GLUCOCORTICOID RECEPTOR LACKING THE TAU-1 TRANSACTIVATION DOMAIN SS AGENE-SPECIFIC REGULATOR OF THE WILD-TYPE GLUCOCORTICOID-RECEPTOR ACTIVITY

The glucocorticoid receptor (GR) contains a major transactivation func tion (tau 1), located in the N-terminal domain. tau 1 contributes to a bout 80% of the ligand-inducible transcriptional activity of GR. In th is study, we show that GR devoid of tau 1 (Delta GR) can inhibit activ ation of gene expression by wild-type GR but this does not occur for a ll 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 an d was not due to squelching. A moderate expression level of stably tra nsfected 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 expressi on can be blocked by the Delta GR mutant in stably transfected L8 cell s. In contrast, no inhibition was observed on glucocorticoid induction of the endogenous glutamine synthetase gene in L8 cells. However, glu cocorticoid induction of a reporter ene driven by the chicken glutamin e synthetase promoter was inhibited by Delta GR in L8 cells. Stable ex pression of wild-type GR in CHO cells rendered the cells glucocorticoi d responsive with regard to glutamine synthetase induction but coexpre ssion of Delta GR did not repress induction of the endogenous glutamin e synthetase gene expression by wild type GR. Expression of Delta GR a lone in CHO cells did not render the glutamine synthetase gene glucoco rticoid responsive, indicating that Delta GR has no transcriptional ac tivity on the glutamine synthetase gene. We conclude from these result s 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.