Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function

Journal Article

Two distinct isoforms of the human progesterone receptor (hPR-A and hPR-B) have been identified previously. They differ only in that hPR-B contains an additional 164 amino acids at the amino terminus. Among various species these two forms arise as a result of either alternate initiation of translation from the same mRNA or by transcription from alternate promoters within the same gene. In order to understand the reason for their existence, we studied the transcriptional capacity of these individual receptors and observed that their activity was influenced strongly by cell and promoter context. More surprising was the observation that in promoter and cell contexts where hPR-A was inactive, it acted as a potent trans-dominant represser of hPR-B-mediated transcription. This event occurred at substoichiometric concentrations of hPR-A and was hormone dependent. Human PR-A was not a general represser of ligand-mediated transcription, as it had no effect on vitamin D receptor function. Interestingly, hPR-A but not hPR-B was capable of a similar inhibition of glucocorticoid, androgen, and mineralocorticoid receptor-mediated gene transcription. This suggests a specific role for the hPR-A isoform in this regulatory process. The trans-dominant effects of hPR-A were induced also by the antiprogestins ZK112993 and ZK98299 and a DNA binding defective hPR-A mutant, suggesting that the inhibitory function of hPR-A does not require DNA binding. The dual role of hPR-A as an activator or represser of transcription defines a potential mechanism by which cells can generate dissimilar responses to a single hormone and provides a molecular explanation for the existence of two distinct forms of the hPR. Copyright © 1993 by The Endocrine Society.

Full Text

Duke Authors

Cited Authors

  • Vegeto, E; Shahbaz, MM; Wen, DX; Goldman, ME; O'Malley, BW; McDonnell, DP

Published Date

  • 1993

Published In

  • Molecular Endocrinology

Volume / Issue

  • 7 / 10

Start / End Page

  • 1244 - 1255

Digital Object Identifier (DOI)

  • 10.1210/me.7.10.1244