Glucocorticoid receptor lacking the τ1 transactivation domain is a gene-specific regulator of the wild-type glucocorticoid-receptor activity

Franck Delaunay, Johan Liden, Jan-Ake Gustafsson, Sam Okret

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The glucocorticoid receptor (GR) contains a major transactivation function (τ1), located in the N-terminal domain. τ1 contributes to about 80% of the ligand-inducible transcriptional activity of GR. In this study, we show that GR devoid of τ1 (ΔGR) can inhibit activation of gene expression by wild-type GR but this does not occur for all target genes. Activation of the mouse mammary tumor virus promoter by wild-type GR in transiently transfected Chinese hamster ovary (CHO) cells lacking endogenous GR was repressed by cotransfecting ΔGR. This effect was proportional to the amount of transfected ΔGR and was not due to squelching. A moderate expression level of stably transfected ΔGR mutant was also shown to repress the transcriptional activity of endogenous GR present in rat skeletal myoblast L8 cells. Glucocorticoid mediated down regulation of endogenous GR gene expression can be blocked by the ΔGR mutant in stably transfected L8 cells. In contrast, no inhibition was observed on glucocorticoid induction of the endogenous glutamine synthetase gene in L8 cells. However, glucocorticoid induction of a reporter gene driven by the chicken glutamine synthetase promoter was inhibited by ΔGR in L8 cells. Stable expression of wild-type GR in CHO cells rendered the cells glucocorticoid responsive with regard to glutamine synthetase induction but coexpression of ΔGR did not repress induction of the endogenous glutamine synthetase gene expression by wild-type GR. Expression of ΔGR alone in CHO cells did not render the glutamine synthetase gene glucocorticoid responsive, indicating that ΔGR has no transcriptional activity on the glutamine synthetase gene. We conclude from these results that the structure of glucocorticoid-response elements within target genes may be very critical for the ability of the mutant receptor to exhibit a dominant negative effect.

Original languageEnglish (US)
Pages (from-to)839-845
Number of pages7
JournalEuropean Journal of Biochemistry
Volume242
Issue number3
DOIs
StatePublished - Jan 1 1996

Keywords

  • Dominant negative mutant
  • Gene regulation
  • Glucocorticoid receptor
  • Glutamine synthetase

ASJC Scopus subject areas

  • Biochemistry

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