Glucocorticoid receptor lacking the tau 1 transactivation domain ss a gene-specific regulator of the wild-type glucocorticoid-receptor activity

The glucocorticoid receptor (GR) contains a major transactivation function (tau 1), located in the N-terminal domain. tau 1 contributes to about 80% of the ligand-inducible transcriptional activity of GR. In this study, we show that GR devoid of tau 1 (Delta GR) 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 Delta GR. This effect was proportional to the amount of transfected Delta GR and was not due to squelching. A moderate expression level of stably transfected Delta GR 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 Delta GR 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 ene driven by the chicken glutamine synthetase promoter was inhibited by Delta GR 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 Delta GR did not repress induction of the endogenous glutamine synthetase gene expression by wild type GR. Expression of Delta GR alone in CHO cells did not render the glutamine synthetase gene glucocorticoid responsive, indicating that Delta GR 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.