The human progesterone receptor A-form functions as a transcriptional modulator of mineralocorticoid receptor transcriptional activity.
The human progesterone receptor (hPR) exists as two distinct molecular forms in most cells, hPR-A and -B. These receptor isoforms display distinct biological functions and demonstrate a cell and promoter specific ability to regulate gene transcription. In cellular contexts where hPR-A is transcriptionally inactive it can function as a ligand dependent inhibitor of mineralocorticoid receptor (MR) transcriptional activity. Inhibition occurs by a non-competitive mechanism as direct binding to MR is not required. Interestingly, PR agonists differ in their ability to facilitate the inhibitory function of hPR-A, suggesting that a specific receptor conformation may be preferred for this activity. Those compounds derived from 19-nor-testosterone are the most effective. The antiprogestins RU486, ZK98299 and ZK112993 are effective MR antagonists in the presence of coexpressed hPR-A. The mechanism of hPR-A mediated inhibition of MR transcriptional activity is unknown. We propose that inhibition results from a competition of hPR-A with MR for a common transcription factor and that the association of hPR-A with this factor is not transcriptionally productive.
McDonnell
D P
DP
Department of Molecular Biology, Ligand Pharmaceuticals Inc., La Jolla, CA 92037.
Shahbaz
M M
MM
Vegeto
E
E
Goldman
M E
ME
D000818:Animals; D002478:Cells, Cultured; D006067:Gonanes / Q000494:pharmacology; D000882:Haplorhini; D006801:Humans; D015735:Mifepristone / Q000031:analogs & derivatives / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists; D008968:Molecular Conformation; D011372:Progestins / Q000037:antagonists & inhibitors; D018161:Receptors, Mineralocorticoid / Q000502:physiology*; D011980:Receptors, Progesterone / Q000187:drug effects / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*
D006067:Gonanes; D000451:Mineralocorticoid Receptor Antagonists; D011372:Progestins; D018161:Receptors, Mineralocorticoid; D011980:Receptors, Progesterone; D012097:Repressor Proteins; C064879:ZK 112993; D015735:Mifepristone; C053238:onapristone