Novel mechanisms of progesterone antagonists and progesterone receptor

The progesterone receptor (PR), as a member of the nuclear receptor superfamily of ligand-dependent transcription factors, activates gene transcription through binding to specific palindromic progesterone response elements (PRE) in the promoter region of progestin-responsive genes. The progesterone antagonists ZK98299 (Onapristone) and RU 486 (Mifepristone) inhibit the transcriptional activity of PR by complex mechanisms at concentrations much lower than the progestins. Altered conformation is central to antagonist inhibition of the transcriptional activity of PR. Antagonists also promote inappropriate association of PR with corepressors. We speculate that the different PR conformations induced by agonist and antagonists results in an asymmetric agonist/antagonist heterodimer that binds inefficiently to palindromic PREs. PR, under the same cellular conditions but with different promotor contexts, can repress (beta-casein) or enhance (3 beta-HSD) signal transducer and activator of transcription (Stat5)-mediated gene activation. The beta-casein promoter appears to contain a composite DNA-binding element for PR and Stat5 and that occupancy by PR in response to progestins or antagonists suppresses Stat5 transactivation function.