This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart 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 Mittelstadt, P. R. Articles by Ashwell, J. D. Search for Related Content PubMed PubMed Citation Articles by Mittelstadt, P. R. Articles by Ashwell, J. D.

Disruption of Glucocorticoid Receptor Exon 2 Yields a Ligand-Responsive C-Terminal Fragment that Regulates Gene Expression

Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Jonathan D. Ashwell, Building 10, Room 1B-40, National Institutes of Health, Bethesda, Maryland 20892. E-mail: jda{at}pop.nci.nih.gov.

Mice in which exon 2 of the glucocorticoid receptor (GR) has been disrupted [GR exon 2 knockout (GR2KO)] have been used as a model to study the requirement for this receptor in a number of biological systems. A recent report showed that these mice actually express a truncated ligand-binding GR fragment, prompting us to ask whether this mutation truly results in a glucocorticoid-insensitive phenotype. Based on cDNA microarray analysis of fetal thymocytes, we found that glucocorticoids were able to enhance or repress activation-induced gene expression in GR2KO and wild-type thymocytes to a similar degree. Moreover, although changes in gene expression induced by glucocorticoids alone were blunted, the expression of a substantial number of genes in GR2KO thymocytes was modulated by stimulation with glucocorticoids. Among these genes, as confirmed by quantitative real-time PCR, was the classic glucocorticoid-responsive gene glutamine synthetase as well as genes implicated in T cell development and function such as IL-7 receptor -chain and glucocorticoid-induced leucine zipper (GIL2). Thus, the truncated C-terminal GR2KO product, which lacks the major transactivation domain, retains, to a large extent, the ability to regulate gene expression both positively and negatively in a ligand-responsive manner when expressed in vivo.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR

Ligands:   Dexamethasone

This article has been cited by other articles:

				W. Chen, I. Rogatsky, and M. J. Garabedian MED14 and MED1 Differentially Regulate Target-Specific Gene Activation by the Glucocorticoid Receptor Mol. Endocrinol., March 1, 2006; 20(3): 560 - 572. [Abstract] [Full Text] [PDF]

				C. M. Bula, J. Huhtakangas, C. Olivera, J. E. Bishop, A. W. Norman, and H. L. Henry Presence of a Truncated Form of the Vitamin D Receptor (VDR) in a Strain of VDR-Knockout Mice Endocrinology, December 1, 2005; 146(12): 5581 - 5586. [Abstract] [Full Text] [PDF]

				T. J. Cole, D. R. Liddicoat, and D. I. Godfrey Intrathymic Glucocorticoid Production and Thymocyte Survival: Another Piece in the Puzzle Endocrinology, June 1, 2005; 146(6): 2499 - 2500. [Full Text] [PDF]

				D. B. Conze, L. Albert, D. A. Ferrick, D. V. Goeddel, W.-C. Yeh, T. Mak, and J. D. Ashwell Posttranscriptional Downregulation of c-IAP2 by the Ubiquitin Protein Ligase c-IAP1 In Vivo Mol. Cell. Biol., April 15, 2005; 25(8): 3348 - 3356. [Abstract] [Full Text] [PDF]

				T. M. Wintermantel, D. Bock, V. Fleig, E. F. Greiner, and G. Schutz The Epithelial Glucocorticoid Receptor Is Required for the Normal Timing of Cell Proliferation during Mammary Lobuloalveolar Development but Is Dispensable for Milk Production Mol. Endocrinol., February 1, 2005; 19(2): 340 - 349. [Abstract] [Full Text] [PDF]

				S. Cho, B. L. Kagan, J. A. Blackford Jr., D. Szapary, and S. S. Simons Jr. Glucocorticoid Receptor Ligand Binding Domain Is Sufficient for the Modulation of Glucocorticoid Induction Properties by Homologous Receptors, Coactivator Transcription Intermediary Factor 2, and Ubc9 Mol. Endocrinol., February 1, 2005; 19(2): 290 - 311. [Abstract] [Full Text] [PDF]

				I. Cima, N. Corazza, B. Dick, A. Fuhrer, S. Herren, S. Jakob, E. Ayuni, C. Mueller, and T. Brunner Intestinal Epithelial Cells Synthesize Glucocorticoids and Regulate T Cell Activation J. Exp. Med., December 20, 2004; 200(12): 1635 - 1646. [Abstract] [Full Text] [PDF]

				I. Rogatsky, J.-C. Wang, M. K. Derynck, D. F. Nonaka, D. B. Khodabakhsh, C. M. Haqq, B. D. Darimont, M. J. Garabedian, and K. R. Yamamoto Target-specific utilization of transcriptional regulatory surfaces by the glucocorticoid receptor PNAS, November 25, 2003; 100(24): 13845 - 13850. [Abstract] [Full Text] [PDF]