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DAX-1 (Dosage-Sensitive Sex Reversal-Adrenal Hypoplasia Congenita Critical Region on the X-Chromosome, Gene 1) Selectively Inhibits Transactivation But Not Transrepression Mediated by the Glucocorticoid Receptor in a LXXLL-Dependent Manner

Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences/National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: John A. Cidlowski, Ph.D., Laboratory of Signal Transduction, National Institute of Environmental Health Sciences/National Institutes of Health, Building 101, MD F3-07, 111 T.W. Alexander Drive, Research Triangle Park, North Carolina 27709. E-mail: cidlows1{at}niehs.nih.gov.

The glucocorticoid receptor (GR) mediates virtually all actions of glucocorticoids, and the nature and magnitude of a cell’s response to these steroids are determined primarily by hormone concentration and GR signaling capacity. DAX-1 (dosagesensitive sex reversal-adrenal hypoplasia congenita critical region on the X-chromosome, gene 1) is an orphan nuclear receptor that functions as a corepressor, and deletion or mutation of DAX-1 causes a decrease in glucocorticoid production. However it is unclear whether DAX-1 also alters GR function as a transcription factor. Here, we demonstrate that DAX-1 acts as a novel selective GR modulator. It specifically inhibits ligand-dependent GR transactivation with little effect on GR-mediated transrepression. As demonstrated by coimmunoprecipitation and glutathione- S-transferase pull-down assays, DAX-1 physically interacts with GR, but this interaction does not influence either ligand-induced GR nuclear translocation or subsequent GR association with glucocorticoid-responsive elements. Instead, DAX-1 competes with coactivators such as GR-interacting protein 1 for binding to the receptor. Specifically, suppression of GR transactivation is mediated by the N-terminal half of DAX-1, and in particular the LXXLL motifs. Thus we demonstrate that DAX-1 directly modulates GR signaling in addition to affecting glucocorticoid hormone levels.

NURSA Molecule Pages Link:

Nuclear Receptors:   DAX1  |  GR

Coregulators:   GRIP1

Ligands:   Dexamethasone