{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:32:23Z","timestamp":1791311543684,"version":"4.3.1"},"reference-count":34,"publisher":"National Academy of Sciences","issue":"36","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,9,6]]},"abstract":"<jats:p>The estrogen receptor (ER) is a ligand-dependent transcription factor containing two transcriptional activation domains. AF-1 is in the N terminus of the receptor protein and AF-2 activity is dependent on helix 12 of the C-terminal ligand-binding domain. Two point mutations of leucines 543 and 544 to alanines (L543A, L544A) in helix 12 minimized estrogen-dependent transcriptional activation and reversed the activity of the estrogen antagonists ICI182780 (ICI) and tamoxifen (TAM) into agonists in a similar manner that TAM activated WT ER\u03b1 through AF-1 activation. To evaluate the physiological role of AF-1 and AF-2 for the tissue-selective function of TAM, we generated an AF-2\u2013mutated ER\u03b1 knock-in (AF2ERKI) mouse model. AF2ERKI homozygote female mice have hypoplastic uterine tissue and rudimentary mammary glands similar to ER\u03b1-KO mice. Female mice were infertile as a result of anovulation from hemorrhagic cystic ovaries and elevated serum LH and E2 levels, although the mutant ER\u03b1 protein is expressed in the AF2ERKI model. The AF2ERKI phenotype suggests that AF-1 is not activated independently, even with high serum E2 levels. ICI and TAM induced uterotropic and ER-mediated gene responses in ovariectomized AF2ERKI female mice in the same manner as in TAM- and E2-treated WT mice. In contrast, ICI and TAM did not act as agonists to regulate negative feedback of serum LH or stimulate pituitary prolactin gene expression in a different manner than TAM- or E2-treated WT mice. The functionality of the mutant ER\u03b1 in the pituitary appears to be different from that in the uterus, indicating that ER\u03b1 uses AF-1 differently in the uterus and the pituitary for TAM action.<\/jats:p>","DOI":"10.1073\/pnas.1109180108","type":"journal-article","created":{"date-parts":[[2011,8,22]],"date-time":"2011-08-22T23:09:01Z","timestamp":1314054541000},"page":"14986-14991","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":91,"title":["Estrogen receptor \u03b1 AF-2 mutation results in antagonist reversal and reveals tissue selective function of estrogen receptor modulators"],"prefix":"10.1073","volume":"108","author":[{"given":"Yukitomo","family":"Arao","sequence":"first","affiliation":[{"name":"Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine J.","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manas K.","family":"Ray","sequence":"additional","affiliation":[{"name":"Knock Out Core, National Institute of Environmental Health Sciences\/National Institutes of Health, Research Triangle Park, NC 27709; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Scott","sequence":"additional","affiliation":[{"name":"Knock Out Core, National Institute of Environmental Health Sciences\/National Institutes of Health, Research Triangle Park, NC 27709; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Mishina","sequence":"additional","affiliation":[{"name":"School of Dentistry, University of Michigan, Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth S.","family":"Korach","sequence":"additional","affiliation":[{"name":"Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,8,22]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/39645"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2005.04.014"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1992.tb05141.x"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M002497200"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.10.4206"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)85204-3"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.136.8.7628351"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.52.31163"},{"key":"e_1_3_3_9_2","first-page":"230","article-title":"Human estrogen receptor ligand activity inversion mutants: receptors that interpret antiestrogens as estrogens and estrogens as antiestrogens and discriminate among different antiestrogens","volume":"10","author":"Montano MM","year":"1996","unstructured":"MM Montano, K Ekena, KD Krueger, AL Keller, BS Katzenellenbogen, Human estrogen receptor ligand activity inversion mutants: receptors that interpret antiestrogens as estrogens and estrogens as antiestrogens and discriminate among different antiestrogens. Mol Endocrinol 10, 230\u2013242 (1996).","journal-title":"Mol Endocrinol"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1043-2760(99)00177-0"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1210\/mend.11.6.0009"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1990.tb07469.x"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.23.11162"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.10.163428"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1210\/edrv.20.3.0370"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M008384200"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2002-0398"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.109.083154"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.15.8.4194"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.043471"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2003-0441"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M601522200"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo-129-4-2000"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.9.4037"},{"key":"e_1_3_3_25_2","first-page":"674","article-title":"Role of estrogen receptor-alpha in the anterior pituitary gland","volume":"11","author":"Scully KM","year":"1997","unstructured":"KM Scully, et al., Role of estrogen receptor-alpha in the anterior pituitary gland. Mol Endocrinol 11, 674\u2013681 (1997).","journal-title":"Mol Endocrinol"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.7.12.4247-4254.1987"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.39.24172"},{"key":"e_1_3_3_28_2","first-page":"659","article-title":"Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens","volume":"9","author":"McDonnell DP","year":"1995","unstructured":"DP McDonnell, DL Clemm, T Hermann, ME Goldman, JW Pike, Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol Endocrinol 9, 659\u2013669 (1995).","journal-title":"Mol Endocrinol"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2007-1526"},{"key":"e_1_3_3_30_2","first-page":"232","article-title":"Identification of residues in the estrogen receptor that confer differential sensitivity to estrogen and hydroxytamoxifen","volume":"7","author":"Danielian PS","year":"1993","unstructured":"PS Danielian, R White, SA Hoare, SE Fawell, MG Parker, Identification of residues in the estrogen receptor that confer differential sensitivity to estrogen and hydroxytamoxifen. Mol Endocrinol 7, 232\u2013240 (1993).","journal-title":"Mol Endocrinol"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2005-0866"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2001-0174"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611514104"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1100454108"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1109180108","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T21:13:54Z","timestamp":1649798034000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1109180108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,8,22]]},"references-count":34,"journal-issue":{"issue":"36","published-print":{"date-parts":[[2011,9,6]]}},"alternative-id":["10.1073\/pnas.1109180108"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1109180108","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,8,22]]},"assertion":[{"value":"2011-08-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}