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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050494-05
Application #
2905791
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Margolis, Ronald N
Project Start
1995-05-01
Project End
2000-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Chang, Ching-yi; Norris, John D; Jansen, Michelle et al. (2003) Application of random peptide phage display to the study of nuclear hormone receptors. Methods Enzymol 364:118-42
Sathya, Ganesan; Chang, Ching-yi; Kazmin, Dmitri et al. (2003) Pharmacological uncoupling of androgen receptor-mediated prostate cancer cell proliferation and prostate-specific antigen secretion. Cancer Res 63:8029-36
Li, Xiaolin; McDonnell, Donald P (2002) The transcription factor B-Myb is maintained in an inhibited state in target cells through its interaction with the nuclear corepressors N-CoR and SMRT. Mol Cell Biol 22:3663-73
Li, Xiaolin; Kimbrel, Erin A; Kenan, Daniel J et al. (2002) Direct interactions between corepressors and coactivators permit the integration of nuclear receptor-mediated repression and activation. Mol Endocrinol 16:1482-91
Chang, C Y; Walther, P J; McDonnell, D P (2001) Glucocorticoids manifest androgenic activity in a cell line derived from a metastatic prostate cancer. Cancer Res 61:8712-7
Ito, A; Lai, C H; Zhao, X et al. (2001) p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J 20:1331-40
Hamilton, M H; Tcherepanova, I; Huibregtse, J M et al. (2001) Nuclear import/export of hRPF1/Nedd4 regulates the ubiquitin-dependent degradation of its nuclear substrates. J Biol Chem 276:26324-31
Wagner, B L; Pollio, G; Giangrande, P et al. (1999) The novel progesterone receptor antagonists RTI 3021-012 and RTI 3021-022 exhibit complex glucocorticoid receptor antagonist activities: implications for the development of dissociated antiprogestins. Endocrinology 140:1449-58
Wagner, B L; Norris, J D; Knotts, T A et al. (1998) The nuclear corepressors NCoR and SMRT are key regulators of both ligand- and 8-bromo-cyclic AMP-dependent transcriptional activity of the human progesterone receptor. Mol Cell Biol 18:1369-78
Imhof, M O; McDonnell, D P (1996) Yeast RSP5 and its human homolog hRPF1 potentiate hormone-dependent activation of transcription by human progesterone and glucocorticoid receptors. Mol Cell Biol 16:2594-605

Showing the most recent 10 out of 11 publications