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.
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.
Zhou
Junguo
J
Laboratory of Signal Transduction, NIEHS/NIH, Research Triangle Park, NC 27709, USA.
Oakley
Robert H
RH
Cidlowski
John A
JA
D021581:Active Transport, Cell Nucleus; D020816:Amino Acid Motifs; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D015533:Transcriptional Activation
D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; C539965:NR0B1 protein, human; D011965:Receptors, Glucocorticoid; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins