Skip to main content
SpringerLink
Log in

Competitive agonists and antagonists of steroid nuclear receptors: Evolution of the concept or its reversal

  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

The mechanisms displaying pure and mixed steroid agonist/antagonist activity as well as principles underlying in vivo action of selective steroid receptor modulators dependent on tissue or cell type including interaction with various types of nuclear receptors are analyzed in this work. Mechanisms of in vitro action for mixed agonist/antagonist steroids are discussed depending on: specific features of their interaction with receptor hormone-binding pocket; steroid-dependent allosteric modulation of interaction between hormone–receptor complex and hormone response DNA elements; features of interacting hormone–receptor complex with protein transcriptional coregulators; level and tissue-specific composition of transcriptional coregulators. A novel understanding regarding context-selective modulators replacing the concept of steroid agonists and antagonists is discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AF1, 2, 3:

activation function 1, 2, 3

BF1, 2, 3:

binding function 1, 2, 3

CBI:

coactivator binding inhibitor

COSMO:

context selective modulator

CTE:

C-terminal extension

DAC:

deacylcortivazol

DBD:

DNA-binding domain

EC50 :

half-maximal effective concentration

ER:

estrogen receptor

GR:

glucocorticoid receptor

IC50 :

half-maximal inhibitory concentration

LBD:

ligand-binding domain

NRAM:

nuclear receptor alternate-site modulator

NTD:

N-terminal domain

PAA:

partial agonist activity

PR:

progestin receptor

SERM:

selective estrogen receptor modulator

SRE:

steroid response element

SSRM:

selective steroid receptor modulator

TAmax :

maximum transcriptional activity

TIF2:

transcription intermediary factor-2

References

  1. Simons, S. S., and Chow, C. C. (2012) The road less trav-eled: new views of steroid receptor action from the path of dose-response curves, Mol. Cell. Endocrinol., 348, 373–382.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Dougherty, E. J., Guo, C., Simons, S. S., and Chow, C. C. (2012) Deducing the temporal order of cofactor function in ligand-regulated gene transcription: theory and experimen-tal verification, PLoS On., 7, 1–10.

    Google Scholar 

  3. Ong, K. M., Blackford, J. A., Kagan, B. L., Simons, S. S., and Chow, C. C. (2010) A theoretical framework for gene induction and experimental comparisons, Proc. Natl. Acad. Sci. US., 107, 7107–7112.

    Article  CAS  Google Scholar 

  4. Feng, Q., and O’Malley, B. W. (2014) Nuclear receptor modulation–role of coregulators in selective estrogen receptor modulator (SERM) actions, Steroid., 90, 39–43.

    Article  CAS  Google Scholar 

  5. Martinkovich, S., Shah, D., Planey, S. L., and Arnott, J. (2014) Selective estrogen receptor modulators: tissue speci-ficity and clinical utility, Clin. Interv. Agin., 20, 1437–1452.

    Google Scholar 

  6. Chabbert-Buffet, N., Meduri, G., Bouchard, P., and Spitz, I. M. (2005) Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications, Hum. Reprod. Updat., 11, 293–307.

    Article  CAS  Google Scholar 

  7. Afhuppe, W., Sommer, A., Muller, J., Schwede, W., Fuhrmann, U., and Moller, C. (2009) Global gene expres-sion profiling of progesterone receptor modulators in T47D cells provides a new classification system, J. Steroid Biochem. Mol. Biol., 113, 105–115.

    Article  PubMed  Google Scholar 

  8. Chabbert-Buffet, N., Pintiaux, A., and Bouchard, P. (2012) The immninent dawn of SPRMs in obstetrics and gynecol-ogy, Mol. Cell. Endocrinol., 358, 232–243.

    Article  CAS  PubMed  Google Scholar 

  9. Klein-Hitpass, L., Cato, A. C. B., Henderson, D., and Ryffel, G. U. (1991) Two types of antiprogestins identified by their differential action in transcriptionally active extracts from T47D cells, Nucleic Acids Res., 19, 1227–1234.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Wagner, B. L., Norris, J. D., Knotts, T. A., and Weigel, N. L. (1998) The nuclear corepressors NCoR and SMRT are key regulators of both ligand- and 8-bromo-cyclic AMP-dependent transcriptional activity of the human proges-terone receptor, Microbiolog., 18, 1369–1378.

    CAS  Google Scholar 

  11. Schoch, G. A., Arcy, B. D., Stihle, M., Burger, D., Bar, D., Benz, J., Thoma, R., and Ruf, A. (2010) Molecular switch in the glucocorticoid receptor: active and passive antagonist conformations, J. Mol. Biol., 395, 568–577.

    Article  CAS  PubMed  Google Scholar 

  12. Pecci, A., Alvarez, L. D., Veleiro, A. S., Ceballos, N. R., Lantos, C. P., and Burton, G. (2009) New lead compounds in the search for pure antiglucocorticoids and the dissocia-tion of antiglucocorticoid effects, J. Steroid Biochem. Mol. Biol., 113, 155–162.

    Article  CAS  PubMed  Google Scholar 

  13. Allan, G. F., Palmer, E., Musto, A., Lai, M.-T., Clancy, J., and Palmer, S. (2006) Molecular properties and preclinical pharmacology of JNJ-1250132, a steroidal progesterone receptor modulator that inhibits binding of the receptor to DNA in vitro, Steroid., 71, 578–584.

    Article  CAS  Google Scholar 

  14. Germain, P., and Bourguet, W. (2013) Dimerization of nuclear receptors, Methods Cell Biol., 117, 21–41.

    Article  CAS  PubMed  Google Scholar 

  15. Kumar, R., and McEwan, I. J. (2012) Allosteric modulators of steroid hormone receptors: structural dynamics and gene regulation, Endocr. Rev., 33, 271–299.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Fang, L., Ricketson, D., Getubig, L., and Darimont, B. (2006) Unliganded and hormone-bound glucocorticoid receptors interact with distinct hydrophobic sites in the Hsp90 C-terminal domain, Proc. Natl. Acad. Sci. US., 103, 18487–18492.

    Article  CAS  Google Scholar 

  17. Hill, K. K., Roemer, S. C., Churchill, M. E., and Edwards, D. P. (2012) Structural and functional analysis of domains of the progesterone receptor, Mol. Cell. Endocrinol., 348, 418–429.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Helsen, C., and Claessens, F. (2014) Looking at nuclear recep-tors from a new angle, Mol. Cell. Endocrinol., 382, 97–106.

    Article  CAS  PubMed  Google Scholar 

  19. Centenera, M. M., Harris, J. M., Tilley, W. D., and Butler, L. M. (2008) The contribution of different androgen recep-tor domains to receptor dimerization and signaling, Mol. Endocrinol., 22, 2373–2382.

    Article  CAS  PubMed  Google Scholar 

  20. Daniels, G., Jha, R., Shen, Y., Logan, S. K., and Lee, P. (2014) Androgen receptor coactivators that inhibit prostate cancer growth, Am. J. Clin. Exp. Urol., 2, 62–70.

    PubMed Central  PubMed  Google Scholar 

  21. Meijsing, S. H., Pufall, M. A., So, A. Y., Bates, D. L., Chen, L., and Yamamoto, K. R. (2009) DNA binding site sequence directs glucocorticoid receptor structure and activity, Scienc., 324, 407–410.

    Article  CAS  Google Scholar 

  22. Oseni, T., Patel, R., Pyle, J., and Jordan, V. C. (2008) Selective estrogen receptor modulators and phytoestrogens, Planta Med., 74, 1656–1665.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Mote, P. A., Arnett-Mansfield, R. L., Gava, N., DeFazio, A., Mulac-Jericevic, B., Conneely, O. M., and Clarke, C. L. (2006) Overlapping and distinct expression of progesterone receptors A and B in mouse uterus and mammary gland dur-ing the estrous cycle, Endocrinolog., 147, 5503–5512.

    Article  CAS  Google Scholar 

  24. Jacobsen, B. M., and Horwitz, K. B. (2012) Progesterone receptors, their isoforms and progesterone regulated tran-scription, Mol. Cell. Endocrinol., 357, 18–29.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Leitman, D. C., Paruthiyil, S., Vivar, O. I., Saunier, E. F., Candice, B., Cohen, I., Tagliaferri, M., and Speed, T. P. (2010) Regulation of specific target genes and biological responses by estrogen receptor subtype agonists, Curr. Opin. Pharmacol., 10, 629–636.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Fox, E. M., Davis, R. J., and Shupnik, M. A. (2008) ERß in breast cancer–onlooker, passive player or active protec-tor? Steroid., 73, 1039–1051.

    Article  CAS  Google Scholar 

  27. Vivar, O. I., Zhao, X., Saunier, E. F., Griffin, C., Mayba, O. S., Tagliaferri, M., Cohen, I., Speed, T. P., and Leitman, D. C. (2010) Estrogen receptor ß binds to and regulates three distinct classes of target genes, J. Biol. Chem., 285, 22059–22066.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Hertrampf, T., Seibel, J., Laudenbach, U., Fritzemeier, K. H., and Diel, P. (2008) Analysis of the effects of oestrogen receptor a (ERa)- and ERß-selective ligands given in com-bination to ovariectomized rats, Br. J. Pharmacol., 153, 1432–1437.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Seidlova-Wuttke, D., Prelle, K., Fritzemeier, K. H., and Wuttke, W. (2008) Effects of estrogen receptor a- and ß-selective substances in the metaphysis of the tibia and on serum parameters of bone and fat tissue metabolism of ovariectomized rats, Bon., 43, 849–855.

    Article  CAS  Google Scholar 

  30. Mulac-Jericevic, B., and Conneely, O. M. (2004) Reproductive tissue selective actions of progesterone recep-tors, Reproductio., 128, 139–146.

    CAS  Google Scholar 

  31. Wagner, B. L., Pollio, G., Giangrande, P., Webster, J. C., Breslin, M., Mais, D. E., Cook, C. E., Vedeckis, W. V., Cidlowski, J. A., and McDonnell, D. P. (1999) The novel progesterone receptor antagonists RTI 3021-012 and RTI 3021-022 exhibit complex glucocorticoid receptor antagonist activities: implications for the development of dissoci-ated antiprogestins, Endocrinolog., 140, 1449–1458.

    CAS  Google Scholar 

  32. Moore, N. L., Hickey, T. E., Butler, L. M., and Tilley, W. D. (2012) Multiple nuclear receptor signaling pathways medi-ate the actions of synthetic progestins in target cells, Mol. Cell. Endocrinol., 357, 60–70.

    Article  CAS  PubMed  Google Scholar 

  33. Wagner, B. L., Pollio, G., Leonhardt, S., Wani, M. C., Lee, D. Y., Imhof, M. O., Edwards, D. P., Cook, C. E., and McDonnell, D. P. (1996) 16 a-substituted analogs of the antiprogestin RU486 induce a unique conformation in the human progesterone receptor resulting in mixed agonist activity, Proc. Natl. Acad. Sci. US., 93, 8739–8744.

    Article  CAS  Google Scholar 

  34. Kojetin, D. J., and Burris, T. P. (2013) Small molecule modulation of nuclear receptor conformational dynamics: implications for function and drug discovery, Mol. Pharmacol., 83, 1–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Kumar, R., and Litwack, G. (2009) Structural and func-tional relationships of the steroid hormone receptors’ N-terminal transactivation domain, Steroid., 74, 877–883.

    Article  CAS  Google Scholar 

  36. Hall, J. M., McDonnell, D. P., and Korach, K. S. (2002) Allosteric regulation of estrogen receptor structure, func-tion, and coactivator recruitment by different estrogen response elements, Mol. Endocrinol., 16, 469–486.

    Article  CAS  PubMed  Google Scholar 

  37. Wardell, S. E., Nelson, E. R., and McDonnell, D. P. (2014) From empirical to mechanism-based discovery of clinically useful selective estrogen receptor modulators (SERMs), Steroid., 90, 30–38.

    Article  CAS  Google Scholar 

  38. Wang, L. H., Yang, X. Y., Zhang, X., An, P., Kim, H. J., Huang, J., Clarke, R., Osborne, C. K., Inman, J. K., Appella, E., and Farrar, W. L. (2006) Disruption of estrogen receptor DNA-binding domain and related intramolecular communication restores tamoxifen sensitivity in resistant breast cancer, Cancer Cel., 10, 487–499.

    Article  CAS  Google Scholar 

  39. Moore, T. W., Mayne, C. G., and Katzenellenbogen, J. A. (2010) Not picking pockets: nuclear receptor alternate-site modulators (NRAMs), Mol. Endocrinol., 24, 683–695.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Biggadike, K., Bledsoe, R. K., Coe, D. M., Cooper, T. W. J., House, D., Iannone, M., MacDonald, S. J. F., Madauss, K. P., McLay, I. M., Shipley, T. J., Taylor, S. J., Tran, T. B., Uings, I. J., Weller, V., and Williams, S. P. (2009) Design and X-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor, Proc. Natl. Acad. Sci. US., 106, 18114–18119.

    Article  CAS  Google Scholar 

  41. Smith, C. L., Nawaz, Z., and O’Malley, B. W. (1997) Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen, Mol. Endocrinol., 11, 657–666.

    Article  CAS  PubMed  Google Scholar 

  42. Redmond, A. M., Bane, F. T., Stafford, A. T., Mcllroy, M., Dillon, M. F., Crotty, T. B., Hill, A. D., and Young, L. S. (2009) Coassociation of estrogen receptor and p160 pro-teins predicts resistance to endocrine treatment; SRC-1 is an independent predictor of breast cancer recurrence, Clin. Cancer Res., 15, 2098–2106.

    Article  CAS  PubMed  Google Scholar 

  43. Luo, M., and Simons, S. S. (2009) Modulation of gluco-corticoid receptor inhibition propertites by cofactors in peripheral blood mononuclear cells, Hum. Immunol., 70, 785–789.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Tao, Y., Xu, Y., Xu, H. E., and Simons, S. S. (2008) Mutations of glucocorticoid receptor differetially affect AF2 domain activity in a steroid-selective manner to alter the potency and efficacy of gene induction and repression, Biochemistr., 47, 7648–7662.

    Article  CAS  Google Scholar 

  45. Cho, S., Kagan, B. L., Blackford, J. A., Szapary, D., and Simons, S. S. (2005) Glucocorticoid receptor ligand bind-ing domain is sufficient for the modulation of glucocorti-coid induction properties by homologous receptors, coacti-vator transcription intermediary factor 2, and Ubc9, Mol. Endocrinol., 19, 290–311.

    Article  CAS  PubMed  Google Scholar 

  46. Lee, G. S., and Simons, S. S. (2011) Ligand binding domain mutations of the glucocorticoid receptor selective-ly modify the effects with, but not binding of, cofactors, Biochemistr., 50, 356–366.

    Article  CAS  Google Scholar 

  47. Kim, Y., Sun, Y., Chow, C., Pommier, Y. G., and Simons, S. S. (2006) Effects of acetylation, polymerase phosphory-lation, and DNA unwinding in glucocorticoid receptor transactivation, J. Steroid Biochem. Mol. Biol., 100, 3–17.

    Article  CAS  PubMed  Google Scholar 

  48. Nagaich, A. K., Walker, D. A., Wolford, R., and Hager, G. L. (2004) Rapid periodic binding and displacement of the glucocorticoid receptor during chromatin remodeling, Mol. Cel., 14, 163–174.

    Article  CAS  Google Scholar 

  49. Stavreva, D. A., Muller, W. G., Hager, G. L., Smith, C. L., and McNally, J. G. (2004) Rapid glucocorticoid receptor exchange at a promoter is coupled to transcription and reg-ulated by chaperones and proteasomes, Mol. Cell. Biol., 24, 2682–2697.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Berrodin, T. J., Jelinsky, S. A., Graciani, N., Butera, J. A., Zhang, Z., Nagpal, S., Winneker, R. C., and Yudt, M. R. (2009) Novel progesterone receptor modulators with gene selective and context-dependent partial agonism, Biochem. Pharmacol., 77, 204–215.

    Article  CAS  PubMed  Google Scholar 

  51. Estebanez-Perpina, E., Arnold, L. A., Nguyen, P., Rodrigues, E. D., Mar, E., Bateman, R., Pallai, P., Shokat, K. M., Baxter, J. D., Guy, R. K., Webb, P., and Fletterick, R. J. (2007) A surface on the androgen receptor that allosterically regulates coactivator binding, Proc. Natl. Acad. Sci. US., 104, 16074–16079.

    Article  CAS  Google Scholar 

  52. Parent, A. A., Gunther, J. R., and Katzenellenbogen, J. A. (2008) Blocking estrogen signaling after the hormone: pyrimidine-core inhibitors of estrogen receptor-coactivator binding, J. Med. Chem., 51, 6512–6530.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Hwang, J. Y., Arnold, L. A., Zhu, F., Kosinski, A., Mangano, T. J., Setola, V., Roth, B., and Guy, R. K. (2009) Improvement of pharmacological properties of irreversible thyroid receptor coactivator binding inhibitors, J. Med. Chem., 52, 3892–3901.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Chandra, V., Huang, P., Hamuro, Y., Raghuram, S., Burris, T. P., and Rastinejad, F. (2008) Structure of the intact PPAR?–RXRa nuclear receptor complex on DNA, Natur., 456, 350–356.

    Article  Google Scholar 

  55. Gunther, J. R., Parent, A. A., and Katzenellenbogen, J. A. (2009) Alternative inhibition of androgen receptor sig-nalling: peptidomimetic pyrimidines as direct androgen receptor/coactivator disruptors, ACS Chem. Biol., 4, 435–440.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Huang, H., Wang, H., Sinz, M., Zoeckler, M., Staudinger, J., Redinbo, M. R., Teotico, D. G., Locker, J., Kalpana, G. V., and Mani, S. (2007) Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketocona-zole, Oncogene., 26, 258–268.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Biological Faculty, Lomonosov Moscow State University, 119991, Moscow, Russia

    O. V. Smirnova

Authors
  1. O. V. Smirnova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to O. V. Smirnova.

Additional information

Original Russian Text © O. V. Smirnova, 2015, published in Biokhimiya, 2015, Vol. 80, No. 10, pp. 1493-1502.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Smirnova, O.V. Competitive agonists and antagonists of steroid nuclear receptors: Evolution of the concept or its reversal. Biochemistry Moscow 80, 1227–1234 (2015). https://doi.org/10.1134/S000629791510003X

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S000629791510003X

Keywords

Search

Navigation