Theory of partial agonist activity of steroid hormones

Carson C. Chow; Karen M. Ong; Benjamin Kagan; S. Stoney Simons Jr.

doi:10.3934/molsci.2015.2.101

AIMS Molecular Science, 2015, 2(2): 101-123. doi: 10.3934/molsci.2015.2.101. Research article Special Issues

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Theory of partial agonist activity of steroid hormones

Carson C. Chow, Karen M. Ong, Benjamin Kagan, S. Stoney Simons Jr.

1 Mathematical Biology Section, NIDDK/LBM, National Institutes of Health, Bethesda, MD 20892-5621, USA;
2 Steroid Hormones Section, NIDDK/LERB, National Institutes of Health, Bethesda, MD 20892-1772, USA;
3 Computational Biology Program, New York University School of Medicine, New York, NY 10016, USA;
4 Science Department, Tuscarora High School, Loudoun County Public Schools, Leesburg, VA 20176, USA

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Special Issues: Steroid hormone receptor regulation and function

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The different amounts of residual partial agonist activity (PAA) of antisteroids under assorted conditions have long been useful in clinical applications but remain largely unexplained. Not only does a given antagonist often afford unequal induction for multiple genes in the same cell but also the activity of the same antisteroid with the same gene changes with variations in concentration of numerous cofactors. Using glucocorticoid receptors as a model system,we have recently succeeded in constructing from first principles a theory that accurately describes how cofactors can modulate the ability of agonist steroids to regulate both gene induction and gene repression. We now extend this framework to the actions of antisteroids in gene induction. The theory shows why changes in PAA cannot be explained simply by differences in ligand affinity for receptor and requires action at a second step or site in the overall sequence of reactions. The theory also provides a method for locating the position of this second site,relative to a concentration limited step (CLS),which is a previously identified step in glucocorticoid-regulated transactivation that always occurs at the same position in the overall sequence of events of gene induction. Finally,the theory predicts that classes of antagonist ligands may be grouped on the basis of their maximal PAA with excess added cofactor and that the members of each class differ by how they act at the same step in the overall gene induction process. Thus,this theory now makes it possible to predict how different cofactors modulate antisteroid PAA,which should be invaluable in developing more selective antagonists.

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Keywords: antisteroid; antagonist; antiestrogen; tamoxifen; raloxifene; ligand; nuclear receptor; steroid receptor; glucocorticoid receptor; gene expression; gene transcription

Citation: Carson C. Chow, Karen M. Ong, Benjamin Kagan, S. Stoney Simons Jr.. Theory of partial agonist activity of steroid hormones. AIMS Molecular Science, 2015, 2(2): 101-123. doi: 10.3934/molsci.2015.2.101

References:

1. Zajchowski DA,Kauser K,Zhu D,et al. (2000) Identification of selective estrogen receptor modulators by their gene expression fingerprints. J Biol Chem 275: 15885-15894.
2. Simons Jr. SS (2003) The importance of being varied in steroid receptor transactivation. TIPS 24: 253-259.
3. Johnson AB,O'Malley BW (2012) Steroid receptor coactivators 1,2,and 3: Critical regulators of nuclear receptor activity and steroid receptor modulator (SRM)-based cancer therapy. Mol Cell Endocrinol 348: 430-439.
4. Shang Y,Brown M (2002) Molecular determinants for the tissue specificity of SERMs. Science 295: 2465-2468.
5. Zalachoras I,Houtman R,Atucha E,et al. (2013) Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator. Proc Natl Acad Sci U S A 110: 7910-7915.
6. MacGregor JI,Jordan VC (1998) Basic guide to the mechanisms of antiestrogen action. Pharmacol Rev 50: 151-196.
7. Ojasoo T,Dore J-C,Gilbert J,Raynaud J-P (1988) Binding of steroids to the progestin and glucocorticoid receptors analyzed by correspondence analysis. J Med Chem 31: 1160-1169.
8. Szapary D,Xu M,Simons Jr. SS (1996) Induction properties of a transiently transfected glucocorticoid-responsive gene vary with glucocorticoid receptor concentration. J Biol Chem 271: 30576-30582.
9. Wang Q,Blackford Jr. JA,Song L-N,et al. (2004) Equilibrium interactions of corepressors and coactivators modulate the properties of agonist and antagonist complexes of glucocorticoid receptors. Mol Endocrinol 18: 1376-1395.
10. Simons Jr. SS,Edwards DP,Kumar R (2014) Minireview: dynamic structures of nuclear hormone receptors: new promises and challenges. Mol Endocrinol 28: 173-182.
11. Simons Jr. SS (2008) What goes on behind closed doors: physiological versus pharmacological steroid hormone actions. Bioessays 30: 744-756.
12. Cho S,Blackford Jr. JA,Simons Jr. SS (2005) Role of activation function domain 1,DNA binding,and coactivator in the expression of partial agonist activity of glucocorticoid receptor complexes. Biochemistry 44: 3547-3561.
13. Cho S,Kagan BL,Blackford Jr. JA,et al. (2005) Glucocorticoid receptor ligand binding domain is sufficient for the modulation of glucocorticoid induction properties by homologous receptors,coactivator transcription intermediary factor 2,and Ubc9. Mol Endo 19: 290-311.
14. Raynaud JP,Bouton MM,Ojasoo T (1980) The use of interaction kinetics to distinguish potential antagonists from agonists. TIPS 324-327.
15. Sistare FD,Hager GL,Simons Jr. SS (1987) Mechanism of dexamethasone 21-mesylate antiglucocorticoid action: I. Receptor-antiglucocorticoid complexes do not competitively inhibit receptor-glucocorticoid complex activation of gene transcription in vivo. Mol Endocrinol 1: 648-658.
16. Miller PA,Simons Jr. SS (1988) Comparison of glucocorticoid receptors in two rat hepatoma cell lines with different sensitivities to glucocorticoids and antiglucocorticoids. Endocrinology 122: 2990-2998.
17. Nagy L,Schwabe JW (2004) Mechanism of the nuclear receptor molecular switch. Trends Biochem Sci 29: 317-324.
18. Szapary D,Huang Y,Simons Jr. SS (1999) Opposing effects of corepressor and coactivators in determining the dose-response curve of agonists,and residual agonist activity of antagonists,for glucocorticoid receptor regulated gene expression. Mol Endocrinol 13: 2108-2121.
19. Shiau AK,Barstad D,Radek JT,et al. (2002) Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism. Nat Struct Biol 9: 359-364.
20. Tao Y-G,Xu Y,Xu HE,et al. (2008) Mutations of glucocorticoid receptor differentially affect AF2 domain activity in a steroid-selective manner to alter the potency and efficacy of gene induction and repression. Biochemistry 47: 7648-7662.
21. Lee G-S,Simons Jr. SS (2011) Ligand binding domain mutations of glucocorticoid receptor selectively modify effects with,but not binding of,cofactors. Biochemistry 50: 356-366.
22. Ong KM,Blackford Jr. JA,Kagan BL,et al. (2010) A theoretical framework for gene induction and experimental comparisons. Proc Natl Acad Sci U S A 107: 7107-7112.
23. Dougherty EJ,Guo C,Simons Jr. SS,et al. (2012) Deducing the temporal order of cofactor function in ligand-regulated gene transcription: theory and experimental verification. PLoS ONE 7: e30225.
24. Blackford Jr. JA,Guo C,Zhu R,et al. (2012) Identification of Location and Kinetically Defined Mechanism of Cofactors and Reporter Genes in the Cascade of Steroid-regulated Transactivation. J Biol Chem 287: 40982-40995.
25. Luo M,Lu X,Zhu R,et al. (2013) A Conserved Protein Motif Is Required for Full Modulatory Activity of Negative Elongation Factor Subunits NELF-A and NELF-B in Modifying Glucocorticoid Receptor-regulated Gene Induction Properties. J Biol Chem 288: 34055-34072.
26. Zhang Z,Sun Y,Cho Y-W,et al. (2013) PA1: a new competitive decelerator acting at more than one step to impede glucocorticoid receptor-mediated transactivation. J Biol Chem 288: 42-58.
27. Zhu R,Lu X,Pradhan M,et al. (2014) A kinase-independent activity of Cdk9 modulates glucocorticoid receptor-mediated gene induction. Biochemistry 53: 1753-1767.
28. Chow CC,Finn KK,Storchan GB,L et al. (2015) Kinetically-defined component actions in gene repression. PLoS Comput Biol 11: e1004122.
29. Perissi V,Rosenfeld MG (2005) Controlling nuclear receptors: the circular logic of cofactor cycles. Nat Rev Mol Cell Biol 6: 542-554.
30. Pons M,Simons Jr. SS (1981) Facile,high yield synthesis of spiro C-17-steroidal oxetan-3'-ones. J Org Chem 46: 3262-3264.
31. Kaul S,Blackford Jr. JA,Chen J,et al. (2000) Properties of the glucocorticoid modulatory element binding proteins GMEB-1 and -2: potential new modifiers of glucocorticoid receptor transactivation and members of the family of KDWK proteins. Mol Endocrinol 14: 1010-1027.
32. He Y,Simons Jr. SS (2007) STAMP: a novel predicted factor assisting TIF2 actions in glucocorticoid receptor-mediated induction and repression. Mol Cell Biol 27: 1467-1485.
33. Kaul S,Blackford Jr. JA,Cho S,et al. (2002) Ubc9 is a novel modulator of the induction properties of glucocorticoid receptors. J Biol Chem 277: 12541-12549.
34. Simons Jr. SS,Thompson EB (1981) Dexamethasone 21-mesylate: an affinity label of glucocorticoid receptors from rat hepatoma tissue culture cells. Proc Natl Acad Sci USA 78: 3541-3545.
35. Stromstedt P-E,Berkenstam A,Jornvall H,et al. (1990) Radiosequence analysis of the human progestin receptor charged with [3H]promegestone. A comparison with the glucocorticoid receptor. J Biol Chem 265: 12973-12977.
36. Luo M,Simons Jr. SS (2009) Modulation of glucocorticoid receptor induction properties by cofactors in peripheral blood mononuclear cells. Hum Immunol 70: 785-789.
37. Blackford Jr. JA,Brimacombe KR,Dougherty EJ,et al. (2014) Modulators of glucocorticoid receptor activity identified by a new high-throughput screening assay. Mol Endocrinol 28: 1194-1206.
38. Simons Jr. SS,Kumar R (2013) Variable steroid receptor responses: Intrinsically disordered AF1 is the key. Mol Cell Endocrinol 376: 81-84.
39. Kim Y,Sun Y,Chow C,et al. (2006) Effects of acetylation,polymerase phosphorylation,and DNA unwinding in glucocorticoid receptor transactivation. J Steroid Biochem Molec Biol 100: 3-17.
40. Giannoukos G,Szapary D,Smith CL,et al. (2001) New antiprogestins with partial agonist activity: potential selective progesterone receptor modulators (SPRMs) and probes for receptor- and coregulator-induced changes in progesterone receptor induction properties. Mol Endocrinol 15: 255-270.

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This article has been cited by:

1. Madhumita A. Pradhan, John A. Blackford, Ballachanda N. Devaiah, Petria S. Thompson, Carson C. Chow, Dinah S. Singer, S. Stoney Simons, Kinetically Defined Mechanisms and Positions of Action of Two New Modulators of Glucocorticoid Receptor-regulated Gene Induction, Journal of Biological Chemistry, 2016, 291, 1, 342, 10.1074/jbc.M115.683722
2. Carson C. Chow, S. Stoney Simons, An Approach to Greater Specificity for Glucocorticoids, Frontiers in Endocrinology, 2018, 9, 10.3389/fendo.2018.00076

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Copyright Info: 2015, Carson C. Chow, S. Stoney Simons Jr., et al., licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

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