Glucocorticoid Receptor-β and Receptor-γ Exert Dominant Negative Effect on Gene Repression But Not on Gene Induction

Glucocorticoid has diverse biological effects through induction or repression of its target genes via glucocorticoid receptor (GR). In addition to the wild-type GR (GR-α), a variety of GR variants has been reported, and these are thought to modify glucocorticoid action. Among others, GR-β is reported be responsible for the glucocorticoid resistance frequently observed in steroid-resistant nephrotic syndrome, rheumatoid arthritis, and hematologic tumors, although the precise molecular mechanism remains unclear. In this study, we examined the function of GR-β and some GR variants (GR-γ and GR-Δ313-338) using GR-deficient BE(2)C and T84 cells in vitro. We found that GR-β, when expressed alone, completely lost the capacity of both trans-activation and trans-repression on GR target genes. Interestingly, however, GR-β showed a dominant-negative effect on GR-α only for its trans-repressive effects on cAMP-mediated and cAMP response element-dependent genes. Furthermore, both GR-β and GR-γ had dominant-negative ef...