title: Glucocorticoid receptor-beta and receptor-gamma exert dominant negative effect on gene repression but not on gene induction.
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.
authors.affiliation: Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Taniguchi
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsugita
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Nishiyama
authors.forename: Takafumi
authors.initials: T
authors.lastname: Taguchi
authors.forename: Mizuho
authors.initials: M
authors.lastname: Okazaki
authors.forename: Shuichi
authors.initials: S
authors.lastname: Nakayama
authors.forename: Machiko
authors.initials: M
authors.lastname: Kambayashi
authors.forename: Kozo
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Terada
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C497471:GRgamma protein, human; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta