Glucocorticoid Receptor-Beta and Receptor-Gamma Exert Dominant Negative Effect on Gene Repression but Not on Gene Induction

Endocrinology. 2010 Jul;151(7):3204-13. doi: 10.1210/en.2009-1254. Epub 2010 May 19.

Abstract

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-alpha), a variety of GR variants has been reported, and these are thought to modify glucocorticoid action. Among others, GR-beta 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-beta and some GR variants (GR-gamma and GR-Delta313-338) using GR-deficient BE(2)C and T84 cells in vitro. We found that GR-beta, when expressed alone, completely lost the capacity of both trans-activation and trans-repression on GR target genes. Interestingly, however, GR-beta showed a dominant-negative effect on GR-alpha only for its trans-repressive effects on cAMP-mediated and cAMP response element-dependent genes. Furthermore, both GR-beta and GR-gamma had dominant-negative effects on GR-alpha selectively for its trans-repressive effects on nuclear factor-kappaB-mediated and inflammation-related genes. These results suggest that 1) the GR-beta variant by itself has no receptor function, but 2) GR-beta and GR-gamma have properties to exert dominant-negative effects on the GR-alpha-mediated trans-repression, which may be responsible for the steroid resistance frequently observed in chronic inflammatory diseases under glucocorticoid therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • Humans
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism
  • Receptors, Glucocorticoid / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • GRgamma protein, human
  • Receptors, Glucocorticoid
  • glucocorticoid receptor alpha
  • glucocorticoid receptor beta