TABLE 2

ERβ

Receptor nomenclature NR3A2
Receptor code 4.10.1:EST:3:A2
Other names ER2, Esr2
Molecular information Hs: 530aa, Q92731, chr. 14q231
Rn: 530aa, Q62986, chr. 6q242
Mm: 530aa, O08537, chr. 12 D1–D33
DNA binding
   Structure Homodimer
   HRE core sequence GGTCAnnnTGACC (ERE, half-site, palindrome)
Partners HSP90 (physical, functional): cellular localization, DNA binding4; AP1 (physical, functional): DNA binding, transcriptional activition5; SP1 (physical, functional): DNA binding, transcriptional activation6
Agonists Diethylstilbestrol (0.17 nM), 17β-estradiol* (0.46 nM), diarylpropionitrile (2.5 nM), estriol (4.0 nM), genistein (6.2 nM), estrone* (11.5 nM), tamoxifen* (68 nM) [Ki]7–8
Antagonists 4-OH-Tamoxifen* (0.023 nM), (R,R)-THC (1.45 nM), ICI18780 (1.83 nM), raloxifen (13.3 nM), HPTE antagonist (23 nM), tamoxifen* (68 nM) [Ki]7,9, 10
Coactivators NCOA1, NCOA2, NCOA3, CREBBP, PPARBP, P68, SRA11
Corepressors NCOR1, NRIP111
Biologically important isoforms ERβCX {Hs}: splicing variant for last exon—changes the amino acid sequence, resulting in reduced ligand binding12; ERβins {Mm, Rn}: splice variant, 18 amino acids inserted between exons 5 and 613
Tissue distribution Prostate, ovary, lungs, mammary gland, bone, uterus, epididymis, kidney, bladder, intestine, central and peripheral nervous system {Hs, Mm, Rn} [Northern blot, Q-PCR, in situ hybridization, Western blot, immunohistology]
Functional assyas Defective ovulatory stimulation {Mm}14
Main target genes Activated: pS2 {Hs}15, progesterone receptor {Hs}16, cathepsin D {Hs}17
Mutant phenotype Reduced fertility (female), prostate hyperplasia, disturbed neuronal migration in embryonic brain, myeloproliferative disease, hypertension {Mm} [knockout]18

  • aa, amino acids; chr., chromosome; HRE, hormone response element; HPTE, 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane; Q-PCR, quantitative polymerase chain reaction; CREBBP, cAMP response element binding protein binding protein; PPARBP, peroxisome proliferator-activated receptor binding protein; SRA, steroid receptor RNA activator

  • ↵* Radioligand

  • ↵1. Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, Hosoi T, Ouchi Y, and Muramatsu M (1998) The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro. Biochem Biophys Res Commun 243: 122-126

  • ↵2. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, and Gustafsson JA (1996) Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93: 5925-5930

  • ↵3. Tremblay GB, Tremblay A, Copeland NG, Gilbert DJ, Jenkins NA, Labrie F, and Giguere V (1997) Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor beta. Mol Endocrinol 11: 353-365

  • ↵4. Devin-Leclerc J, Meng X, Delahaye F, Leclerc P, Baulieu EE, and Catelli MG (1998) Interaction and dissociation by ligands of estrogen receptor and Hsp90: the antiestrogen RU 58668 induces a protein synthesis-dependent clustering of the receptor in the cytoplasm. Mol Endocrinol 12: 842-854

  • ↵5. Teyssier C, Belguise K, Galtier F, and Chalbos D (2001) Characterization of the physical interaction between estrogen receptor alpha and JUN proteins. J Biol Chem 276: 36361-36369

  • ↵6. Safe S (2001) Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitam Horm 62: 231-252

  • ↵7. Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, and Gustafsson JA (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138: 863-870

  • ↵8. Meyers MJ, Sun J, Carlson KE, Marriner GA, Katzenellenbogen BS, and Katzenellenbogen JA (2001) Estrogen receptor-beta potency-selective ligands: structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. J Med Chem 44: 4230-4251

  • ↵9. Meyers MJ, Sun J, Carlson KE, Katzenellenbogen BS, and Katzenellenbogen JA (1999) Estrogen receptor subtype-selective ligands: asymmetric synthesis and biological evaluation of cis- and trans-5,11-dialkyl- 5,6,11, 12-tetrahydrochrysenes. J Med Chem 42: 2456-2468

  • ↵10. Yoon K, Pallaroni L, Stoner M, Gaido K, and Safe S (2001) Differential activation of wild-type and variant forms of estrogen receptor alpha by synthetic and natural estrogenic compounds using a promoter containing three estrogen-responsive elements. J Steroid Biochem Mol Biol 78: 25-32

  • ↵11. Hall JM and McDonnell DP (2005) Coregulators in nuclear estrogen receptor action: from concept to therapeutic targeting. Mol Interv 5: 343-357

  • ↵12. Ogawa S, Inoue S, Watanabe T, Orimo A, Hosoi T, Ouchi Y, and Muramatsu M (1998) Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor ofestrogen action in human. Nucleic Acids Res 26: 3505-3512

  • ↵13. Chu S and Fuller PJ (1997) Identification of a splice variant of the rat estrogen receptor beta gene. Mol Cell Endocrinol 132: 195-199

  • ↵14. Rosenfeld CS, Roberts RM, and Lubahn DB (2001) Estrogen receptor- and aromatase-deficient mice provide insight into the roles of estrogen within the ovary and uterus. Mol Reprod Dev 59: 336-346

  • ↵15. Barkhem T, Haldosen LA, Gustafsson JA, and Nilsson S (2002) pS2 gene expression in HepG2 cells: complex regulation through crosstalk between the estrogen receptor alpha, an estrogen-responsive element, and the activator protein 1 response element. Mol Pharmacol 61: 1273-1283

  • ↵16. Petz LN, Ziegler YS, Schultz JR, Kim H, Kemper JK, and Nardulli AM (2004) Differential regulation of the human progesterone receptor gene through an estrogen response element half site and Sp1 sites. J Steroid Biochem Mol Biol 88: 113-122

  • ↵17. Wang F, Porter W, Xing W, Archer TK, and Safe S (1997) Identification of a functional imperfect estrogen-responsive element in the 5′-promoter region of the human cathepsin D gene. Biochemistry 36: 7793-7801

  • ↵18. Walker VR and Korach KS (2004) Estrogen receptor knockout mice as a model for endocrine research. ILAR J 45: 455-461