TABLE 3

PR

Receptor nomenclature NR3C3
Receptor code 4.10.1:PG:3:C3
Other names PGR, progesterone receptor
Molecular information Hs: 933aa, P06401, chr. 11q221
Rn: 923aa, Q63449, chr. 8q112
Mm: 923aa, Q00175, chr. 9 Al3
DNA binding
   Structure Homodimer
   HRE core sequence GGTACANNNTGTTCT (GRE, palindrome)
Partners HSP90 (physical): cellular localization4,5; HMGB (physical, functional): DNA binding6,7
Src family kinases (physical): activation of rapid signalling cascades, independent of PR DNA binding8
Agonists Levonorgestrel, medroxyprogesterone,* promegestone (R5020),* dydrogesterone, norethisterone, progesterone (P4)9
Antagonists Asoprisnil, mifepristone (RU486),* RTI 3021-012, RTI 3021-022, onapristone (ZK98299)
Coactivator NCOA1, NCOA3, CREBBP, SRA1, JDP21020
Corepressor NCOR22124
Biologically important isoform PRA {Hs, Mm, Rn}: N-terminally truncated isoform that is a weak transcriptional activator of specific target genes in a cell type-dependent manner and a strong repressor of transactivation by PRB and other steroid receptors25,26; PRB{Hs}: full-length protein that strongly activates target genes27
Tissue distribution Mammary gland, uterus, brain, muscle, testis, ovary {Hs, Mm, Rn} [Northern blot, in situ hybridization, Western blot, immunohistology]28,29
Functional assay Inhibition of proliferation in endometrial cells caused by treatment of ovariectomized (estrogen-treated) mice with progesterone{Mm}30,31; proliferation in PR-positive breast cancer cells and normal breast epithelial cells{Hs}32,33; mammary gland ductal tree branching and lobuloalveolar development in ovariectomized (estrogen-treated) mice treated with progesterone{Mm}34,35
Main target genes Activated: FSHβ,36 multidrug resistance 1B{Mm},37 Stat5A{Hs},38 11β-hydroxysteroid dehydrogenase{Hs},38 Indian hedgehog{Mm}39
Mutant phenotype Disruption of both PRA and B isoforms results in impaired sexual behavior, anovulation, uterine dysfunction, and reduced ductal branching and lobuloalveolar development in the mammary gland {Mm} [knockout]40; targeted overexpression of PRA in the mammary gland results in reduced induction of apoptosis {Mm} [overexpression]41
Human disease Pseudocorpus luteum insufficiency: due to decreased PR expression42; breast cancer: higher PRA/PRB ratio correlates with increased tumor grade43; endometriosis: due to reduced expression of PRB (not PRA) in diseased tissue44,45; endometrial cancer: increased risk caused by polymorphisms in the PR promoter favoring expression of PRB46,47
  • aa, amino acids; chr., chromosome; HRE, hormone response element; HMGB, chromosomal high mobility group B; Q-PCR, quantitative polymerase chain reaction; GRE, glucocorticoid response element; CREBBP, cAMP response element binding protein binding protein

  • * Radioligand

  • 1. Mattei MG, Krust A, Stropp U, Mattei JF, and Chambon P (1988) Assignment of the human progesterone receptor to the q22 band of chromosome 11. Hum Genet 78: 96-97

  • 2. Johansson A, Helou K, and Levan G (1998) Cytogenetic localization of cancer-related genes in the rat and comparative mapping studies in human and mouse. Cytogenet Cell Genet 81: 217-221

  • 3. Naylor SL, Helen-Davis D, Hughes MR, O'Malley BW, and Lalley PA (1989) The progesterone receptor gene is on mouse chromosome 9. Cytogenet Cell Genet 51: 1051

  • 4. Elbi C, Walker DA, Romero G, Sullivan WP, Toft DO, Hager GL, DeFranco DB (2004) Molecular chaperones function as steroid receptor nuclear mobility factors. Proc Natl Acad Sci USA 101: 2876-2881

  • 5. Sullivan WP and Toft DO (1993) Mutational analysis of hsp90 binding to the progesterone receptor. J Biol Chem 268: 20373-20379

  • 6. Boonyaratanakornkit V, Scott MP, Ribon V, Sherman L, Anderson SM, Maller JL, Miller WT, and Edwards DP (2001) Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases. Mol Cell 8: 269-280

  • 7. Onate SA, Prendergast P, Wagner JP, Nissen M, Reeves R, Pettijohn DE, and Edwards DP (1994) The DNA-bending protein HMG-1 enhances progesterone receptor binding to its target DNA sequences. Mol Cell Biol 14: 3376-3391

  • 8. Boonyaratanakornkit V, Scott MP, Ribon V, Sherman L, Anderson SM, Maller JL, Miller WT, and Edwards DP (2001) Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases. Mol Cell 8: 269-280

  • 9. Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, and Thijssen JH (2003) Classification and pharmacology of progestins. Maturitas 46: S7-S16

  • 10. Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, and Meltzer PS (1997) AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science (Wash DC) 277: 965-968

  • 11. Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, and Evans RM (1997) Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90: 556-580

  • 12. Lanz RB, McKenna NJ, Onate SA, Albrecht U, Wong J, Tsai SY, Tsai MJ, and O'Malley BW (1999) A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex. Cell 97: 17-27

  • 13. Li X, Wong J, Tsai SY, Tsai MJ, and O'Malley BW (2003) Progesterone and glucocorticoid receptors recruit distinct coactivator complexes and promote distinct patterns of local chromatin modification. Mol Cell Biol 23: 3763-3773

  • 14. Liu Z, Wong J, Tsai SY, Tsai MJ, and O'Malley BW (1999) Steroid receptor coactivator-1 (SRC-1) enhances ligand-dependent and receptor-dependent cell-free transcription of chromatin. Proc Natl Acad Sci USA 96: 9485-9490

  • 15. Sheppard HM, Harries JC, Hussain S, Bevan C, and Heery DM (2001) Analysis of the steroid receptor coactivator 1 (SRC1)-CREB binding protein interaction interface and its importance for the function of SRC1. Mol Cell Biol 21: 39

  • 16. Shi Y, Downes M, Xie W, Kao HY, Ordentlich P, Tsai CC, Hon M, and Evans RM (2001) Sharp, an inducible cofactor that integrates nuclear receptor repression and activation. Genes Dev 15: 1140-1151

  • 17. Shiozawa T, Shih HC, Miyamoto T, Feng YZ, Uchikawa J, Itoh K, and Konishi I (2003) Cyclic changes in the expression of steroid receptor coactivators and corepressors in the normal human endometrium. J Clin Endocrinol Metab 88: 871-878

  • 18. Smith CL, Onate SA, Tsai MJ, and O'Malley BW (1996) CREB binding protein acts synergistically with steroid receptor coactivator-1 to enhance steroid receptor-dependent transcription. Proc Natl Acad Sci USA 93: 8884-8888

  • 19. Spencer TE, Jenster G, Burcin MM, Allis CD, Zhou J, Mizzen CA, McKenna NJ, Onate SA, Tsai SY, Tsai MJ, et al. (1997) Steroid receptor coactivator-1 is a histone acetyltransferase. Nature (Lond) 389: 194-198

  • 20. Wardell SE, Boonyaratanakornkit V, Adelman JS, Aronheim A, and Edwards DP (2002) Jun dimerization protein 2 functions as a progesterone receptor N-terminal domain coactivator. Mol Cell Biol 22: 5451-5466

  • 21. Giangrande PH, Kimbrel EA, Edwards DP, and McDonnell DP (2000) The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding. Mol Cell Biol 20: 3102-3115

  • 22. Liu Z, Auboeuf D, Wong J, Chen JD, Tsai SY, Tsai MJ, and O'Malley BW (2002) Coactivator/corepressor ratios modulate PR-mediated transcription by the selective receptor modulator RU486. Proc Natl Acad Sci USA 99: 7940-7944

  • 23. Nagy L, Kao HY, Chakravarti D, Lin RJ, Hassig CA, Ayer DE, Schreiber SL, and Evans RM (1997) Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89: 373-380

  • 24. Wagner BL, Norris JD, Knotts TA, Weigel NL, and McDonnell DP (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 receptors. Mol Cell Biol 18: 1369-1378

  • 25. Giangrande PH, Pollio G, and McDonnell DP (1997) Mapping and characterization of the functional domains responsible for the differential activity of the A and B isoforms of the human progesterone receptor. J Biol Chem 272: 32889-32900

  • 26. Vegeto E, Shahbaz MM, Wen DX, Goldman ME, O'Malley BW, and McDonnell DP (1993) Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function. Mol Endocrinol 7: 1244-1255

  • 27. Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, and Chambon P (1990) Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO (Eur Mol Biol Organ) J 9: 1603-1614

  • 28. Mangal RK, Wiehle RD, Poindexter ANR, and Weigel NL (1997) Differential expression of uterine progesterone receptor forms A and B during the menstrual cycle. J Steroid Biochem Mol Biol 63: 195-2002

  • 29. Robker RL, Russell DL, Espey LL, Lydon JP, O'Malley BW, and Richards JS (2000) Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases. Proc Natl Acad Sci USA 97: 4689-4694

  • 30. Finn CA and Pope M (1984) Vascular and cellular changes in the decidualized endometrium of the ovariectomized mouse following cessation of hormone treatment: a possible model for menstruation. J Endocrinol 100: 295-300

  • 31. Parandoosh Z, Crombie DL, Tetzke TA, Hayes JS, Heap RB, and Wang MW (1995) Progesterone and oestrogen receptors in the decidualized mouse uterus and effects of different types of anti-progesterone treatment. J Reprod Fertil 105: 215-220

  • 32. Kramer EA, Seeger H, Kramer B, Wallwiener D, and Mueck AO (2005) The effects of progesterone, medroxyprogesterone acetate, and norethisterone on growth factor- and estradiol-treated human cancerous and noncancerous breast cells. Menopause 12: 468-474

  • 33. Saitoh M, Ohmichi M, Takahashi K, Kawagoe J, Ohta T, Doshida M, Takahashi T, Igarashi H, Mori-Abe A, Du B, et al. (2005) Medroxyprogesterone acetate induces cell proliferation through upregulation of cyclin D1 expression via P13K/Akt/NF kappa B cascade in human breast cancer cells. Endocrinology 146: 4917-4925

  • 34. Aupperlee MD, Smith KT, Kariagina A, and Haslam SZ (2005) Progesterone receptor isoforms A and B: temporal and spatial differences in expression during murine mammary gland development. Endocrinology 146: 3577-3588

  • 35. Ismail PM, Amato P, Soyal SM, DeMayo FJ, Conneely OM, O'Malley BW, and Lydon JP (2003) Progesterone involvement in breast development and tumorigenesis—as revealed by progesterone receptor `knockout' and `knockin' mouse models. Steroids 68: 779-787

  • 36. Webster JC, Pedersen NR, Edwards DP, Beck CA, and Miller WL (1995) The 5′-flanking region of the ovine follicle-stimulating hormone-β gene contain six progesterone response elements: three proximal elements are sufficient to increase transcription in the presence of progesterone. Endocrinology 136: 1049-1058

  • 37. Mallick S and Horwitz SB (1997) Transcriptional regulation of the murine multidrug resistance gene mdr1b by progesterone occurs via an indirect mechanism. DNA Cell Biol 16: 807-818

  • 38. Richer JK, Jacobsen BM, Manning NG, Abel MG, Wolf DM, and Horwitz KB (2002) Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J Biol Chem 277: 5209-5218

  • 39. Takamoto N, Zhao B, Tsai SY, and DeMayo FJ (2002) Identification of Indian hedgehog as a progesterone-responsive gene in the murine uterus. Mol Endocrinol 16: 2338-2348

  • 40. Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, CA Montgomery J, Shyamala G, Conneely OM, and O'Malley BW (1995) Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 9: 2266-2278

  • 41. Shyamala G, Yang X, Silberstein G, Barcellos-Hoff MH, and Dale E (1998) Transgenic mice carrying an imbalance in the native ratio of A to B forms of progesterone receptor exhibit developmental abnormalities in mammary glands. Proc Natl Acad Sci USA 95: 696-701

  • 42. Keller DW, Wiest WG, Askin FB, Johnson LW, and Strickler RC (1979) Pseudocorpus luteum insufficiency: a local defect of progesterone action on endometrial stroma. J Clin Endocrinol Metab 48: 127-132

  • 43. Bamberger AM, Milde-Langosch K, Schulte HM, and Loning T (2000) Progesterone receptor isoforms, PR-B and PR-A, in breast cancer: correlations with clinicopathologic tumor parameters and expression of AP-1 factors. Horm Res 54: 32-37

  • 44. Attia GR, Zeitoun K, Edwards D, Johns A, Carr BR, and Bulun SE (2000) Progesterone receptor isoform A but not B is expressed in endometriosis. J Clin Endocrinol Metab 85: 2897-2902

  • 45. Chwalisz K, DeManno D, Garg R, Larsen L, Mattia-Goldberg C, and Stickler T (2004) Therapeutic potential for the selective progesterone receptor modulator asoprisnil in the treatment of leiomyomata. Semin Reprod Med 22: 113-119

  • 46. De Vivo I, Huggins GS, Hankinson SE, Lescault PJ, Boezen M, Colditz GA, and Hunter DJ (2002) A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proc Natl Acad Sci USA 99: 12263-12268

  • 47. Terry KL, De Vivo I, Titus-Ernstoff L, Sluss PM, and Cramer DW (2005) Genetic variation in the progesterone receptor gene and ovarian cancer risk. Am J Epidemiol 161: 442-451