. Cyclin-Dependent Kinase 5 Differentially Regulates the Transcriptional Activity of the Glucocorticoid Receptor through Phosphorylation: Clinical Implications for the Nervous System Response to Glucocorticoids and Stress Mol. Endocrinol., July 1, 2007; 21(7): 1552 - 1568. [Abstract] [Full Text] [PDF]

				D. L. Kozaci, Y. Chernajovsky, and I. C. Chikanza The differential expression of corticosteroid receptor isoforms in corticosteroid-resistant and -sensitive patients with rheumatoid arthritis Rheumatology, April 1, 2007; 46(4): 579 - 585. [Abstract] [Full Text] [PDF]

				L.-b. Li, D. Y. M. Leung, C. F. Hall, and E. Goleva Divergent expression and function of glucocorticoid receptor {beta} in human monocytes and T cells J. Leukoc. Biol., April 1, 2006; 79(4): 818 - 827. [Abstract] [Full Text] [PDF]

				E. Goleva, L.-b. Li, P. T. Eves, M. J. Strand, R. J. Martin, and D. Y. M. Leung Increased Glucocorticoid Receptor beta Alters Steroid Response in Glucocorticoid-insensitive Asthma Am. J. Respir. Crit. Care Med., March 15, 2006; 173(6): 607 - 616. [Abstract] [Full Text] [PDF]

				G. P. Chrousos and T. Kino Intracellular Glucocorticoid Signaling: A Formerly Simple System Turns Stochastic Sci. Signal., October 4, 2005; 2005(304): pe48 - pe48. [Abstract] [Full Text] [PDF]

				J. D Turner and C. P Muller Structure of the glucocorticoid receptor (NR3C1) gene 5' untranslated region: identification, and tissue distribution of multiple new human exon 1 J. Mol. Endocrinol., October 1, 2005; 35(2): 283 - 292. [Abstract] [Full Text] [PDF]

				H. Russcher, E. F. C. van Rossum, F. H. de Jong, A. O. Brinkmann, S. W. J. Lamberts, and J. W. Koper Increased Expression of the Glucocorticoid Receptor-A Translational Isoform as a Result of the ER22/23EK Polymorphism Mol. Endocrinol., July 1, 2005; 19(7): 1687 - 1696. [Abstract] [Full Text] [PDF]

				E. Charmandari, A. Raji, T. Kino, T. Ichijo, A. Tiulpakov, K. Zachman, and G. P. Chrousos A Novel Point Mutation in the Ligand-Binding Domain (LBD) of the Human Glucocorticoid Receptor (hGR) Causing Generalized Glucocorticoid Resistance: The Importance of the C Terminus of hGR LBD in Conferring Transactivational Activity J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3696 - 3705. [Abstract] [Full Text] [PDF]