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

Mol Endocrinol. 2008 Jul;22(7):1521-34. doi: 10.1210/me.2007-0273. Epub 2008 Apr 16.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Motifs
  • Animals
  • COS Cells
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Gene Expression Regulation*
  • Glucocorticoids / metabolism
  • Humans
  • Models, Biological
  • Protein Binding
  • Receptors, Glucocorticoid / metabolism*
  • Receptors, Retinoic Acid / metabolism
  • Receptors, Retinoic Acid / physiology*
  • Repressor Proteins / metabolism
  • Repressor Proteins / physiology*
  • Signal Transduction
  • Transcriptional Activation*


  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins
  • Glucocorticoids
  • NR0B1 protein, human
  • Receptors, Glucocorticoid
  • Receptors, Retinoic Acid
  • Repressor Proteins