Comparison of chromatin remodeling and transcriptional activation of the mouse mammary tumor virus promoter by the androgen and glucocorticoid receptor

We examined the interaction between the androgen (AR) and glucocorticoid re ceptor (GR) at the transcriptional level using mouse fibroblast cell lines harboring an integrated mouse mammary tumor virus (MMTV) promoter. We found that the AR, after induction with dihydrotestosterone (DHT), caused a prog ressive increase in MMTV-CAT reporter activity over 72 h which was correlat ed to an increase in chromatin remodeling of the MMTV promoter in the vicin ity of the hormone response element (HRE). In contrast, stimulation of the GR by the synthetic glucocorticoid dexamethasone (Dex) caused a transient i ncrease in MMTV transcriptional activity which returned to basal levels aft er 72 h. These changes were correlated to a transient increase in chromatin remodeling in the region of the HRE. Neither cotreatment nor pretreatment with Dex affected the DHT response. In fact, there was a more than additive effect of the two hormones on transcription at early time points. This sug gests that the inability of GR to remodel chromatin, after 24 h of hormone treatment, is most likely related to changes in the GR itself and not the c hromatin remodeling process. Consistent with this, nuclear GR levels droppe d by greater than 50% after Dex treatment whereas the AR was induced fourfo ld after 24 h of DHT treatment. We conclude that a promoter with an ordered chromatin structure can still respond to androgens even after its glucocor ticoid responsiveness is lost. This may be one mechanism cells utilize to e stablish target gene specificity for nuclear receptors that recognize ident ical DNA sequences. (C) 1999 Academic Press.