The steroid hormone progesterone is a key modulator of the cellular processes associated with the maintenance and development of female reproductive function and promoter context. These actions are mediated by specific nuclear receptors located in target cell nuclei. Abnormalities in the progesterone receptor (PR) signal transduction pathway are implicated in pathological states such as breast cancer, endometriosis and uterine fibroids. As a consequence of the medical need to modulate the action of PR, antiprogestins, compounds which oppose the actions of progesterone have been developed. This proposal focuses on a determination of the molecular mechanisms which distinguish between agonist and antagonist activated receptor. In particular, we propose to define the role of the individual forms of the human progesterone receptor (hPR-A & hPR-B ) in manifesting the actions of progesterone and how antiprogestins influence this activity. We have shown that progesterone and the known antiprogestins interact with distinct regions within PR, and additionally that they induce different structural alterations in receptor conformation. Our preliminary data report on the development of the genetic systems in yeast required to dissect the PR signal transduction pathway and how these systems have been used to study the molecular events which occur upon interaction of ligands with PR. Our genetic approaches in yeast are complemented with studies in mammalian cells. It is anticipated that the use of yeast and mammalian cell models, as proposed, will permit a definition of the molecular mechanism of action of the known antiprogestins and will impact the development of novel pharmaceuticals with improved therapeutic profiles.
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