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
Junguo ZhouJohn A Cidlowski

Abstract

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 parti...Continue Reading

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