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The Transactivating Function 2 (AF-2) of Estrogen Receptor (ER) α Is Indispensable for ERα-Mediated Physiological Responses and AF-1 Activity

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DOI: 10.4236/ojemd.2013.34A2002    2,541 Downloads   4,035 Views   Citations

ABSTRACT

Estrogen has various physiological functions and the estrogen receptor (ER) is a key regulator of those functions. ERα is a ligand-dependent transcription factor and that activity is mediated by the transactivating function-1 (AF-1) in the N-terminal domain and transactivating function-2 (AF-2) in the C-terminal ligand-binding domain. The functions of ERα AF-1 and AF-2 have been characterized by various in vitro experiments, however, there is still less information about the in vivo physiological functions of ERα AF-1 and AF-2. Recently, we established a genetically mutated ERα AF-2 knock-in mouse (AF2ERKI) that possessed L543A, L544A mutated-ERα. This AF-2 core mutation disrupted AF-2 function and resulted in ERα null phenotypes. This mouse model revealed that proper AF-2 core structure and function were indispensable for ERα-mediated physiological responses and AF-1 functionality. AF2ER mutation reverses the ERα antagonists to agonists and that activity is mediated by AF-1 solely. The pure antagonist, ICI182780/fulvestrant, activated several estrogen-mediated physiological responses in the AF2ERKI mouse. The AF2ERKI mouse model will be useful to discern estrogen physiological functions which involve AF-1.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Y. Arao, K. Hamilton and K. Korach, "The Transactivating Function 2 (AF-2) of Estrogen Receptor (ER) α Is Indispensable for ERα-Mediated Physiological Responses and AF-1 Activity," Open Journal of Endocrine and Metabolic Diseases, Vol. 3 No. 4B, 2013, pp. 12-19. doi: 10.4236/ojemd.2013.34A2002.

References

[1] D. J. Mangelsdorf, C. Thummel, M. Beato, P. Herrlich, G. Schütz, K. Umesono, B. Blumberg, P. Kastner, M. Mark, P. Chambon and R. M. Evans, “The Nuclear Receptor Superfamily: The Second Decade,” Cell, Vol. 83, No. 6, 1995, pp. 835-839. doi:10.1016/0092-8674(95)90199-X
[2] P. Germain, B. Staels, C. Dacquet, M. Spedding and V. Laudet, “Overview of Nomenclature of Nuclear Receptors,” Pharmacological Reviews, Vol. 58, No. 4, 2006, pp. 685-704. doi:10.1124/pr.58.4.2
[3] W. Wahli and E. Martinez, “Superfamily of Steroid Nuclear Receptors: Positive and Negative Regulators of Gene Expression,” FASEB Journal, Vol. 5, No. 9, 1991, pp. 2243-2249.
[4] W. Bourguet, P. Germain and H. Gronemeyer, “Nuclear Receptor Ligand-Binding Domains: Three-Dimensional Structures, Molecular Interactions and Pharmacological Implications,” Trends in Pharmacological Sciences, Vol. 21, No. 10, 2000, pp. 381-388. doi:10.1016/S0165-6147(00)01548-0
[5] A. M. Brzozowski, A. C. Pike, Z. Dauter, R. E. Hubbard, T. Bonn, O. Engstrom, L. Ohman, G. L. Greene, J. A. Gustafsson and M. Carlquist, “Molecular Basis of Agonism and Antagonism in the Oestrogen Receptor,” Nature, Vol. 389, No. 6652, 1997, pp. 753-758. doi:10.1038/39645
[6] J. M. Hall and D. P. McDonnell, “Coregulators in Nuclear Estrogen Receptor Action: From Concept to Therapeutic Targeting,” Molecular Interventions, Vol. 5, No. 6, 2005, pp. 343-357. doi:10.1124/mi.5.6.7
[7] K. A. Green and J. S. Carroll, “Oestrogen-Receptor-Mediated Transcription and the Influence of Co-Factors and Chromatin State,” Nature Reviews Cancer, Vol. 7, No. 9, 2007, pp. 713-722. doi:10.1038/nrc2211
[8] C. M. Klinge, “Estrogen Receptor Interaction with CoActivators and Co-Repressors,” Steroids, Vol. 65, No. 5, 2000, pp. 227-251. doi:10.1016/S0039-128X(99)00107-5
[9] J. A. Lees, S. E. Fawell and M. G. Parker, “Identification of Two Transactivation Domains in the Mouse Oestrogen Receptor,” Nucleic Acids Research, Vol. 17, No. 14, 1989, pp. 5477-5488. doi:10.1093/nar/17.14.5477
[10] M. Berry, D. Metzger and P. Chambon, “Role of the Two Activating Domains of the Oestrogen Receptor in the Cell-Type and Promoter-Context Dependent Agonistic Activity of the Anti-Oestrogen 4-Hydroxytamoxifen,” EMBO Journal, Vol. 9, No. 9, 1990, pp. 2811-2818.
[11] R. S. Thomas, N. Sarwar, F. Phoenix, R. C. Coombes and S. Ali, “Phosphorylation at Serines 104 and 106 by Erk1/2 MAPK Is Important for Estrogen Receptor-Activity,” Journal of Molecular Endocrinology, Vol. 40, No. 4, 2008, pp. 173-184. doi:10.1677/JME-07-0165
[12] S. Kato, H. Endoh, Y. Masuhiro, T. Kitamoto, S. Uchiyama, H. Sasaki, S. Masushige, Y. Gotoh, E. Nishida, H. Kawashima, D. Metzger and P. Chambon, “Activation of the Estrogen Receptor through Phosphorylation by Mitogen-Activated Protein Kinase,” Science, Vol. 270, No. 5241, 1995, pp. 1491-1494. doi:10.1126/science.270.5241.1491
[13] G. Bunone, P. A. Briand, R. J. Miksicek and D. Picard, “Activation of the Unliganded Estrogen Receptor by EGF Involves the MAP Kinase Pathway and Direct Phosphorylation,” EMBO Journal, Vol. 15, No. 9, 1996, pp. 2174-2183.
[14] P. B. Joel, J. Smith, T. W. Sturgill, T. L. Fisher, J. Blenis and D. A. Lannigan, “pp90rsk1 Regulates Estrogen Receptor-Mediated Transcription through Phosphorylation of Ser-167,” Molecular and Cellular Biology, Vol. 18, No. 4, 1998, pp. 1978-1984.
[15] H. Lahooti, R. White, S. A. Hoare, D. Rahman, D. J. Pappin and M. G. Parker, “Identification of Phosphorylation Sites in the Mouse Oestrogen Receptor,” Journal of Steroid Biochemistry and Molecular Biology, Vol. 55, no. 3, 1995, pp. 305-313. doi:10.1016/0960-0760(95)00188-3
[16] S. Ali, D. Metzger, J. M. Bornert and P. Chambon, “Modulation of Transcriptional Activation by LigandDependent Phosphorylation of the Human Oestrogen Receptor A/B Region,” EMBO Journal, Vol. 12, No. 3, 1993, pp. 1153-1160.
[17] V. S. Likhite, F. Stossi, K. Kim, B. S. Katzenellenbogen and J. A. Katzenellenbogen, “Kinase-Specific Phosphorylation of the Estrogen Receptor Changes Receptor Interactions with Ligand, Deoxyribonucleic Acid, and Coregulators Associated with Alterations in Estrogen and Tamoxifen Activity,” Molecular Endocrinology, Vol. 20, No. 12, 2006, pp. 3120-3132. doi:10.1210/me.2006-0068
[18] C. L. Waller, T. I. Oprea, K. Chae, H. K. Park, K. S. Korach, S. C. Laws, T. E. Wiese, W. R. Kelce and L. E. Gray, “Ligand-Based Identification of Environmental Estrogens,” Chemical Research in Toxicology, Vol. 9, No. 8, 1996, pp. 1240-1248. doi:10.1021/tx960054f
[19] G. G. Kuiper, J. G. Lemmen, B. Carlsson, J. C. Corton, S. H. Safe, P. T. van der Saag, B. van der Burg and J. A. Gustafsson, “Interaction of Estrogenic Chemicals and Phytoestrogens with Estrogen Receptor Beta,” Endocrinology, Vol. 139, No. 10, 1998, pp. 4252-4263. doi:10.1210/en.139.10.4252
[20] R. M. Blair, “The Estrogen Receptor Relative Binding Affinities of 188 Natural and Xenochemicals: Structural Diversity of Ligands,” Toxicological Sciences, Vol. 54, No. 1, 2000, pp. 138-153. doi:10.1093/toxsci/54.1.138
[21] N. G. Coldham, M. Dave, S. Sivapathasundaram, D. P. McDonnell, C. Connor and M. J. Sauer, “Evaluation of a Recombinant Yeast Cell Estrogen Screening Assay,” Environmental Health Perspectives, Vol. 105, No. 7, 1997, pp. 734-742.
[22] Y. Arao, N. Kanamori, E. Kikkawa, H. Otsuka, Y. Arimoto, K. Ikeda, T. Inakuma and F. Kayama, “A Two-Step Screening Method, Using Estrogen Receptor-Mediated Transactivation, to Measure Estrogenicity in Edible Plants,” Food Chemistry, Vol. 104, No. 3, 2007, pp. 1288-1294. doi:10.1016/j.foodchem.2007.01.076
[23] V. C. Jordan and M. Morrow, “Tamoxifen, Raloxifene, and the Prevention of Breast Cancer,” Endocrine Reviews, Vol. 20, No. 3, 1999, pp. 253-278. doi:10.1210/er.20.3.253
[24] D. McDonnell, “The Molecular Pharmacology of SERMs,” Trends in Endocrinology & Metabolism, Vol. 10, No. 8, 1999, pp. 301-311. doi:10.1016/S1043-2760(99)00177-0
[25] V. C. Jordan, “Tamoxifen: A Most Unlikely Pioneering Medicine,” Nature Reviews Drug Discovery, Vol. 2, No. 3, 2003, pp. 205-213. doi:10.1038/nrd1031
[26] C. L. Smith, “Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators,” Endocrine Reviews, Vol. 25, No. 1, 2004, pp. 45-71. doi:10.1210/er.2003-0023
[27] S. Dauvois, P. S. Danielian, R. White and M. G. Parker, “Antiestrogen ICI 164,384 Reduces Cellular Estrogen Receptor Content by Increasing Its Turnover,” Proceedings of the National Academy of Sciences of USA, Vol. 89, No. 9, 1992, pp. 4037-4041. doi:10.1073/pnas.89.9.4037
[28] M. K. Gibson, L. A. Nemmers, W. C. Beckman, V. L. Davis, S. W. Curtis and K. S. Korach, “The Mechanism of ICI 164,384 Antiestrogenicity Involves Rapid Loss of Estrogen Receptor in Uterine Tissue,” Endocrinology, Vol. 129, No. 4, 1991, pp. 2000-2010. doi:10.1210/endo-129-4-2000
[29] A. Howell, “Pure Oestrogen Antagonists for the Treatment of Advanced Breast Cancer,” Endocrine Related Cancer, Vol. 13, No. 3, 2006, pp. 689-706. doi:10.1677/erc.1.00846
[30] J. F. Couse and K. S. Korach, “Estrogen Receptor Null Mice: What Have We Learned and Where Will They Lead Us?” Endocrine Reviews, Vol. 20, No. 3, 1999, pp. 358-417. doi:10.1210/er.20.3.358
[31] D. B. Lubahn, J. S. Moyer, T. S. Golding, J. F. Couse, K. S. Korach and O. Smithies, “Alteration of Reproductive Function but Not Prenatal Sexual Development after Insertional Disruption of the Mouse Estrogen Receptor gene,” Proceedings of the National Academy of Sciences of USA, Vol. 90, No. 23, 1993, pp. 11162-11166. doi:10.1073/pnas.90.23.11162
[32] S. C. Hewitt, G. E. Kissling, K. E. Fieselman, F. L. Jayes, K. E. Gerrish and K. S. Korach, “Biological and Biochemical Consequences of Global Deletion of Exon 3 from the Erα Gene,” The FASEB Journal, Vol. 24, No. 12, 2010, pp. 4660-4667. doi:10.1096/fj.10-163428
[33] Y. Arao, K. J. Hamilton, M. K. Ray, G. Scott, Y. Mishina and K. S. Korach, “Estrogen Receptor α AF-2 Mutation Results in Antagonist Reversal and Reveals Tissue Selective Function of Estrogen Receptor Modulators,” Proceedings of the National Academy of Sciences of USA, Vol. 108, No. 36, 2011, pp. 14986-14991. doi:10.1073/pnas.1109180108
[34] Y. Arao, K. J. Hamilton, E. H. Goulding, K. S. Janardhan, E. M. Eddy and K. S. Korach, “Transactivating Function (AF) 2-Mediated AF-1 Activity of Estrogen Receptor α Is Crucial to Maintain Male Reproductive Tract Function,” Proceedings of the National Academy of Sciences of USA, Vol. 109, No. 51, 2012, pp. 21140-21145. doi:10.1073/pnas.1216189110
[35] A. Mahfoudi, E. Roulet, S. Dauvois, M. G. Parker and W. Wahli, “Specific Mutations in the Estrogen Receptor Change the Properties of Antiestrogens to Full Agonists,” Proceedings of the National Academy of Sciences of USA, Vol. 92, No. 10, 1995, pp. 4206-4210. doi:10.1073/pnas.92.10.4206
[36] S. W. Curtis, T. Washburn, C. Sewall, R. DiAugustine, J. Lindzey, J. F. Couse and K. S. Korach, “Physiological Coupling of Growth Factor and Steroid Receptor Signaling Pathways: Estrogen Receptor Knockout Mice Lack Estrogen-Like Response to Epidermal Growth Factor,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 22, 1996, pp. 12626-12630. doi:10.1073/pnas.93.22.12626
[37] C. L. Smith, “Cross-Talk between Peptide Growth Factor and Estrogen Receptor Signaling Pathways,” Biology of Reproduction, Vol. 58, No. 3, 1998, pp. 627-632. doi:10.1095/biolreprod58.3.627
[38] E. M. Eddy, T. F. Washburn, D. O. Bunch, E. H. Goulding, B. C. Gladen, D. B. Lubahn and K. S. Korach, “Targeted Disruption of the Estrogen Receptor Gene in Male Mice Causes Alteration of Spermatogenesis and Infertility,” Endocrinology, Vol. 137, No. 11, 1996, pp. 4796-4805. doi:10.1210/en.137.11.4796
[39] E. H. Goulding, S. C. Hewitt, N. Nakamura, K. Hamilton, K. S. Korach and E. M. Eddy, “Ex3αERKO Male Infertility Phenotype Recapitulates the αERKO Male Phenotype,” Journal of Endocrinology, Vol. 207, No. 3, 2010, pp. 281-288. doi:10.1677/JOE-10-0290
[40] Q. Zhou, L. Clarke, R. Nie, K. Carnes, L. W. Lai, Y. H. Lien, A. Verkman, D. Lubahn, J. S. Fisher, B. S. Katzenellenbogen and R. A. Hess, “Estrogen Action and Male Fertility: Roles of the Sodium/Hydrogen Exchanger-3 and Fluid Reabsorption in Reproductive Tract Function,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 24, 2001, pp. 14132-14137. doi:10.1073/pnas.241245898
[41] L. Zhu, W. C. Brown, Q. Cai, A. Krust, P. Chambon, O. P. McGuinness and J. M. Stafford, “Estrogen Treatment after Ovariectomy Protects against Fatty Liver and May Improve Pathway-Selective Insulin Resistance,” Diabetes, Vol. 62, No. 2, 2013, pp. 424-434. doi:10.2337/db11-1718
[42] P. A. Heine, J. A. Taylor, G. A. Iwamoto, D. B. Lubahn and P. S. Cooke, “Increased Adipose Tissue in Male and Female Estrogen Receptor-Alpha Knockout Mice,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 23, 2000, pp. 12729-12734. doi:10.1073/pnas.97.23.12729
[43] M. E. Jones, A. W. Thorburn, K. L. Britt, K. N. Hewitt, N. G. Wreford, J. Proietto, O. K. Oz, B. J. Leury, K. M. Robertson, S. Yao and E. R. Simpson, “Aromatase-Deficient (ArKO) Mice Have a Phenotype of Increased Adiposity,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 23, 2000, pp. 12735-12740. doi:10.1073/pnas.97.23.12735
[44] J. E. Compston, “Sex Steroids and Bone,” Physiological Reviews, Vol. 81, No. 1, 2001, pp. 419-447.
[45] Y. Imai, S. Kondoh, A. Kouzmenko and S. Kato, “Minireview: Osteoprotective Action of Estrogens Is Mediated by Osteoclastic Estrogen Receptor-Alpha,” Molecular Endocrinology, Vol. 24, No. 5, 2010, pp. 877-885. doi:10.1210/me.2009-0238
[46] R. A. Maurer and A. C. Notides, “Identification of an Estrogen-Responsive Element from the 5’-Flanking Region of the Rat Prolactin Gene,” Molecular and Cellular Biology, Vol. 7, No. 12, 1987, pp. 4247-4254.
[47] K. M. Scully, A. S. Gleiberman, J. Lindzey, D. B. Lubahn, K. S. Korach and M. G. Rosenfeld, “Role of Estrogen Receptor-Alpha in the Anterior Pituitary Gland,” Molecular Endocrinology, Vol. 11, No. 6, 1997, pp. 674-681. doi:10.1210/me.11.6.674
[48] J. E. Valentine, “Mutations in the Estrogen Receptor Ligand Binding Domain Discriminate between HormoneDependent Transactivation and Transrepression,” Journal of Biological Chemistry, Vol. 275, No. 33, 2000, pp. 25322-25329. doi:10.1074/jbc.M002497200
[49] Y. Arao, K. J. Hamilton, L. A. Coons and K. S. Korach, “Estrogen Receptor α L543A, L544A Mutation Changes Antagonists to Agonists which Correlates with the Ligand Binding Domain Dimerization Associated with DNA Binding Activity,” Journal of Biological Chemistry, Vol. 288, No. 29, 2013, pp. 21105-21116. doi:10.1074/jbc.M113.463455

  
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