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Science 289 (5485): 1751-1754

Copyright © 2000 by the American Association for the Advancement of Science

Subgroup of Reproductive Functions of Progesterone Mediated by Progesterone Receptor-B Isoform

Biserka Mulac-Jericevic, Robert A. Mullinax, Francesco J. DeMayo, John P. Lydon, Orla M. Conneely*

Progesterone regulates reproductive function through two intracellular receptors, progesterone receptor-A (PR-A) and progesterone receptor-B (PR-B), that arise from a single gene and function as transcriptional regulators of progesterone-responsive genes. Although in vitro studies show that PR isoforms can display different transcriptional regulatory activities, their physiological significance is unknown. By selective ablation of PR-A in mice, we show that the PR-B isoform modulates a subset of reproductive functions of progesterone by regulation of a subset of progesterone-responsive target genes. Thus, PR-A and PR-B are functionally distinct mediators of progesterone action in vivo and should provide suitable targets for generation of tissue-selective progestins.

Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
*   To whom correspondence should be addressed. E-mail: orlac{at}

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Mol. Hum. Reprod. 15, 241-249
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The pattern of {beta}-catenin responsiveness within the mammary gland is regulated by progesterone receptor.
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Cancer Epidemiol. Biomarkers Prev. 15, 1738-1741
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Effect of age on progesterone receptor expression, and osteoprogenitor proliferation and differentiation in female rat vertebral cell populations.
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Steroid hormone regulation of Clca3 expression in the murine uterus..
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J. Endocrinol. 189, 473-484
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Biol Reprod 73, 833-839
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Null Mutation of Kruppel-Like Factor9/Basic Transcription Element Binding Protein-1 Alters Peri-Implantation Uterine Development in Mice.
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Biol Reprod 73, 472-481
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Molecular and Pharmacological Properties of a Potent and Selective Novel Nonsteroidal Progesterone Receptor Agonist Tanaproget.
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Progesterone induces the fibulin-1 expression in human endometrial stromal cells.
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Hum. Reprod. 20, 1447-1455
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Reproductive Sciences 12, 219-221
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Reproductive Sciences 12, 285-292
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Hum. Reprod. Update 11, 293-307
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Differentiation of endometrial stromal cells in vitro: down-regulation of suppression of the cell cycle inhibitor p57 by HOXA10?.
K. Qian, H. Chen, Y. Wei, J. Hu, and G. Zhu (2005)
Mol. Hum. Reprod. 11, 245-251
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Progesterone-Receptor Antagonists and Statins Decrease De Novo Cholesterol Synthesis and Increase Apoptosis in Rat and Human Periovulatory Granulosa Cells In Vitro.
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Biol Reprod 72, 538-545
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Reproduction 128, 679-695
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Reproductive tissue selective actions of progesterone receptors.
B. Mulac-Jericevic and O. M Conneely (2004)
Reproduction 128, 139-146
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Subfertility, Uterine Hypoplasia, and Partial Progesterone Resistance in Mice Lacking the Kruppel-like Factor 9/Basic Transcription Element-binding Protein-1 (Bteb1) Gene.
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No Association between the Progesterone Receptor Gene +331G/A Polymorphism and Breast Cancer.
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Cancer Epidemiol. Biomarkers Prev. 13, 1084-1085
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Breast Cancer Patients with Progesterone Receptor PR-A-Rich Tumors Have Poorer Disease-Free Survival Rates.
T. A. Hopp, H. L. Weiss, S. G. Hilsenbeck, Y. Cui, D. C. Allred, K. B. Horwitz, and S. A. W. Fuqua (2004)
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G. Cheng, Z. Weihua, M. Warner, and J.-A. Gustafsson (2004)
PNAS 101, 3739-3746
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Nuclear Receptor Coactivator Function in Reproductive Physiology and Behavior.
H. A. Molenda, C. P. Kilts, R. L. Allen, and M. J. Tetel (2003)
Biol Reprod 69, 1449-1457
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Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform.
B. Mulac-Jericevic, J. P. Lydon, F. J. DeMayo, and O. M. Conneely (2003)
PNAS 100, 9744-9749
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Selective Interactions of Kruppel-like Factor 9/Basic Transcription Element-binding Protein with Progesterone Receptor Isoforms A and B Determine Transcriptional Activity of Progesterone-responsive Genes in Endometrial Epithelial Cells.
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J. Biol. Chem. 278, 21474-21482
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Regulated Expression of Osteopontin in the Peri-Implantation Rabbit Uterus.
K.B.C. Apparao, M. J. Illera, S. A. Beyler, G. E. Olson, K. G. Osteen, M. H. Corjay, K. Boggess, and B. A. Lessey (2003)
Biol Reprod 68, 1484-1490
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Progesterone Induces Calcitonin Expression in the Baboon Endometrium Within the Window of Uterine Receptivity.
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Biol Reprod 68, 1318-1323
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Progesterone receptors mediate male aggression toward infants.
J. S. Schneider, M. K. Stone, K. E. Wynne-Edwards, T. H. Horton, J. Lydon, B. O'Malley, and J. E. Levine (2003)
PNAS 100, 2951-2956
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EcR isoforms in Drosophila: testing tissue-specific requirements by targeted blockade and rescue.
L. Cherbas, X. Hu, I. Zhimulev, E. Belyaeva, and P. Cherbas (2003)
Development 130, 271-284
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Expression of Progesterone Receptor (PR) A and B Isoforms in Mouse Granulosa Cells: Stage-Dependent PR-Mediated Regulation of Apoptosis and Cell Proliferation.
R. Shao, E. Markstrom, P. A. Friberg, M. Johansson, and H. Billig (2003)
Biol Reprod 68, 914-921
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Stimulatory Effect of Progesterone on the Expression of Steroidogenic Acute Regulatory Protein in MA-10 Leydig Cells.
H. Schwarzenbach, P. R. Manna, D. M. Stocco, G. Chakrabarti, and A. K. Mukhopadhyay (2003)
Biol Reprod 68, 1054-1063
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The Yolkless Egg and the Evolution of Eutherian Viviparity.
I. Rothchild (2003)
Biol Reprod 68, 337-357
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Distinct Functional Differences of Human Progesterone Receptors A and B on Gene Expression and Growth Regulation in Two Endometrial Carcinoma Cell Lines.
E. Smid-Koopman, L. J. Blok, L. C. M. Kuhne,, C. W. Burger, T. J. M. Helmerhorst, A. O. Brinkman, and F. J. Huikeshoven (2003)
Reproductive Sciences 10, 49-57
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A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk.
I. De Vivo, G. S. Huggins, S. E. Hankinson, P. J. Lescault, M. Boezen, G. A. Colditz, and D. J. Hunter (2002)
PNAS 99, 12263-12268
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New Human Breast Cancer Cells to Study Progesterone Receptor Isoform Ratio Effects and Ligand-independent Gene Regulation.
B. M. Jacobsen, J. K. Richer, S. A. Schittone, and K. B. Horwitz (2002)
J. Biol. Chem. 277, 27793-27800
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Connections and Regulation of the Human Estrogen Receptor.
D. P. McDonnell and J. D. Norris (2002)
Science 296, 1642-1644
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Transcriptional regulation of the mouse steroid 5{alpha}-reductase type II gene by progesterone in brain.
D. Matsui, M. Sakari, T. Sato, A. Murayama, I. Takada, M. Kim, K.-i. Takeyama, and S. Kato (2002)
Nucleic Acids Res. 30, 1387-1393
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Differential Gene Regulation by the Two Progesterone Receptor Isoforms in Human Breast Cancer Cells.
J. K. Richer, B. M. Jacobsen, N. G. Manning, M. G. Abel, D. M. Wolf, and K. B. Horwitz (2002)
J. Biol. Chem. 277, 5209-5218
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Progesterone Inhibits Human Endometrial Cancer Cell Growth and Invasiveness: Down-Regulation of Cellular Adhesion Molecules through Progesterone B Receptors.
D. Dai, D. M. Wolf, E. S. Litman, M. J. White, and K. K. Leslie (2002)
Cancer Res. 62, 881-886
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Identification of a Phosphorylation Site in the Hinge Region of the Human Progesterone Receptor and Additional Amino-terminal Phosphorylation Sites.
T. A. Knotts, R. S. Orkiszewski, R. G. Cook, D. P. Edwards, and N. L. Weigel (2001)
J. Biol. Chem. 276, 8475-8483
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Identification of a phosphorylation site in the hinge region of human progesterone receptor and additional amino terminal phosphorylation sites.
T. A. Knotts, R. S. Orkiszewski, R. G. Cook, D. P. Edwards, and N. L. Weigel (2000)
J. Biol. Chem.
   Abstract »

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