The human glucocorticoid receptor (GR) isoform β differentially suppresses GRα-induced transactivation stimulated by synthetic glucocorticoids

Oren Fruchter, Tomoshige Kino, Emmanouil Zoumakis, Salvatore Alesci, Massimo De Martino, George Chrousos, Ze'ev Hochberg

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The β-isoform of human glucocorticoid receptor β (hGRβ) acts as a natural dominant negative inhibitor of hGRα-induced transactivation of glucocorticoid-responsive genes. We determined hGRβ ability to suppress hGRα transactivation that was induced by commonly used synthetic glucocorticoids. HepG2/C3A cells were transiently cotransfected with GR cDNA and a glucocorticoid-responsive promoter, luciferase (MMTV-luc). Transfected cells were incubated for 16 h with glucocorticoid and luciferase. For each compound, a dose-response curve was constructed, and half-maximal effective concentrations and maximal transcriptional activities were compared. hGRβ, at a 1:1 ratio to hGRα, differentially suppressed hGRα-induced maximal transcriptional activity stimulated by triamcinolone, dexamethasone, hydrocortisone, and betamethasone (by 96, 68, 62, and 49%, respectively) but not by methylprednisolone. The suppressive effect of hGRβ on hGRα-induced transactivation was stronger at lower concentrations of all tested glucocorticoids, whereas it was blunted at higher concentrations. We conclude that the potency of the dominant negative effect of hGRβ on hGRα-induced transactivation depends on both the type and the dose of the synthetic glucocorticoids in use. These results may provide helpful information concerning the selection of synthetic glucocorticoids for treatment of pathological conditions in which hGRβ modulates the sensitivity of tissues to glucocorticoids.

Original languageEnglish
Pages (from-to)3505-3509
Number of pages5
JournalJournal of Clinical Endocrinology and Metabolism
Volume90
Issue number6
DOIs
Publication statusPublished - Jun 2005
Externally publishedYes

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Glucocorticoid Receptors
Transcriptional Activation
Glucocorticoids
Protein Isoforms
Luciferases
Triamcinolone
Betamethasone
Methylprednisolone
Hep G2 Cells
Dexamethasone
Hydrocortisone
Complementary DNA
Genes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

The human glucocorticoid receptor (GR) isoform β differentially suppresses GRα-induced transactivation stimulated by synthetic glucocorticoids. / Fruchter, Oren; Kino, Tomoshige; Zoumakis, Emmanouil; Alesci, Salvatore; De Martino, Massimo; Chrousos, George; Hochberg, Ze'ev.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 90, No. 6, 06.2005, p. 3505-3509.

Research output: Contribution to journalArticle

Fruchter, Oren ; Kino, Tomoshige ; Zoumakis, Emmanouil ; Alesci, Salvatore ; De Martino, Massimo ; Chrousos, George ; Hochberg, Ze'ev. / The human glucocorticoid receptor (GR) isoform β differentially suppresses GRα-induced transactivation stimulated by synthetic glucocorticoids. In: Journal of Clinical Endocrinology and Metabolism. 2005 ; Vol. 90, No. 6. pp. 3505-3509.
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