TABLE 1

ERα

Receptor nomenclature NR3A1
Receptor code 4.10.1:EST:3:A1
Other names ER1, Esr1
Molecular information Hs: 595aa, P03372, chr. 6q251
Rn: 600aa, P06211, chr. 1q122
Mm: 599aa, P19785, chr. 10 A13
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 (0.04 nM), 4-hydroxytamoxifen* (0.14 nM), 17β-estradiol* (0.15 nM), propylpyrazole triol (0.23 nM), raloxifen (0.31 nM), estriol (2.2 nM), estrone (3.2 nM), (R,R)-THC (4.2 nM), tamoxifen* (15 nM) [Ki]7–9
Antagonists Hexestrol (0.05 nM), 4-OH-tamoxifen* (0.14 nM), raloxifen (0.31 nM), ICI182780 (0.24 nM), tamoxifen* (15 nM) [Ki]7
Coactivators NCOA1, NCOA2, NCOA3, CREBBP, PPARBP, P68, SRA10
Corepressors NCOR1, NRIP110
Biologically important isoforms ERα46 {Hs}: translation is started at an internal ATG and produces a protein that lacks most of AF111; A908 {Hs}: mutation appears in premalignant breast lesions and malignant breast cancers12
Tissue distribution Endometrium, liver, white adipose tissue, breast, bone, central and peripheral nervous system, ovary, cardiovascular system, brain, testis, prostate, epididymis {Hs, Mm, Rn} [Northern blot, Q-PCR, in situ hybridization, Western blot, immunohistology]
Functional assays Uterotrophic assay {Mm, Rn}13; HGP axis (gonadotropin suppression) {Hs, Mm, Rn}14; vaginal cornification {Mm, Rn}15
Main target genes Activated: pS2 {Hs}16, progesterone receptor {Hs}17, cathepsin D {Hs}18
Mutant phenotype Obesity, insulin resistance, diabetes, infertility (male and female), uterine atrophy, female loss of negative gonadotropin feedback, loss of female sexual and maternal behavior, genu valgum, elevated gonadotropins, autoimmune glomerularnephritis, osteopenia, cardiovascular vasodilation resistance {Mm} [knockout]19
Human disease Breast cancer20; endometrial cancer21; obesity22; insulin resistance and diabetes22

  • aa, amino acids; chr., chromosome; HRE, hormone response element; 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; HGP, hypothalamus-gonadotropin-pituitary axis

  • ↵* Radioligand

  • ↵1. Greene GL, Gilna P, Waterfield M, Baker A, Hort Y, and Shine J (1986) Sequence and expression of human estrogen receptor complementary DNA. Science 231: 1150-1154

  • ↵2. Koike S, Sakai M, and Muramatsu M (1987) Molecular cloning and characterization of rat estrogen receptor cDNA. Nucleic Acids Res 15: 2499-2513

  • ↵3. White R, Lees JA, Needham M, Ham J, and Parker M (1987) Structural organization and expression of the mouse estrogen receptor. Mol Endocrinol 1: 735-744

  • ↵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. Stauffer SR, Coletta CJ, Tedesco R, Nishiguchi G, Carlson K, Sun J, Katzenellenbogen BS, and Katzenellenbogen JA (2000) Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-alpha-selective agonists. J Med Chem 43: 4934-4947

  • ↵9. Sun J, Meyers MJ, Fink BE, Rajendran R, Katzenellenbogen JA, and Katzenellenbogen BS (1999) Novel ligands that function as selective estrogens or antiestrogens for estrogen receptor-alpha or estrogen receptor-beta. Endocrinology 140: 800-804

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

  • ↵11. Flouriot G, Brand H, Denger S, Metivier R, Kos M, Reid G, Sonntag-Buck V, and Gannon F (2000) Identification of a new isoform of the human estrogen receptor-alpha (hER-alpha) that is encoded by distinct transcripts and that is able to repress hER-alpha activation function 1. EMBO (Eur Mol Biol Organ) J 19: 4688-4700

  • ↵12. Fuqua SA, Wiltschke C, Zhang QX, Borg A, Castles CG, Friedrichs WE, Hopp T, Hilsenbeck S, Mohsin S, O'Connell P, et al. (2000) A hypersensitive estrogen receptor-alpha mutation in premalignant breast lesions. Cancer Res 60: 4026-4029

  • ↵13. Kim SS, Kwack SJ, Lee RD, Lim KJ, Rhee GS, Seok JH, Kim BH, Won YH, Lee GS, Jeung EB, et al. (2005) Assessment of estrogenic and androgenic activities of tetramethrin in vitro and in vivo assays. J Toxicol Environ Health A 68: 2277-2289

  • ↵14. de Koning J, Lambalk CB, Helmerhorst FM, and Helder MN (2001) Is GnRH self-priming an obligatory feature of the reproductive cycle? Hum Reprod 16: 209-214

  • ↵15. Couse JF, Dixon D, Yates M, Moore AB, Ma L, Maas R, and Korach KS (2001) Estrogen receptor-alpha knockout mice exhibit resistance to the developmental effects of neonatal diethylstilbestrol exposure on the female reproductive tract. Dev Biol 238: 224-238

  • ↵16. 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

  • ↵17. 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

  • ↵18. 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

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

  • ↵20. Lewis JS and Jordan VC (2005) Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance. Mutat Res 591: 247-263

  • ↵21. Burke C (2005) Endometrial cancer and tamoxifen. Clin J Oncol Nurs 9: 247-249

  • ↵22. Simpson E, Jones M, Misso M, Hewitt K, Hill R, Maffei L, Carani C, and Boon WC (2005) Estrogen, a fundamental player in energy homeostasis. J Steroid Biochem Mol Biol 95: 3-8