Progesterone regulation of reproductive function through functionally distinct progesterone receptor isoforms

Molecular dissection of progesterone signaling mechanisms using in vitro systems has demonstrated that the PR- A and PR-B proteins can respond to the same steroid ligand to induce both overlapping and distinct transcriptional responses that are promoter and cell context dependent. The use of genetically manipulated mouse models in which one or both of the PR isoforms is ablated has been pivotal in defining the physiological spectrum of progesterone receptor action as well as the contribution of the individual protein isoforms to the plieotropic activities of the hormone. These approaches have provided compelling evidence that the differences in transactivation properties of the PR isoforms observed in vitro are reflected in a differential capacity to regulate the tissue selective reproductive activities of progesterone. From a mechanistic standpoint, the differences in physiological activities observed between the PR-A and PR-B isoforms provides an important illustration of the key role played by the amino terminal AF domains in distinguishing tissue specific responses to steroidal ligand. The results demonstrate that the inclusion or deletion of the N-terminal AF3 transactivation domain in PR is sufficient to alter tissue specific responses to progesterone. Although the studies carried out to date have selectively addressed the role of PR isoforms in mediating reproductive activities of progesterone, the genetic mouse models will provide valuable tools to address the physiological significance of ligand independent pathways of receptor activation as well as the contribution of specific receptor subtypes to the activities of tissue selective receptor modulators. In this regard, our observations to date in these models predict that isoform specific modulators of progesterone receptor action should facilitate the identification of novel tissue selective modulators of progesterone receptor dependent reproductive functions.