Dynamic Regulation of Progesterone Receptor Activity in Female Reproductive Tissues

  • S. J. Han
  • F. J. DeMayo
  • B. W. O'Malley
Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2007/1)


The progesterone receptor (PR) in cooperation with coregulator complexes coordinates crucial processes in female reproduction. To investigate the dynamic regulation of PR activity in vivo, a new transgenic mouse model utilizing a PR activity indicator (PRAI) system was generated. Studies utilizing the PRAI mouse have revealed that progesterone temporally regulates PR activity in female reproductive tissues. Specifically, progesterone rapidly enhances PR activity immediately after administration. However, chronic progesterone stimulation represses PR activity in female reproductive organs. Like progesterone, RU486 also temporally regulates PR activity in female reproductive organs. However, the temporal regulation of PR activity by RU486 is the inverse of progesterone's activity. RU486 acutely represses PR activity after injection but increases PR activity after chronic treatment in female reproductive tissues. Treatment with a mixed antagonist/agonist of PR, when compared to natural hormone, results in dramatically different tissue-specific patterns of intracellular PR activity, coregulator levels, and kinase activity. Transcriptional regulation of gene expression by PR is facilitated by coordinate interactions with the steroid receptor coactivators (SRCs). Bigenic PRAI–SRC knockout mouse models enabled us to draw a tissue-specific coactivator atlas for PR activity in vivo. Based on this atlas, we conclude that the endogenous physiological function of PR in distinct tissues is modulated by different SRCs. SRC-3 is the primary coactivator for PR in the breast and SRC-1 is the primary coactivator for PR in the uterus.


Mammary Gland Progesterone Receptor Bacterial Artificial Chromosome Clone Mammary Gland Development Progesterone Treatment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Baird DT, Brown A, Cheng L, Critchley HO, Lin S, Narvekar N, Williams AR (2003) Mifepristone: a novel estrogen-free daily contraceptive pill. Steroids 68:1099–1105PubMedCrossRefGoogle Scholar
  2. Baulieu EE (1991) On the mechanism of action of RU486. Ann N Y Acad Sci 626:545–560PubMedCrossRefGoogle Scholar
  3. Baulieu EE (1997) RU 486 (mifepristone). A short overview of its mechanisms of action and clinical uses at the end of 1996. Ann N Y Acad Sci 828:47–58PubMedCrossRefGoogle Scholar
  4. Beck CA, Weigel NL, Moyer ML, Nordeen SK, Edwards DP (1993) The progesterone antagonist RU486 acquires agonist activity upon stimulation of cAMP signaling pathways. Proc Natl Acad Sci U S A 90:4441–4445PubMedCrossRefGoogle Scholar
  5. Bocchinfuso WP, Korach KS (1997) Mammary gland development and tumorigenesis in estrogen receptor knockout mice. J Mammary Gland Biol Neoplasia 2:323–334PubMedCrossRefGoogle Scholar
  6. Chabbert-Buffet N, Meduri G, Bouchard P, Spitz IM (2005) Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications. Hum Reprod Update 11:293–307PubMedCrossRefGoogle Scholar
  7. Chauchereau A, Amazit L, Quesne M, Guiochon-Mantel A, Milgrom E (2003) Sumoylation of the progesterone receptor and of the steroid receptor coactivator SRC-1. J Biol Chem 278:12335–12343PubMedCrossRefGoogle Scholar
  8. Cheon YP, DeMayo FJ, Bagchi MK, Bagchi IC (2004) Induction of cytotoxic T-lymphocyte antigen-2beta, a cysteine protease inhibitor in decidua: a potential regulator of embryo implantation. J Biol Chem 279:10357–10363PubMedCrossRefGoogle Scholar
  9. Chwalisz K, Perez MC, DeManno D, Winkel C, Schubert G, Elger W (2005) Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis. Endocr Rev 26:423–438PubMedCrossRefGoogle Scholar
  10. Collins RL, Hodgen GD (1986) Blockade of the spontaneous midcycle gonadotropin surge in monkeys by RU 486: a progesterone antagonist or agonist? J Clin Endocrinol Metab 63:1270–1276PubMedCrossRefGoogle Scholar
  11. Elger W, Bartley J, Schneider B, Kaufmann G, Schubert G, Chwalisz K (2000) Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity. Steroids 65:713–723PubMedCrossRefGoogle Scholar
  12. Ellis HM, Yu D, DiTizio T, Court DL (2001) High efficiency mutagenesis, repair, and engineering of chromosomal DNA using single-stranded oligonucleotides. Proc Natl Acad Sci U S A 98:6742–6746PubMedCrossRefGoogle Scholar
  13. Feng Q, Yi P, Wong J, O'Malley BW (2006) Signaling within a coactivator complex: methylation of SRC-3/AIB1 is a molecular switch for complex disassembly. Mol Cell Biol 26:7846–7857PubMedCrossRefGoogle Scholar
  14. Fuhrmann U, Hess-Stumpp H, Cleve A, Neef G, Schwede W, Hoffmann J, Fritzemeier KH, Chwalisz K (2000) Synthesis and biological activity of a novel, highly potent progesterone receptor antagonist. J Med Chem 43:5010–5016PubMedCrossRefGoogle Scholar
  15. Gehin M, Mark M, Dennefeld C, Dierich A, Gronemeyer H, Chambon P (2002) The function of TIF2/GRIP1 in mouse reproduction is distinct from those of SRC-1 and p/CIP. Mol Cell Biol 22:5923–5937PubMedCrossRefGoogle Scholar
  16. Gianni M, Parrella E, Raska I Jr, Gaillard E, Nigro EA, Gaudon C, Garattini E, Rochette-Egly C (2006) P38MAPK-dependent phosphorylation and degradation of SRC-3/AIB1 and RARalpha-mediated transcription. EMBO J 25:739–751PubMedCrossRefGoogle Scholar
  17. Gong S, Zheng C, Doughty ML, Losos K, Didkovsky N, Schambra UB, Nowak NJ, Joyner A, Leblanc G, Hatten ME, Heintz N (2003) A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425:917–925PubMedCrossRefGoogle Scholar
  18. Gravanis A, Schaison G, George M, de Brux J, Satyaswaroop PG, Baulieu EE, Robel P (1985) Endometrial and pituitary responses to the steroidal antiprogestin RU 486 in postmenopausal women. J Clin Endocrinol Metab 60:156–163PubMedCrossRefGoogle Scholar
  19. Han SJ, Jeong J, DeMayo FJ, Xu J, Tsai SY, Tsai MJ, O'Malley BW (2005) Dynamic cell type specificity of SRC-1 coactivator in modulating uterine progesterone receptor function in mice. Mol Cell Biol 25:8150–8165PubMedCrossRefGoogle Scholar
  20. Han SJ, DeMayo FJ, Xu J, Tsai SY, Tsai MJ, O'Malley BW (2006) Steroid receptor coactivator (SRC)-1 and SRC-3 differentially modulate tissue-specific activation functions of the progesterone receptor. Mol Endocrinol 20:45–55PubMedCrossRefGoogle Scholar
  21. Han SJ, Tsai SY, Tsai MJ, O'Malley BW (2007) Distinct temporal and spatial activities of RU486 on progesterone receptor function in reproductive organs of ovariectomized mice. Endocrinology 148:2471–2486PubMedCrossRefGoogle Scholar
  22. Heintz N (2000) Analysis of mammalian central nervous system gene expression and function using bacterial artificial chromosome-mediated transgenesis. Hum Mol Genet 9:937–943PubMedCrossRefGoogle Scholar
  23. Jeong JW, Lee KY, Kwak I, White LD, Hilsenbeck SG, Lydon JP, DeMayo FJ (2005) Identification of murine uterine genes regulated in a ligand-dependent manner by the progesterone receptor. Endocrinology 146:3490–3505PubMedCrossRefGoogle Scholar
  24. Knott KK, McGinley JN, Lubet RA, Steele VE, Thompson HJ (2001) Effect of the aromatase inhibitor vorozole on estrogen and progesterone receptor content of rat mammary carcinomas induced by 1-methyl-1-nitrosourea. Breast Cancer Res Treat 70:171–183PubMedCrossRefGoogle Scholar
  25. Kuang SQ, Liao L, Zhang H, Lee AV, O'Malley BW, Xu J (2004) AIB1/SRC-3 deficiency affects insulin-like growth factor I signaling pathway and suppresses v-Ha-ras-induced breast cancer initiation and progression in mice. Cancer Res 64:1875–1885PubMedCrossRefGoogle Scholar
  26. Kuang SQ, Liao L, Wang S, Medina D, O'Malley BW, Xu J (2005) Mice lacking the amplified in breast cancer 1/steroid receptor coactivator-3 are resistant to chemical carcinogen-induced mammary tumorigenesis. Cancer Res 65:7993–8002PubMedGoogle Scholar
  27. Lange CA, Shen T, Horwitz KB (2000) Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26S proteasome. Proc Natl Acad Sci U S A 97:1032–1037PubMedCrossRefGoogle Scholar
  28. Li Y, Je HD, Malek S, Morgan KG (2004) Role of ERK1/2 in uterine contractility and preterm labor in rats. Am J Physiol Regul Integr Comp Physiol 287:R328–R335PubMedCrossRefGoogle Scholar
  29. Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA Jr, Shyamala G, Conneely OM, O'Malley BW (1995) Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 9:2266–2278PubMedCrossRefGoogle Scholar
  30. Lydon JP, DeMayo FJ, Conneely OM, O'Malley BW (1996) Reproductive phenotypes of the progesterone receptor null mutant mouse. J Steroid Biochem Mol Biol 56:67–77PubMedCrossRefGoogle Scholar
  31. Marsaud V, Gougelet A, Maillard S, Renoir JM (2003) Various phosphorylation pathways, depending on agonist and antagonist binding to endogenous estrogen receptor-alpha (ERalpha), differentially affect ER(alpha) extractability, proteasome-mediated stability, and transcriptional activity in human breast cancer cells. Mol Endocrinol 17:2013–2027PubMedCrossRefGoogle Scholar
  32. Meyer ME, Pornon A, Ji JW, Bocquel MT, Chambon P, Gronemeyer H (1990) Agonistic and antagonistic activities of RU486 on the functions of the human progesterone receptor. EMBO J 9:3923–3932PubMedGoogle Scholar
  33. Michna H, Schneider MR, Nishino Y, el Etreby MF (1989) The antitumor mechanism of progesterone antagonists is a receptor mediated antiproliferative effect by induction of terminal cell death. J Steroid Biochem 34:447–453PubMedCrossRefGoogle Scholar
  34. Mukherjee A, Soyal SM, Fernandez-Valdivia R, Gehin M, Chambon P, DeMayo FJ, Lydon JP, O'Malley BW (2006) Steroid receptor coactivator 2 is critical for progesterone-dependent uterine function and mammary morphogenesis in the mouse. Mol Cell Biol 26:6571–6583PubMedCrossRefGoogle Scholar
  35. Rowan BG, Garrison N, Weigel NL, O'Malley BW (2000a) 8-Bromo-cyclic AMP induces phosphorylation of two sites in SRC-1 that facilitate ligand-independent activation of the chicken progesterone receptor and are critical for functional cooperation between SRC-1 and CREB binding protein. Mol Cell Biol 20:8720–8730PubMedCrossRefGoogle Scholar
  36. Rowan BG, Weigel NL, O'Malley BW (2000b) Phosphorylation of steroid receptor coactivator-1. Identification of the phosphorylation sites and phosphorylation through the mitogen-activated protein kinase pathway. J Biol Chem 275:4475–4483PubMedCrossRefGoogle Scholar
  37. Sartorius CA, Tung L, Takimoto GS, Horwitz KB (1993) Antagonist-occupied human progesterone receptors bound to DNA are functionally switched to transcriptional agonists by cAMP. J Biol Chem 268:9262–9266PubMedGoogle Scholar
  38. Seval Y, Cakmak H, Kayisli UA, Arici A (2006) Estrogen-mediated regulation of p38 mitogen-activated protein kinase in human endometrium. J Clin Endocrinol Metab 91:2349–2357PubMedCrossRefGoogle Scholar
  39. Spitz IM, Croxatto HB, Robbins A (1996) Antiprogestins: mechanism of action and contraceptive potential. Annu Rev Pharmacol Toxicol 36:47–81PubMedCrossRefGoogle Scholar
  40. Teng J, Wang ZY, Bjorling DE (2003) Progesterone induces the proliferation of urothelial cells in an epidermal growth factor dependent manner. J Urol 170:2014–2018PubMedCrossRefGoogle Scholar
  41. Wagner BL, Pollio G, Leonhardt S, Wani MC, Lee DY, Imhof MO, Edwards DP, Cook CE, McDonnell DP (1996) 16 alpha-substituted analogs of the antiprogestin RU486 induce a unique conformation in the human progesterone receptor resulting in mixed agonist activity. Proc Natl Acad Sci U S A 93:8739–8744PubMedCrossRefGoogle Scholar
  42. Wu RC, Qin J, Yi P, Wong J, Tsai SY, Tsai MJ, O'Malley BW (2004) Selective phosphorylations of the SRC-3/AIB1 coactivator integrate genomic responses to multiple cellular signaling pathways. Mol Cell 15:937–949PubMedCrossRefGoogle Scholar
  43. Xu J, Qiu Y, DeMayo FJ, Tsai SY, Tsai MJ, O'Malley BW (1998) Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene. Science 279:1922–1925PubMedCrossRefGoogle Scholar
  44. Xu J, Liao L, Ning G, Yoshida-Komiya H, Deng C, O'Malley BW (2000) The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development. Proc Natl Acad Sci U S A 97:6379–6384PubMedCrossRefGoogle Scholar
  45. Yu D, Court DL (1998) A new system to place single copies of genes, sites and lacZ fusions on the Escherichia coli chromosome. Gene 223:77–81PubMedCrossRefGoogle Scholar
  46. Zhang Y, Beck CA, Poletti A, Edwards DP, Weigel NL (1994) Identification of phosphorylation sites unique to the B form of human progesterone receptor. In vitro phosphorylation by casein kinase II. J Biol Chem 269:31034–31040PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonUSA

Personalised recommendations