Mechanisms Controlling Agonist and Antagonist Potential of Selective Progesterone Receptor Modulators (SPRMs)

 

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ABSTRACT

Progesterone exhibits diverse biological activities, inducing proliferation of the mammary gland epithelium, but it opposes the mitogenic activity of estrogen in the uterus. These tissue-selective activities of progesterone are mediated by the progesterone receptor (PR), a member of the nuclear receptor superfamily of ligand-dependent transcription factors. Several clinically useful PR antagonists that block progesterone activity have been described, yet some of these compounds exhibit tissue-selective partial agonist activity, leading them to be termed selective progesterone receptor modulators (SPRMs). This partial agonist activity is mediated primarily through the N-domain of the B isoform of PR, although the mechanism has not yet been defined. In this review, we discuss mechanisms by which PR activates transcription and ways in which antagonists oppose progesterone activity. We discuss mechanisms by which the N-domain mediates tissue specific partial agonist activity of SPRMs, as well as receptor interacting coregulatory proteins that influence this activity of the N-domain. We also describe newly developed SPRMs that mediate subsets of agonist and/or antagonist activities, and discuss the clinical potential of these compounds.

REFERENCES

• 1 Conneely O, Jericevic B, Lydon J. Progesterone receptors in mammary gland development and tumorigenesis.  J Mammary Gland Biol Neoplasia. 2003;  8 205-214
  CrossrefPubMedGoogle Scholar
• 2 Conneely O, Mulac-Jericevic B, DeMayo F, Lydon J, O'Malley B. Reproductive functions of progesterone receptors.  Recent Prog Horm Res. 2002;  57 339-355
  CrossrefPubMedGoogle Scholar
• 3 Moutsatsou P, Sekeris C. Steroid receptors in the uterus: implications in endometriosis.  Ann N Y Acad Sci. 2003;  997 209-222
  CrossrefPubMedGoogle Scholar
• 4 Neville M. Physiology of lactation.  Clin Perinatol. 1999;  26 251-279
  PubMedGoogle Scholar
• 5 Yasui T, Uemura H, Takikawa M, Irahara M. Hormone replacement therapy in postmenopausal women.  J Med Invest . 2003;  50 136-145
  PubMedGoogle Scholar
• 6 Turgeon J, McDonnell D, Martin K, Wise P. Hormone therapy: physiological complexity belies therapeutic simplicity.  Science. 2004;  304 1269-1273
  CrossrefPubMedGoogle Scholar
• 7 Samsioe G. HRT and cardiovascular disease.  Ann N Y Acad Sci. 2003;  997 358-372
  CrossrefPubMedGoogle Scholar
• 8 Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk.  JAMA. 2000;  283 485-491
  CrossrefPubMedGoogle Scholar
• 9 Persson I, Weiderpass E, Bergkvist L, Bergstrom R, Schairer C. Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement.  Cancer Causes Control. 1999;  10 253-260
  CrossrefPubMedGoogle Scholar
• 10 Spitz I, Croxatto H, Robbins A. Antiprogestins: mechanism of action and contraceptive potential.  Annu Rev Pharmacol Toxicol. 1996;  36 47-81
  PubMedGoogle Scholar
• 11 Horwitz K. The molecular biology of RU486. Is there a role of antiprogestins in the treatment of breast cancer?.  Endocr Rev. 1992;  13 146-163
  CrossrefPubMedGoogle Scholar
• 12 Li X, O'Malley B. Unfolding the action of progesterone receptors.  J Biol Chem. 2003;  278 39261-39264
  CrossrefPubMedGoogle Scholar
• 13 Petz L, Nardulli A, Kim J, Horwitz K, Freedman L, Shapiro D. DNA bending is induced by binding of the glucocorticoid receptor DNA binding domain and progesterone receptors to their response elements.  J Steroid Biochem Mol Biol. 1997;  60 31-41
  CrossrefPubMedGoogle Scholar
• 14 Prendergast P, Pan Z, Edwards D. Progesterone receptor-induced bending of its target DNA: distinct effects of the A and B receptor forms.  Mol Endocrinol. 1996;  10 393-407
  CrossrefPubMedGoogle Scholar
• 15 Wen D, Xu Y-F, Mais D, Goldman M, McDonnell D. The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells.  Mol Cell Biol. 1994;  14 8356-8364
  PubMedGoogle Scholar
• 16 Hovland A, Powell R, Takimoto G, Horwitz K. An N-terminal inhibitory function, IF, suppresses transcription by the A-isoform but not the B-isoform of human progesterone receptors.  J Biol Chem. 1998;  273 5455-5460
  CrossrefPubMedGoogle Scholar
• 17 Giangrande P, Pollio G, McDonnell D. 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. 1997;  272 32889-32900
  CrossrefPubMedGoogle Scholar
• 18 Giangrande P, Kimbrel E, Edwards D, McDonnell D. The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding.  Mol Cell Biol. 2000;  20 3102-3115
  CrossrefPubMedGoogle Scholar
• 19 Bourguet W, Germain P, Gronemeyer H. Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications.  Trends Pharmacol Sci. 2000;  21 381-387
  CrossrefPubMedGoogle Scholar
• 20 Steinmetz A, Renaud J-P, Moras D. Binding of ligands and activation of transcription by nuclear receptors.  Annu Rev Biophys Biomol Struct. 2001;  30 329-359
  CrossrefPubMedGoogle Scholar
• 21 Egner U, Heinrich N, Ruff M, Gangloff M, Mueller-Fahrnow A, Wurtz J-M. Different ligands-different receptor conformations: modeling of the hERα LBD in complex with agonists and antagonists.  Med Res Rev. 2001;  21 523-539
  CrossrefPubMedGoogle Scholar
• 22 Weatherman R, Fletterick R, Scanlan T. Nuclear-receptor ligands and ligand-binding domains.  Annu Rev Biochem. 1999;  68 559-581
  CrossrefPubMedGoogle Scholar
• 23 McKenna N, Lanz R, O'Malley B. Nuclear receptor coregulators: cellular and molecular biology.  Endocr Rev. 1999;  20 321-344
  CrossrefPubMedGoogle Scholar
• 24 Edwards D. The role of coactivators and corepressors in the biology and mechanism of action of steroid hormone receptors.  J Mammary Gland Biol Neoplasia. 2000;  5 295-310
  CrossrefPubMedGoogle Scholar
• 25 Glass C, Rosenfeld M. The coregulator exchange in transcriptional functions of nuclear receptors.  Genes Dev. 2000;  14 121-141
  PubMedGoogle Scholar
• 26 Feng W, Ribeiro R, Wagner R et al.. Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors.  Science. 1998;  280 1747-1749
  CrossrefPubMedGoogle Scholar
• 27 Heery D, Kalkhoven E, Hoare S, Parker M. A signature motif in transcriptional coactivators mediates binding to nuclear receptors.  Nature. 1997;  387 733-736
  CrossrefPubMedGoogle Scholar
• 28 Leo C, Chen J. The SRC family of nuclear receptor coactivators.  Gene. 2000;  245 1-11
  CrossrefPubMedGoogle Scholar
• 29 Hong H, Kohei K, Garabedian M, Stallcup M. GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors.  MolCell Biol. 1997;  17 2735-2744
  PubMedGoogle Scholar
• 30 Yao T-P, Ku G, Zhou N, Scully R, Livingston D. The nuclear hormone receptor coactivator SRC-1 is a specific target of p300.  Proc Natl Acad Sci USA. 1996;  93 10626-10631
  CrossrefPubMedGoogle Scholar
• 31 Spencer T, Jenster G, Burcin M et al.. Steroid receptor coactivator-1 is a histone acetyltransferase.  Nature. 1997;  389 194-198
  CrossrefPubMedGoogle Scholar
• 32 Kurokawa R, Kalafus D, Ogliastro M-H et al.. Differential use of CREB binding protein-coactivator complexes.  Science. 1998;  279 700-703
  CrossrefPubMedGoogle Scholar
• 33 Koh S, Chen D, Lee Y-H, Stallcup M. Synergistic enhancement of nuclear receptor function by p160 coactivators and two coactivators with protein methyltransferase activities.  J Biol Chem. 2001;  276 1089-1098
  CrossrefPubMedGoogle Scholar
• 34 Chen D, Ma H, Hong H et al.. Regulation of transcription by a protein methyltransferase.  Science. 1999;  284 2174-2177
  CrossrefPubMedGoogle Scholar
• 35 Ogryzko V, Schiltz R, Russanova V, Howard B, Nakatani Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases.  Cell. 1996;  87 953-959
  CrossrefPubMedGoogle Scholar
• 36 Schwabe J, Neuhaus D, Rhodes D. Solution structure of the DNA binding domain of the oestrogen receptor.  Nature. 1990;  348 458-461
  CrossrefPubMedGoogle Scholar
• 37 Hard T, Kellenbach E, Boelens R et al.. Solution structure of the glucocorticoid receptor DNA binding domain.  Science. 1990;  249 157-160
  PubMedGoogle Scholar
• 38 van Tilborg M, Lefstin J, Kruiskamp M et al.. Mutations in the glucocorticoid receptor DNA-binding domain mimic an allosteric effect in DNA.  J Mol Biol. 2000;  301 947-958
  CrossrefPubMedGoogle Scholar
• 39 Lefstin J, Thomas J, Yamamoto K. Influence of a steroid receptor DNA-binding domain on transcriptional regulatory functions.  Genes Dev. 1994;  8 2842-2856
  PubMedGoogle Scholar
• 40 Godowski P, Picard D, Yamamoto K. Signal transduction and transcriptional regulation by glucocorticoid receptor-LexA fusion proteins.  Science. 1988;  241 812-816
  PubMedGoogle Scholar
• 41 Lefstin J, Yamamoto K. Allosteric effects of DNA on transcriptional regulators.  Nature. 1998;  392 885-888
  CrossrefPubMedGoogle Scholar
• 42 Loven M, Wood J, Nardulli A. Interaction of estrogen receptors α and β with estrogen response elements.  Mol Cell Endocrinol. 2001;  181 151-163
  CrossrefPubMedGoogle Scholar
• 43 Wood J, Greene G, Nardulli A. Estrogen response elements function as allosteric modulators of receptor conformation.  Mol Cell Biol. 1998;  18 1927-1934
  PubMedGoogle Scholar
• 44 Wood J, Likhite V, Loven M, Nardulli A. Allosteric modulation of estrogen receptor conformation by different estrogen response elements.  Mol Endocrinol. 2001;  15 1114-1126
  CrossrefPubMedGoogle Scholar
• 45 Hall J, McDonnell D, Korach K. Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements.  Mol Endocrinol. 2002;  16 469-486
  CrossrefPubMedGoogle Scholar
• 46 Blanco J, Minucci S, Lu J et al.. The histone acetylase PCAF is a nuclear receptor coactivator.  Genes Dev. 1998;  12 1638-1651
  PubMedGoogle Scholar
• 47 Wardell S, Boonyaratanakornkit V, Adelman J, Aronheim A, Edwards D. Jun dimerization protein 2 functions as a progesterone receptor N-terminal domain coactivator.  Mol Cell Biol. 2002;  22 5451-5466
  CrossrefPubMedGoogle Scholar
• 48 Ko L, Cardona G, Henrion-Caude A, Chin W. Identification and characterization of a tissue-specific coactivator, GT198, that interacts with the DNA-binding domains of nuclear receptors.  Mol Cell Biol. 2002;  22 357-369
  CrossrefPubMedGoogle Scholar
• 49 Allan G, Leng S, Tsai S et al.. Hormone and antihormone induce distinct conformational changes which are central to steroid receptor activation.  J Biol Chem. 1992;  267 19513-19520
  PubMedGoogle Scholar
• 50 Vegeto E, Allan G, Schrader W, Tsai M-J, McDonnell D, O'Malley B. The mechanism of RU486 antagonism in dependent on the conformation of the carboxyl-terminal tail of the human progesterone receptor.  Cell. 1992;  69 703-713
  CrossrefPubMedGoogle Scholar
• 51 Brzozowski A, Pike A, Dauter Z et al.. Molecular basis of agonism and antagonism in the oestrogen receptor.  Nature. 1997;  389 753-757
  CrossrefPubMedGoogle Scholar
• 52 Shiau A, Barstad D, Loria P et al.. The structural basis of estrogen receptor/coactivator recognition and the antagonistm of this interaction by tamoxifen.  Cell. 1998;  95 927-937
  Google Scholar
• 53 Wagner B, Norris J, Knotts T, Weigel N, McDonnell D. 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. 1998;  18 1369-1378
  PubMedGoogle Scholar
• 54 Jackson T, Richer J, Bain D, Takimoto G, Tung L, Horwitz K. The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR and SMRT.  Mol Endocrinol. 1997;  11 693-705
  CrossrefPubMedGoogle Scholar
• 55 Smith C, Nawaz Z, O'Malley B. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen.  Mol Endocrinol. 1997;  11 657-666
  PubMedGoogle Scholar
• 56 Zhang X, Jeyakumar M, Petukhov S, Bagchi M. A nuclear receptor corepressor modulates transcriptional activity of antagonist-occupied steroid hormone receptor.  Mol Endocrinol. 1998;  12 513-524
  CrossrefPubMedGoogle Scholar
• 57 Zamir I, Zhang J, Lazar M. Stoichiometric and steric principles governing repression by nuclear hormone receptors.  Genes Dev. 1997;  11 835-846
  PubMedGoogle Scholar
• 58 Hu X, Lazar M. The CoRNR motif controls the recruitment of corepressors by nuclear hormone repressors.  Nature. 1999;  402 93-96
  CrossrefPubMedGoogle Scholar
• 59 Nagy L, Kao H-Y, Love J et al.. Mechanism of corepressor binding and release from nuclear hormone receptors.  Genes Dev. 1999;  13 3209-3216
  CrossrefPubMedGoogle Scholar
• 60 Perissi V, Staszewski L, McInerney E et al.. Molecular determinants of nuclear receptor-corepressor interaction.  Genes Dev. 1999;  13 3198-3208
  CrossrefPubMedGoogle Scholar
• 61 Wagner B, Pollio G, Leonhardt S et al.. 16a-substituted analogs of the antiprogestin RU486 induce a unique conformation in the human progesterone receptor resulting in mixed agonist activity.  Proc Natl Acad Sci USA. 1996;  93 8739-8744
  CrossrefPubMedGoogle Scholar
• 62 Meyer M-E, Pornon A, Ji J, Bocquel M-T, Chambon P, Gronemeyer H. Agonistic and antagonistic activities of RU486 on the functions of the human progesterone receptor.  EMBO J. 1990;  9 3923-3932
  PubMedGoogle Scholar
• 63 Klein-Hitpass L, Cato A, Henderson D, Ryffel G. Two types of antiprogestins indentified by their differential action in transcriptionally active extracts from T47D cells.  Nucleic Acids Res. 1991;  19 1227-1234
  CrossrefPubMedGoogle Scholar
• 64 Gass E, Leonhardt S, Nordeen S, Edwards D. The antagonists RU486 and ZK98299 stimulate progesterone receptor binding to deoxyribonucleic acid in vitro and in vivo, but have distinct effects on receptor conformation.  Endocrinology. 1998;  139 1905-1919
  CrossrefPubMedGoogle Scholar
• 65 Tetel M, Giangrande P, Leonhardt S, McDonnell D, Edwards D. Hormone-dependent interaction between the amino- and carboxyl-terminal domains of progesterone receptor in vitro and in vivo.  Mol Endocrinol. 1999;  13 910-924
  CrossrefPubMedGoogle Scholar
• 66 Leonhardt S, Edwards D. Mechanism of action of progesterone antagonists.  Exp Biol Med. 2002;  227 969-980
  PubMedGoogle Scholar
• 67 Leonhardt S, Altmann M, Edwards D. Agonist and antagonists induce homodimerization and mixed ligand heterodimerization of human progesterone receptors in vivo by mammalian two-hybrid assay.  Mol Endocrinol. 1998;  12 1914-1930
  CrossrefPubMedGoogle Scholar
• 68 El-ashry D, Onãte S, Nordeen S, Edwards D. Human progesterone receptor complexed with the antagonist RU486 binds to hormone response elements in a structurally altered form.  Mol Endocrinol. 1989;  3 1545-1558
  PubMedGoogle Scholar
• 69 Xu J, Nawaz Z, Tsai S, Tsai M-J, O'Malley B. The extreme C terminus of progesterone receptor contains a transcriptional repressor domain that functions through a putative corepressor.  Proc Natl Acad Sci USA. 1996;  93 12195-12199
  CrossrefPubMedGoogle Scholar
• 70 Smith C, O'Malley B. Coregulator function: a key to understanding tissue specificity of selective receptor modulators.  Endocr Rev. 2004;  25 45-71
  CrossrefPubMedGoogle Scholar
• 71 McDonnell D, Wijayaratne A, Chang C-Y, Norris J. Elucidation of the molecular mechanism of action of selective estrogen receptor modulators.  Am J Cardiol. 2002;  90 35F-43F
  CrossrefPubMedGoogle Scholar
• 72 Giannoukos G, Szaparay D, Smith C, Meeker J, Simons S J. New antiprogestins with partial agonist activity: potential selective progesterone receptor modulator (SPRMs) and probes for receptor and coregulator-induced changes in progesterone receptor induction properties.  Mol Endocrinol. 2001;  15 255-270
  CrossrefPubMedGoogle Scholar
• 73 Takimoto G, Graham J, Jackson T et al.. Tamoxifen resistant breast cancer: coregulators determine the direction of transcription by antagonist-occupied receptors.  J Steroid Biochem Mol Biol. 1999;  69 45-50
  CrossrefPubMedGoogle Scholar
• 74 Shang Y, Brown M. Molecular determinants for the tissue specificity of SERMs.  Science. 2002;  295 2465-2468
  CrossrefPubMedGoogle Scholar
• 75 Liu Z, Auboeuf D, Wong J et al.. Coactivator/corepressor ratios modulate PR-mediated transcription by the selective receptor modulator RU486.  Proc Natl Acad Sci USA. 2002;  99 7940-7944
  CrossrefPubMedGoogle Scholar
• 76 Rogatsky I, Wang J-C, Derynck M et al.. Target-specific utilization of transcriptional regulatory surfaces by the glucocorticoid receptor.  Proc Natl Acad Sci USA. 2003;  100 13845-13850
  CrossrefPubMedGoogle Scholar
• 77 Kraus W, McInerney E, Katzenellenbogen B. Ligand-dependent, transcriptionally productive association of the amino- and carboxyl-terminal regions of a steroid hormone nuclear receptor.  Proc Natl Acad Sci USA. 1995;  92 12314-12318
  PubMedGoogle Scholar
• 78 Tora L, White J, Brou C et al.. The human estrogen receptor has two independent nonacidic transcriptional activation functions.  Cell. 1989;  59 477-487
  CrossrefPubMedGoogle Scholar
• 79 Weigel N. Steroid hormone receptors and their regulation by phosphorylation.  BiochemJ. 1996;  319 657-667
  PubMedGoogle Scholar
• 80 Rochette-Egly C. Nuclear receptors: integration of multiple signalling pathways through phosphorylation.  Cell Signal. 2003;  15 355-366
  CrossrefPubMedGoogle Scholar
• 81 Monsalve M, Wu Z, Adelmant G, Puigserver P, Fan M, Spiegelman B. Direct coupling of trancription and mRNA processing through the thermogenic coactivator PGC-1.  Mol Cell. 2000;  6 307-316
  CrossrefPubMedGoogle Scholar
• 82 Auboeuf D, Dowhan D, Li X et al.. CoAA, a nuclear receptor coactivator protein at the interface of transcriptional coactivation and RNA splicing.  Mol Cell Biol. 2004;  24 442-453
  CrossrefPubMedGoogle Scholar
• 83 Auboeuf D, Honig A, Berget S, O'Malley B. Coordinate regulation of transcription and splicing by steroid receptor coregulators.  Science. 2002;  298 416-419
  CrossrefPubMedGoogle Scholar
• 84 Wu X, Li H, Chen J. The human homologue of the yeast DNA repair and TFIIH regulator MMS19 is an AF-1-specific coactivator of estrogen receptor.  J Biol Chem. 2001;  276 23962-23968
  CrossrefPubMedGoogle Scholar
• 85 Kumar R, Lee J-C, Bolen D, Thompson E. The conformation of the glucocorticoid receptor AF1/tau1 domain induced by osmolyte binds co-regulatory proteins.  J Biol Chem. 2001;  276 18146-18152
  CrossrefPubMedGoogle Scholar
• 86 Lanz R, McKenna N, Onãte S et al.. A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex.  Cell. 1999;  97 17-27
  CrossrefPubMedGoogle Scholar
• 87 Lanz R, Razani B, Goldberg A, O'Malley B. Distinct RNA motifs are important for coactivation of steroid hormone receptors by steroid receptor RNA coactivator.  Proc Natl Acad Sci USA. 2002;  99 16081-16086
  CrossrefPubMedGoogle Scholar
• 88 Endoh H, Maruyama K, Masuhiro Y et al.. Purification and identification of p68 helicase acting as a transcriptional coactivator specific for the activation function 1 of human estrogen receptor α.  Mol Cell Biol. 1999;  19 5363-5372
  PubMedGoogle Scholar
• 89 Wansa K, Harris J, Yan G, Ordentlich P, Muscat G. The AF-1 domain of the orphan nuclear receptor NOR-1 mediates trans-activation, coactivator recruitment, and activation by the purine anti-metabolite 6-mercaptopurine.  J Biol Chem. 2003;  278 24776-24790
  CrossrefPubMedGoogle Scholar
• 90 Wansa K, Harris J, Muscat G. The activation function-1 domain of Nur77/NR4A1 mediates trans-activation, cell specificity, and coactivator recruitment.  J Biol Chem. 2002;  277 33001-33011
  CrossrefPubMedGoogle Scholar
• 91 Callewaert L, Verrijdt G, Christiaens V, Haelens A, Claessens F. Dual function of an amino-terminal amphipathic helix in androgen receptor-mediated transactivation through specific and non-specific response elements.  J Biol Chem. 2003;  278 8212-8218
  CrossrefPubMedGoogle Scholar
• 92 Wallberg A, Neely K, Gustafsson J-A, Workman J, Wright A, Grant P. Histone acetyltransferase complexes can mediate transcriptional activation by the major glucocorticoid receptor activation domain.  Mol Cell Biol. 1999;  19 5952-5959
  PubMedGoogle Scholar
• 93 Ma H, Hong H, Huang S-M et al.. Multiple signal input and output domains of the 160-kilodalton nuclear receptor coactivator proteins.  Mol Cell Biol. 1999;  19 6164-6173
  PubMedGoogle Scholar
• 94 Onãte S, Boonyaratanakornkit V, Spencer T et al.. The steroid receptor coactivator-1 contains multiple receptor interacting and activation domains that cooperatively enhance the activation function 1 (AF1) and AF2 domains of steroid receptors.  J Biol Chem. 1998;  273 12101-12108
  CrossrefPubMedGoogle Scholar
• 95 Alen P, Claessens F, Verhoeven G, Rombauts W, Peeters B. The androgen receptor amino-terminal domain plays a key role in p160 coactivator-stimulated gene transcription.  Mol Cell Biol. 1999;  19 6085-6097
  PubMedGoogle Scholar
• 96 Webb P, Nguyen P, Shinsako J et al.. Estrogen receptor activation function 1 works by binding p160 coactivator proteins.  Mol Endocrinol. 1998;  12 1605-1618
  CrossrefPubMedGoogle Scholar
• 97 Bommer M, Benecke A, Gronemeyer H, Rochette-Egly C. TIF2 mediates the synergy between RARα1 activation functions AF-1 and AF-2.  J Biol Chem. 2002;  277 37961-37966
  CrossrefPubMedGoogle Scholar
• 98 Hittelman A, Burakov D, Ineguez-Lluhi J, Freedman L, Garabedian M. Differential regulation of glucocorticoid receptor transcriptional activation via AF-1-associated proteins.  EMBOJ. 1999;  18 5380-5388
  CrossrefPubMedGoogle Scholar
• 99 Reid R, Kelly S, Watt K, Price N, McEwan I. Conformational analysis of the androgen receptor amino-terminal domain involved in transactivation.  J Biol Chem. 2002;  277 20079-20086
  CrossrefPubMedGoogle Scholar
• 100 Baskakov I, Kumar R, Srinivasan G, Ji Y-S, Bolen D, Thompson E. Trimethylamine N-oxide-induced cooperative folding of am intrinsically unfolded transcription-activating fragment of human glucocorticoid receptor.  J Biol Chem. 1999;  274 10693-10696
  CrossrefPubMedGoogle Scholar
• 101 Warnmark A, Wikstrom A, Wright A, Gustafsson J-A, Hard T. The N-terminal regions of estrogen receptor alpha and beta are unstructured and show different TBP binding properties.  J Biol Chem. 2001;  276 45939-45944
  CrossrefPubMedGoogle Scholar
• 102 Shen F, Triezenberg S, Hensley P, Porter D, Knutson J. Transcriptional activation domain of the herpesvirus protein VP16 becomes conformationally constrained upon interaction with basal transcription factors.  J Biol Chem. 1996;  271 4827-4837
  CrossrefPubMedGoogle Scholar
• 103 Radhakrishnan I, Perez-Alvarado G, Parker D, Dyson H, Montminy M, Wright P. Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: a model for activator:coactivator interactions.  Cell. 1997;  91 741-752
  CrossrefPubMedGoogle Scholar
• 104 Schmitz M, dos Santos Silva M, Altmann H, Czisch M, Holak T, Baeuerle P. Structural and functional analysis of the NF-κB p65 C terminus.  J Biol Chem. 1994;  269 25613-25620
  PubMedGoogle Scholar
• 105 Folkers G, van Heerde E, van der Saag P. Activation function 1 of retinoic acid receptor β2 is an acidic activator resembling VP16.  J Biol Chem. 1995;  270 23552-23559
  CrossrefPubMedGoogle Scholar
• 106 Bain D, Franden M, McManaman J, Takimoto G, Horwitz K. The N-terminal region of the human progesterone A-receptor.  J Biol Chem. 2000;  275 7313-7320
  CrossrefPubMedGoogle Scholar
• 107 Bain D, Franden M, McManaman J, Takimoto G, Horwitz K. The N-terminal region of human progesterone B-receptors.  J Biol Chem. 2001;  276 23825-23831
  CrossrefPubMedGoogle Scholar
• 108 Meyer M-E, Quirin-Stricker C, Lerouge T, Bocquel M-T, Gronemeyer H. A limiting factor mediates the differential activation of promoters by the human progesterone receptor isoforms.  J Biol Chem. 1992;  267 10882-10887
  PubMedGoogle Scholar
• 109 Sartorius C, Melville M, Hovland A, Tung L, Takimoto G, Horwitz K. A third transactivation function (AF3) of human progesterone receptors located in the unique N-terminal segment of the B-isoform.  Mol Endocrinol. 1994;  8 1347-1360
  CrossrefPubMedGoogle Scholar
• 110 Takimoto G, Tung L, Abdel-Hafiz H et al.. Functional properties of the N-terminal region of progesterone receptors and their mechanistic relationship to structure.  J Steroid Biochem Mol Biol. 2003;  85 209-219
  CrossrefPubMedGoogle Scholar
• 111 Abdel-Hafiz H, Takimoto G, Tung L, Horwitz K. The inhibitory function of human progesterone receptor N termini binds SUMO-1 protein to regulate autoinhibition and transrepression.  J Biol Chem. 2002;  277 33950-33956
  CrossrefPubMedGoogle Scholar
• 112 Huse B, Verca S, Matthey P, Rusconi S. Definition of a negative modulation domain in the human progesterone receptor.  Mol Endocrinol. 1998;  12 1334-1342
  CrossrefPubMedGoogle Scholar
• 113 McInerney E, Katzenellenbogen B. Different regions in activation function-1 of the human estrogen receptor required for antiestrogen- and estradiol-dependent transcriptional activation.  J Biol Chem. 1996;  271 24172-24178
  CrossrefPubMedGoogle Scholar
• 114 Chwalisz K, DeManno D, Garg R, Larsen L, Mattia-Goldberg C, Stickler T. Therapeutic potential for the selective progesterone receptor modulator asoprisnil in the treatment of leiomyomata.  Semin Reprod Med. 2004;  22 113-119
  Article in Thieme ConnectPubMedGoogle Scholar
• 115 DeManno D, Elger W, Garg R et al.. Asoprisnil (J867): a selective progesterone receptor modulator for gynecological therapy.  Steroids. 2003;  68 1019-1032
  CrossrefPubMedGoogle Scholar
• 116 Dong Y, Rogberge J, Wang Z et al.. Characterization of a new class of selective nonsteroidal progesterone receptor agonists.  Steroids. 2004;  69 201-217
  CrossrefPubMedGoogle Scholar
• 117 Zhi L, Tegley C, Pio B et al.. Synthesis and biological activity of 5-methylidene 1,2-dihydrochromeno[3,4-f]quinoline derivatives as progesterone receptor modulators.  Bioorg Med Chem. 2003;  13 2071-2074
  PubMedGoogle Scholar
• 118 Zhi L, Tegley C, Pio B et al.. 5-Benzylidene-1,2-dihydrochormeno[3,4-f]quinolines as selective progesterone receptor modulators.  J Med Chem. 2003;  46 4104-4112
  CrossrefPubMedGoogle Scholar
• 119 Mangal R, Wiehle R, Poindester A R, Weigel N. Differential expression of uterine progesterone receptor forms A and B during the menstrual cycle.  JSteroid Biochem Mol Biol. 1997;  63 195-202
  CrossrefPubMedGoogle Scholar
• 120 Graham J, Yeates C, Balleine R et al.. Characterization of progesterone receptor A and B expression in human breast cancer.  Cancer Res. 1995;  55 5063-5068
  PubMedGoogle Scholar

Dean P Edwards

Pathology Dept., P.O. Box 6511

Mail Stop 8104, Aurora, CO 80045

Email: Dean.Edwards@uchsc.edu