Estrogen receptor: Difference between revisions

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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{infobox protein
 
| Name = [[estrogen receptor alpha|estrogen receptor 1]] (ER-alpha)
 
| caption =A dimer of the ligand-binding region of ERα ([[Protein Data Bank|PDB]] rendering based on {{PDB2|3erd}}).
 
| image =PBB_Protein_ESR1_image.png
{{PBB_Controls
| width =
| update_page = yes
| HGNCid = 3467
| require_manual_inspection = no
| Symbol = [[estrogen receptor alpha|ESR1]]
| update_protein_box = yes
| AltSymbols = ER-α, NR3A1
| update_summary = no
| EntrezGene = 2099
| update_citations = no
| OMIM = 133430
| RefSeq = NM_000125
| UniProt = P03372
| PDB = 1ERE
| ECnumber =  
| Chromosome = 6
| Arm = q
| Band = 24
| LocusSupplementaryData = -q27
}}
}}
<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{infobox protein
{{GNF_Protein_box
| Name = [[estrogen receptor beta|estrogen receptor 2]] (ER-beta)
| image = PBB_Protein_ESR1_image.png
| caption = A dimer of the ligand-binding region of ERβ ([[Protein Data Bank|PDB]] rendering based on {{PDB2|1u3s}}).
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 3erd.
| image = Estrogen receptor beta 1U3S.png
| Name = Estrogen receptor 1
| HGNCid = 3467
| Symbol = ESR1
| AltSymbols =; ER; DKFZp686N23123; ESR; ESRA; Era; NR3A1
| OMIM = 133430
| ECnumber = 
| Homologene = 47906
| MGIid = 1352467
<!-- The Following entry is a time stamp of the last bot update.  It is typically hidden data -->
| DateOfBotUpdate = 23:43, 14 September 2007 (UTC)
| Function = {{GNF_GO|id=GO:0003677 |text = DNA binding}} {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0003707 |text = steroid hormone receptor activity}} {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0005496 |text = steroid binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0008289 |text = lipid binding}} {{GNF_GO|id=GO:0030235 |text = nitric-oxide synthase regulator activity}} {{GNF_GO|id=GO:0030284 |text = estrogen receptor activity}} {{GNF_GO|id=GO:0043565 |text = sequence-specific DNA binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016585 |text = chromatin remodeling complex}}
| Process = {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0016049 |text = cell growth}} {{GNF_GO|id=GO:0030520 |text = estrogen receptor signaling pathway}} {{GNF_GO|id=GO:0045839 |text = negative regulation of mitosis}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 2099
    | Hs_Ensembl = ENSG00000091831
    | Hs_RefseqProtein = NP_000116
    | Hs_RefseqmRNA = NM_000125
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 6
    | Hs_GenLoc_start = 152170379
    | Hs_GenLoc_end = 152466099
    | Hs_Uniprot = P03372
    | Mm_EntrezGene = 13982
    | Mm_Ensembl = ENSMUSG00000019768
    | Mm_RefseqmRNA = XM_985634
    | Mm_RefseqProtein = XP_990728
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 10
    | Mm_GenLoc_start = 5342780
    | Mm_GenLoc_end = 5734495
    | Mm_Uniprot = Q3UT58
  }}
}}
{{protein
| Name = [[estrogen receptor beta]]
| caption = A dimer of the ligand-binding region of ERβ
| image = ERbeta.jpg
| width = 200
| width = 200
| HGNCid = 3468
| HGNCid = 3468
| Symbol = [[ESR2|ERβ]]
| Symbol = [[ESR2]]
| AltSymbols = (''ESR2'')
| AltSymbols = ER-β, NR3A2
| EntrezGene = 2100
| EntrezGene = 2100
| OMIM = 601663
| OMIM = 601663
| RefSeq = NM_001040275
| RefSeq = NM_001040275
| UniProt = Q92731
| UniProt = Q92731
| PDB = 1QKM
| ECnumber =  
| ECnumber =  
| Chromosome = 14
| Chromosome = 14
Line 66: Line 37:
| LocusSupplementaryData = -q22
| LocusSupplementaryData = -q22
}}
}}
{{SI}}


The '''estrogen receptor''' (ER) is a member of the [[nuclear receptor|nuclear hormone]] family of [[intracellular]] [[receptor (biochemistry)|receptor]]s which is activated by the [[hormone]] [[estrogen|17β-estradiol]].<ref name="pmid17132854">{{cite journal | author = Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA | title = International Union of Pharmacology. LXIV. Estrogen receptors | journal = Pharmacol. Rev. | volume = 58 | issue = 4 | pages = 773-81 | year = 2006 | pmid = 17132854 | doi = 10.1124/pr.58.4.8}}</ref> The main function of the estrogen receptor is as a DNA binding [[transcription factor]] which regulates gene expression. However the estrogen receptor also has additional functions independent of DNA binding.<ref name="pmid15705661">{{cite journal | author = Levin ER | title = Integration of the extranuclear and nuclear actions of estrogen | journal = Mol. Endocrinol. | volume = 19 | issue = 8 | pages = 1951-9 | year = 2005 | pmid = 15705661 | doi = 10.1210/me.2004-0390}}</ref>
'''Estrogen receptors''' ('''ERs''') are a group of [[proteins]] found inside [[cell (biology)|cells]]. They are [[receptor (biochemistry)|receptor]]s that are activated by the [[hormone]] [[estrogen]] ([[17β-estradiol]]).<ref name="pmid17132854">{{cite journal | vauthors = Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA | title = International Union of Pharmacology. LXIV. Estrogen receptors | journal = Pharmacological Reviews | volume = 58 | issue = 4 | pages = 773–81 | date = Dec 2006 | pmid = 17132854 | doi = 10.1124/pr.58.4.8 }}</ref> Two classes of ER exist: nuclear estrogen receptors ([[ERα]] and [[ERβ]]), which are members of the [[nuclear receptor]] family of [[intracellular]] receptors, and [[membrane estrogen receptor]]s (mERs) ([[GPER]] (GPR30), [[ER-X]], and [[Gq-mER|G<sub>q</sub>-mER]]), which are mostly [[G protein-coupled receptor]]s. This article refers to the former (ER).
 
Once activated by estrogen, the ER is able to [[protein targeting|translocate]] into the nucleus and bind to DNA to regulate the activity of different genes (i.e. it is a DNA-binding [[transcription factor]]). However, it also has additional functions independent of DNA binding.<ref name="pmid15705661">{{cite journal | vauthors = Levin ER | title = Integration of the extranuclear and nuclear actions of estrogen | journal = Molecular Endocrinology | volume = 19 | issue = 8 | pages = 1951–9 | date = Aug 2005 | pmid = 15705661 | pmc = 1249516 | doi = 10.1210/me.2004-0390 }}</ref>
 
As [[hormone receptor]]s for [[sex steroid]]s ([[steroid hormone receptor]]s), ERs, [[androgen receptor]]s (ARs), and [[progesterone receptor]]s (PRs) are important in [[sexual maturity|sexual maturation]] and [[gestation]].


==Proteomics==
==Proteomics==
There are two different forms of the estrogen receptor usually referred to as α and β each encoded by a separate gene ({{gene|ESR1}} and {{gene|ESR2}} respectively). Hormone activated estrogen receptors form [[dimer]]s, and since the two forms are coexpressed in many cell types, the receptors may form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers.<ref name="pmid15314175">{{cite journal | author = Li X, Huang J, Yi P, Bambara RA, Hilf R, Muyan M | title = Single-chain estrogen receptors (ERs) reveal that the ERalpha/beta heterodimer emulates functions of the ERalpha dimer in genomic estrogen signaling pathways | journal = Mol. Cell. Biol. | volume = 24 | issue = 17 | pages = 7681-94 | year = 2004 | pmid = 15314175 | doi = 10.1128/MCB.24.17.7681-7694.2004}}</ref>
There are two different forms of the estrogen receptor, usually referred to as '''[[estrogen receptor alpha|α]]''' and '''[[estrogen receptor beta|β]]''', each encoded by a separate gene ({{gene|ESR1}} and {{gene|ESR2}}, respectively). Hormone-activated estrogen receptors form [[protein dimer|dimer]]s, and, since the two forms are coexpressed in many cell types, the receptors may form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers.<ref name="pmid15314175">{{cite journal | vauthors = Li X, Huang J, Yi P, Bambara RA, Hilf R, Muyan M | title = Single-chain estrogen receptors (ERs) reveal that the ERalpha/beta heterodimer emulates functions of the ERalpha dimer in genomic estrogen signaling pathways | journal = Molecular and Cellular Biology | volume = 24 | issue = 17 | pages = 7681–94 | date = Sep 2004 | pmid = 15314175 | pmc = 506997 | doi = 10.1128/MCB.24.17.7681-7694.2004 }}</ref>
Estrogen receptor alpha and beta show significant overall sequence homology, and both are composed of seven [[protein domain|domains]] (listed from the N- to C-terminus; [[amino acid]] sequence numbers refer to human ER):
Estrogen receptor alpha and beta show significant overall sequence homology, and both are composed of five [[protein domain|domains]] designated A/B through F (listed from the N- to C-terminus; [[amino acid]] sequence numbers refer to human ER).
[[Image:Er_domains.svg|left|400px|The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand independent regulation.]]
 
<br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br />
[[Image:Er domains.svg|thumb|center|none|400px|The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand-independent regulation.]]
 
The [[N-terminus|N-terminal]] A/B domain is able to [[transactivation|transactivate]] gene transcription in the absence of bound [[ligand (biochemistry)|ligand]] (e.g., the estrogen hormone). While this region is able to activate gene transcription without ligand, this activation is weak and more selective compared to the activation provided by the E domain. The C domain, also known as the [[DNA-binding domain]], binds to estrogen [[response element]]s in DNA. The D domain is a hinge region that connects the C and E domains.  The E domain contains the ligand binding cavity as well as binding sites for [[coactivator (genetics)|coactivator]] and [[corepressor (genetics)|corepressor]] proteins. The E-domain in the presence of bound ligand is able to activate gene transcription. The [[C-terminus|C-terminal]] F domain function is not entirely clear and is variable in length.
 
{|
|- valign=top
|{{Pfam_box
| Symbol = Oest_recep
| Name = Estrogen receptor alpha<br/>N-terminal AF1 domain
| image =
| width =
| caption =
| Pfam= PF02159
| InterPro= IPR001292
| SMART=
| Prosite =         
| SCOP = 1hcp
| TCDB =
| OPM family=
| OPM protein=
| PDB=
}}
|{{Pfam_box
| Symbol = ESR1_C
| Name = Estrogen and estrogen related receptor C-terminal domain
| image =
| width =
| caption =
| Pfam= PF12743
| InterPro=
| SMART=
| Prosite =         
| SCOP =
| TCDB =
| OPM family=
| OPM protein=
| PDB=
}}
|}
 
Due to alternative RNA splicing, several ER isoforms are known to exist. At least three ERα and five ERβ isoforms have been identified. The ERβ isoforms receptor subtypes can transactivate transcription only when a heterodimer with the functional ERß1 receptor of 59 kDa is formed. The ERß3 receptor was detected at high levels in the testis. The two other ERα isoforms are 36 and 46kDa.<ref>{{cite journal | vauthors = Nilsson S, Mäkelä S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JA | title = Mechanisms of estrogen action | journal = Physiological Reviews | volume = 81 | issue = 4 | pages = 1535–65 | date = Oct 2001 | pmid = 11581496 | doi =  | url = http://physrev.physiology.org/cgi/pmidlookup?view=long&pmid=11581496 }}</ref><ref>{{cite journal | vauthors = Leung YK, Mak P, Hassan S, Ho SM | title = Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 35 | pages = 13162–7 | date = Aug 2006 | pmid = 16938840 | pmc = 1552044 | doi = 10.1073/pnas.0605676103 }}</ref>
 
Only in fish, but not in humans, an ERγ receptor has been described.<ref>{{cite journal | vauthors = Hawkins MB, Thornton JW, Crews D, Skipper JK, Dotte A, Thomas P | title = Identification of a third distinct estrogen receptor and reclassification of estrogen receptors in teleosts | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 20 | pages = 10751–6 | date = Sep 2000 | pmid = 11005855 | pmc = 27095 | doi = 10.1073/pnas.97.20.10751 }}</ref>
 
== Genetics ==
In humans, the two forms of the estrogen receptor are encoded by different [[gene]]s, {{gene|ESR1}} and {{gene|ESR2}} on the sixth and fourteenth [[chromosome]] (6q25.1 and 14q23.2), respectively.
 
== Distribution ==
Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns:<ref name="pmid9348186">{{cite journal | vauthors = Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS | title = Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse | journal = Endocrinology | volume = 138 | issue = 11 | pages = 4613–21 | date = Nov 1997 | pmid = 9348186 | doi = 10.1210/en.138.11.4613 }}</ref>
* The ''ERα'' is found in [[endometrium]], [[breast cancer]] cells, ovarian stromal cells, and the [[hypothalamus]].<ref name="pmid15990721">{{cite journal | vauthors = Yaghmaie F, Saeed O, Garan SA, Freitag W, Timiras PS, Sternberg H | title = Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice | journal = Neuro Endocrinology Letters | volume = 26 | issue = 3 | pages = 197–203 | date = Jun 2005 | pmid = 15990721 | url = http://www.nel.edu/pdf_/26_3/260305A01_15990721_Yaghmaie_.pdf }}</ref> In males, ''ERα'' protein is found in the epithelium of the [[efferent ducts]].<ref name="pmid12904263">{{cite journal | vauthors = Hess RA | title = Estrogen in the adult male reproductive tract: a review | journal = Reproductive Biology and Endocrinology | volume = 1 | issue = 52 | pages = 52 | date = Jul 2003 | pmid = 12904263 | pmc = 179885 | doi = 10.1186/1477-7827-1-52 }}</ref>
* The expression of the ''ERβ'' protein has been documented in ovarian [[granulosa cells]], [[kidney]], [[brain]], [[bone]], [[heart]],<ref name="pmid11861041">{{cite journal | vauthors = Babiker FA, De Windt LJ, van Eickels M, Grohe C, Meyer R, Doevendans PA | title = Estrogenic hormone action in the heart: regulatory network and function | journal = Cardiovascular Research | volume = 53 | issue = 3 | pages = 709–19 | date = Feb 2002 | pmid = 11861041 | doi = 10.1016/S0008-6363(01)00526-0 }}</ref> [[lungs]], [[intestine|intestinal]] mucosa, [[prostate]], and [[endothelium|endothelial]] cells.
The ERs are regarded to be cytoplasmic receptors in their unliganded state, but visualization research has shown that only a small fraction of the ERs reside in the cytoplasm, with most ER constitutively in the nucleus.<ref>{{cite journal | vauthors = Htun H, Holth LT, Walker D, Davie JR, Hager GL | title = Direct visualization of the human estrogen receptor alpha reveals a role for ligand in the nuclear distribution of the receptor | journal = Molecular Biology of the Cell | volume = 10 | issue = 2 | pages = 471–86 | date = Feb 1999 | pmid = 9950689 | pmc = 25181 | doi = 10.1091/mbc.10.2.471 }}</ref>
The "ERα" primary transcript gives rise to several alternatively spliced variants of unknown function.<ref>{{cite journal | vauthors = Pfeffer U, Fecarotta E, Vidali G | title = Coexpression of multiple estrogen receptor variant messenger RNAs in normal and neoplastic breast tissues and in MCF-7 cells | journal = Cancer Research | volume = 55 | issue = 10 | pages = 2158–65 | date = May 1995 | pmid = 7743517 }}</ref>
 
==Ligands==


==Genetics==
===Agonists===
The two forms of the estrogen receptor are encoded by different [[gene]]s, {{gene|ESR1}} and {{gene|ESR2}} on the sixth and fourteenth [[chromosome]] (6q25.1 and 14q), respectively.
* [[Endogenous]] [[estrogen]]s (e.g., [[estradiol]], [[estrone]], [[estriol]], [[estetrol]])
* [[Natural product|Natural]] [[estrogen]]s (e.g., [[conjugated estrogens]])
* [[Synthetic compound|Synthetic]] [[estrogen]]s (e.g., [[ethinylestradiol]], [[diethylstilbestrol]])


==Distribution==
===Mixed===
Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns:
* [[Phytoestrogen]]s (e.g., [[coumestrol]], [[daidzein]], [[genistein]], [[miroestrol]])
* The ''ERα'' is found in [[endometrium]], [[breast cancer]] cells, ovarian stroma cells and in the [[hypothalamus]].<ref name="pmid15990721">{{cite journal | author = Yaghmaie F, Saeed O, Garan SA, Freitag W, Timiras PS, Sternberg H | title = Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice | journal = Neuro Endocrinol. Lett. | volume = 26 | issue = 3 | pages = 197-203 | year = 2005 | pmid = 15990721 | doi = | url = http://www.nel.edu/pdf_/26_3/260305A01_15990721_Yaghmaie_.pdf}}</ref>
* [[Selective estrogen receptor modulator]]s (e.g., [[tamoxifen]], [[clomifene]], [[raloxifene]])
* The expression of the ''ERβ'' protein has been documented in [[kidney]], [[brain]], [[bone]], [[heart]],<ref name="pmid11861041">{{cite journal | author = Babiker FA, De Windt LJ, van Eickels M, Grohe C, Meyer R, Doevendans PA | title = Estrogenic hormone action in the heart: regulatory network and function | journal = Cardiovasc. Res. | volume = 53 | issue = 3 | pages = 709-19 | year = 2002 | pmid = 11861041 | doi = | url = http://linkinghub.elsevier.com/retrieve/pii/s0008636301005260}}</ref> [[lungs]], [[intestine|intestinal]] mucosa, [[prostate]], and [[endothelium|endothelial]] cells.


==Binding and Functional Selectivity==
===Antagonists===
* [[Antiestrogen]]s (e.g., [[fulvestrant]], [[ICI-164384]], [[ethamoxytriphetol]])


[[Image:Estrogen receptor bound to estradiol and tamoxifen.png|thumb|left|Estrogen receptor bound to the estradiol hormone (top;  and to anticancer drug tamoxifen (bottom; . These two ligands induce different conformations in the receptor (highlighted in green) which accounts for their different functional activity (agonist vs. antagonist respectively). See the [http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb45_1.html estrogen molecule of the month] web page for more details.]]
==Binding and functional selectivity==
The ER's helix 12 domain plays a crucial role in determining interactions with coactivators and corepressors and, therefore, the respective agonist or antagonist effect of the ligand.<ref>{{cite journal | vauthors = Ascenzi P, Bocedi A, Marino M | title = Structure-function relationship of estrogen receptor alpha and beta: impact on human health | journal = Molecular Aspects of Medicine | volume = 27 | issue = 4 | pages = 299–402 | date = Aug 2006 | pmid = 16914190 | doi = 10.1016/j.mam.2006.07.001 }}</ref><ref>{{cite journal | vauthors = Bourguet W, Germain P, Gronemeyer H | title = Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications | journal = Trends in Pharmacological Sciences | volume = 21 | issue = 10 | pages = 381–8 | date = Oct 2000 | pmid = 11050318 | doi = 10.1016/S0165-6147(00)01548-0 }}</ref>


Different [[ligand]]s may differ in their affinity for alpha and beta isoforms of the estrogen receptor:  
Different [[ligand]]s may differ in their affinity for alpha and beta isoforms of the estrogen receptor:


* 17-beta-[[estradiol]] binds equally well to both receptors
* [[17β-estradiol|estradiol]] binds equally well to both receptors<ref name=pmid16728493>{{cite journal | vauthors = Zhu BT, Han GZ, Shim JY, Wen Y, Jiang XR | title = Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor alpha and beta subtypes: Insights into the structural determinants favoring a differential subtype binding | journal = Endocrinology | volume = 147 | issue = 9 | pages = 4132–50 | date = Sep 2006 | pmid = 16728493 | doi = 10.1210/en.2006-0113 }}</ref>
* [[estrone]] and [[raloxifene]] bind preferentially to the alpha receptor
* [[estrone]], and [[raloxifene]] bind preferentially to the alpha receptor<ref name=pmid16728493/>
* [[estriol]] and [[genistein]] to the beta receptor
* [[estriol]], and [[genistein]] to the beta receptor<ref name=pmid16728493/>


Subtype [[selective estrogen receptor modulator]]s preferentially bind to either the α- or β-subtype of the receptor. Additionally, the different estrogen receptor combinations may respond differently to various ligands which may translate into tissue selective agonistic and antagonistic effects.<ref name="pmid15950373">{{cite journal | author = Kansra S, Yamagata S, Sneade L, Foster L, Ben-Jonathan N | title = Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release | journal = Mol. Cell. Endocrinol. | volume = 239 | issue = 1-2 | pages = 27-36 | year = 2005 | pmid = 15950373 | doi = 10.1016/j.mce.2005.04.008}}</ref>
Subtype [[selective estrogen receptor modulator]]s preferentially bind to either the α- or the β-subtype of the receptor. In addition, the different estrogen receptor combinations may respond differently to various ligands, which may translate into tissue selective agonistic and antagonistic effects.<ref name="pmid15950373">{{cite journal | vauthors = Kansra S, Yamagata S, Sneade L, Foster L, Ben-Jonathan N | title = Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release | journal = Molecular and Cellular Endocrinology | volume = 239 | issue = 1–2 | pages = 27–36 | date = Jul 2005 | pmid = 15950373 | doi = 10.1016/j.mce.2005.04.008 }}</ref> The ratio of α- to β- subtype concentration has been proposed to play a role in certain diseases.<ref name="pmid18166184">{{cite journal | vauthors = Bakas P, Liapis A, Vlahopoulos S, Giner M, Logotheti S, Creatsas G, Meligova AK, Alexis MN, Zoumpourlis V | title = Estrogen receptor alpha and beta in uterine fibroids: a basis for altered estrogen responsiveness | journal = Fertility and Sterility | volume = 90 | issue = 5 | pages = 1878–85 | date = Nov 2008 | pmid = 18166184 | doi = 10.1016/j.fertnstert.2007.09.019 }}</ref>


The concept of [[selective estrogen receptor modulator]]s is based on the ability to promote ER interactions with different proteins such as [[transcription coregulator|transcriptional]] [[coactivator (genetics)|coactivator]] or [[corepressor (genetics)|corepressor]]s. Furthermore the ratio of coactivator to corepressor protein varies in different tissues.<ref name="Shang_2002">{{cite journal |author=Shang Y, Brown M|title=Molecular determinants for the tissue specificity of SERMs|journal= Science |volume= 295 |issue= 5564 |pages= 2465-8 |year= 2002 | doi = 10.1126/science.1068537 |pmid= 11923541}}</ref>  As a consequence, the same ligand may be an agonist in some tissue (where coactivators predominate) while antagonistic in other tissues (where corepressors dominate). Tamoxifen, for example, is an antagonist in [[breast]] and is therefore used as a [[breast cancer]] treatment<ref name="pmid16511588">{{cite journal | author = Deroo BJ, Korach KS | title = Estrogen receptors and human disease | journal = J. Clin. Invest. | volume = 116 | issue = 3 | pages = 561-70 | year = 2006 | pmid = 16511588 | doi = 10.1172/JCI27987}}</ref> but an ER agonist in [[bone]] (thereby preventing [[osteoporosis]]) and an agonist in the [[endometrium]] (increasing the risk of [[uterine cancer]]) .
The concept of [[selective estrogen receptor modulator]]s is based on the ability to promote ER interactions with different proteins such as [[transcription coregulator|transcriptional]] [[coactivator (genetics)|coactivator]] or [[corepressor (genetics)|corepressor]]s. Furthermore, the ratio of coactivator to corepressor protein varies in different tissues.<ref name="Shang_2002">{{cite journal | vauthors = Shang Y, Brown M | title = Molecular determinants for the tissue specificity of SERMs | journal = Science | volume = 295 | issue = 5564 | pages = 2465–8 | date = Mar 2002 | pmid = 11923541 | doi = 10.1126/science.1068537 }}</ref>  As a consequence, the same ligand may be an agonist in some tissue (where coactivators predominate) while antagonistic in other tissues (where corepressors dominate). Tamoxifen, for example, is an antagonist in [[breast]] and is, therefore, used as a [[breast cancer]] treatment<ref name="pmid16511588">{{cite journal | vauthors = Deroo BJ, Korach KS | title = Estrogen receptors and human disease | journal = The Journal of Clinical Investigation | volume = 116 | issue = 3 | pages = 561–70 | date = Mar 2006 | pmid = 16511588 | pmc = 2373424 | doi = 10.1172/JCI27987 }}</ref> but an ER agonist in [[bone]] (thereby preventing [[osteoporosis]]) and a partial agonist in the [[endometrium]] (increasing the risk of [[uterine cancer]]).


==Signal transduction==
== Signal transduction ==
Since estrogen is a [[steroid]]al hormone it can pass through the [[phospholipid membrane]]s of the cell, and receptors therefore do not need to be membrane bound in order to bind with estrogen.
Since estrogen is a [[steroidal hormone]], it can pass through the [[phospholipid membrane]]s of the cell, and receptors therefore do not need to be membrane-bound in order to bind with estrogen.


===Genomic===
=== Genomic ===
In the absence of hormone, estrogen receptors are largely located in the [[cytosol]]. Hormone binding to the receptor triggers a number of events starting with migration of the receptor from the cytosol into the nucleus, dimerization of the receptor, and subsequently binding of the receptor dimer to specific sequences of DNA known as [[hormone response element]]s. The DNA/receptor complex then recruits other proteins which are responsible for the [[transcription (genetics)|transcription]] of downstream DNA into mRNA and finally protein which results in a change in cell function. Estrogen receptors also occur within the [[cell nucleus]] and both estrogen receptor subtypes have a [[DNA]]-binding [[protein domain|domain]] and can function as [[transcription factor]]s to regulate the production of [[protein]]s.
In the absence of hormone, estrogen receptors are largely located in the cytosol. Hormone binding to the receptor triggers a number of events starting with migration of the receptor from the cytosol into the nucleus, dimerization of the receptor, and subsequent binding of the receptor dimer to specific sequences of DNA known as [[hormone response element]]s. The DNA/receptor complex then recruits other proteins that are responsible for the [[transcription (genetics)|transcription]] of downstream DNA into mRNA and finally protein that results in a change in cell function. Estrogen receptors also occur within the [[cell nucleus]], and both estrogen receptor subtypes have a [[DNA]]-binding [[protein domain|domain]] and can function as [[transcription factor]]s to regulate the production of [[protein]]s.


The receptor also interacts with [[AP-1 (transcription factor)|activator protein 1]] and [[Sp1 (biology)|Sp-1]] to promote transcription, via several coactivators such as [[PELP-1]].<ref name="pmid15705661">{{cite journal | author = Levin ER | title = Integration of the extranuclear and nuclear actions of estrogen | journal = Mol. Endocrinol. | volume = 19 | issue = 8 | pages = 1951-9 | year = 2005 | pmid = 15705661 | doi = 10.1210/me.2004-0390}}</ref>
The receptor also interacts with [[AP-1 (transcription factor)|activator protein 1]] and [[Sp1 (biology)|Sp-1]] to promote transcription, via several coactivators such as [[PELP-1]].<ref name="pmid15705661"/>


===Nongenomic===
Direct acetylation of the estrogen receptor alpha at the lysine residues in hinge region by p300 regulates transactivation and hormone sensitivity.<ref name=pmid11279135>{{cite journal | vauthors = Wang C, Fu M, Angeletti RH, Siconolfi-Baez L, Reutens AT, Albanese C, Lisanti MP, Katzenellenbogen BS, Kato S, Hopp T, Fuqua SA, Lopez GN, Kushner PJ, Pestell RG | title = Direct acetylation of the estrogen receptor alpha hinge region by p300 regulates transactivation and hormone sensitivity | journal = The Journal of Biological Chemistry | volume = 276 | issue = 21 | pages = 18375–83 | date = May 2001 | pmid = 11279135 | doi = 10.1074/jbc.M100800200 }}</ref>
Some estrogen receptors associate with the [[plasma membrane|cell surface membrane]] and can be rapidly activated by exposure of cells to  estrogen.<ref name="pmid15642158">{{cite journal | author = Zivadinovic D, Gametchu B, Watson CS | title = Membrane estrogen receptor-alpha levels in MCF-7 breast cancer cells predict cAMP and proliferation responses | journal = Breast Cancer Res. | volume = 7 | issue = 1 | pages = R101-12 | year = 2005 | pmid = 15642158 | doi = 10.1186/bcr958}}</ref><ref name="Björnström_2004">{{cite journal |author=Björnström L, Sjöberg M|title=Estrogen receptor-dependent activation of AP-1 via non-genomic signalling|journal= Nucl Recept |volume= 2 |issue= 1 |pages= 3 |year= 2004 | doi =10.1186/1478-1336-2-3 |pmid= 15196329}}</ref>


Additionally some ER may associate with cell membranes by attachment to [[Caveolin|caveolin-1]] and form complexes with [[G protein]]s, striatin, receptor [[tyrosine kinase]]s (e.g. [[EGFR]] and [[IGF-1]]), and non-receptor tyrosine kinases (e.g. [[Src (gene)|Src]])<ref name=pmid15642158/><ref name=pmid15705661/>. Through striatin, some of this membrane bound ER may lead to increased levels of [[calcium|Ca<small><sup>2+</sup></small>]] and [[nitric oxide]] (NO).<ref name="pmid15569929">{{cite journal | author = Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, Karas RH | title = Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 49 | pages = 17126-31 | year = 2004 | pmid = 15569929 | doi = 10.1073/pnas.0407492101}}</ref>  Through the receptor tyrosine kinases signals are sent to the nucleus through the [[mitogen-activated protein kinase]] (MAPK/ERK) pathway and [[phosphoinositide 3-kinase]] (Pl3K/[[AKT]]) pathway.<ref name="pmid7491495">{{cite journal | author = Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D, Chambon P | title = Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase | journal = Science | volume = 270 | issue = 5241 | pages = 1491-4 | year = 1995 | pmid = 7491495 | doi = 10.1126/science.270.5241.1491}}</ref>  [[GSK-3|Glycogen synthase kinase-3]] (GSK)-3β inhibits transcription by nuclear ER by inhibiting [[phosphorylation]] of [[serine]] 118 of nuclear ERα. Phosphorylation of GSK-3β removes its inhibitory effect, and this can be achieved by the PI3K/AKT pathway and the MAPK/ERK pathway, via [[Ribosomal s6 kinase|rsk]].
=== Non-genomic ===
Some estrogen receptors associate with the [[plasma membrane|cell surface membrane]] and can be rapidly activated by exposure of cells to estrogen.<ref name="pmid15642158">{{cite journal | vauthors = Zivadinovic D, Gametchu B, Watson CS | title = Membrane estrogen receptor-alpha levels in MCF-7 breast cancer cells predict cAMP and proliferation responses | journal = Breast Cancer Research | volume = 7 | issue = 1 | pages = R101–12 | year = 2005 | pmid = 15642158 | pmc = 1064104 | doi = 10.1186/bcr958 }}</ref><ref name="Björnström_2004">{{cite journal | vauthors = Björnström L, Sjöberg M | title = Estrogen receptor-dependent activation of AP-1 via non-genomic signalling | journal = Nuclear Receptor | volume = 2 | issue = 1 | pages = 3 | date = Jun 2004 | pmid = 15196329 | pmc = 434532 | doi = 10.1186/1478-1336-2-3 }}</ref>
 
In addition, some ER may associate with cell membranes by attachment to [[Caveolin|caveolin-1]] and form complexes with [[G protein]]s, [[STRN|striatin]], receptor [[tyrosine kinase]]s (e.g., [[Epidermal growth factor receptor|EGFR]] and [[IGF-1]]), and non-receptor tyrosine kinases (e.g., [[Src (gene)|Src]]).<ref name=pmid15705661/><ref name=pmid15642158/>  Through striatin, some of this membrane bound ER may lead to increased levels of [[calcium|Ca<sup>2+</sup>]] and [[nitric oxide]] (NO).<ref name="pmid15569929">{{cite journal | vauthors = Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, Karas RH | title = Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 49 | pages = 17126–31 | date = Dec 2004 | pmid = 15569929 | pmc = 534607 | doi = 10.1073/pnas.0407492101 }}</ref>  Through the receptor tyrosine kinases, signals are sent to the nucleus through the [[mitogen-activated protein kinase]] (MAPK/ERK) pathway and [[phosphoinositide 3-kinase]] (Pl3K/[[AKT]]) pathway.<ref name="pmid7491495">{{cite journal | vauthors = Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D, Chambon P | title = Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase | journal = Science | volume = 270 | issue = 5241 | pages = 1491–4 | date = Dec 1995 | pmid = 7491495 | doi = 10.1126/science.270.5241.1491 }}</ref>  [[GSK-3|Glycogen synthase kinase-3]] (GSK)-3β inhibits transcription by nuclear ER by inhibiting [[phosphorylation]] of [[serine]] 118 of nuclear ERα. Phosphorylation of GSK-3β removes its inhibitory effect, and this can be achieved by the PI3K/AKT pathway and the MAPK/ERK pathway, via [[Ribosomal s6 kinase|rsk]].
 
17β-Estradiol has been shown to activate the [[G protein-coupled receptor]] [[GPR30]].<ref name="pmid17222505">{{cite journal | vauthors = Prossnitz ER, Arterburn JB, Sklar LA | title = GPR30: A G protein-coupled receptor for estrogen | journal = Molecular and Cellular Endocrinology | volume = 265-266 | issue =  | pages = 138–42 | date = Feb 2007 | pmid = 17222505 | pmc = 1847610 | doi = 10.1016/j.mce.2006.12.010 }}</ref> However the subcellular localization and role of this receptor are still object of controversy.<ref name="pmid18566127">{{cite journal | vauthors = Otto C, Rohde-Schulz B, Schwarz G, Fuchs I, Klewer M, Brittain D, Langer G, Bader B, Prelle K, Nubbemeyer R, Fritzemeier KH | title = G protein-coupled receptor 30 localizes to the endoplasmic reticulum and is not activated by estradiol | journal = Endocrinology | volume = 149 | issue = 10 | pages = 4846–56 | date = Oct 2008 | pmid = 18566127 | doi = 10.1210/en.2008-0269 }}</ref>


== Disease ==
== Disease ==
[[File:Nolvadex.jpg|thumb|160px|Nolvadex ([[tamoxifen]]) 20 mg]]
[[File:Arimidex.jpg|thumb|160px|Arimidex ([[anastrozole]]) 1 mg]]
=== Cancer ===
Estrogen receptors are over-expressed in around 70% of [[breast cancer]] cases, referred to as "ER-positive", and can be demonstrated in such tissues using [[immunohistochemistry]]. Two hypotheses have been proposed to explain why this causes [[tumorigenesis]], and the available evidence suggests that both mechanisms contribute:
* First, binding of estrogen to the ER stimulates proliferation of [[Mammary gland|mammary cell]]s, with the resulting increase in [[cell division]] and [[DNA replication]], leading to mutations.
* Second, estrogen metabolism produces [[genotoxic]] waste.


=== Aging ===
The result of both processes is disruption of [[cell cycle]], [[apoptosis]] and [[DNA repair]], and, therefore, tumour formation. ERα is certainly associated with more differentiated tumours, while evidence that ERβ is involved is controversial. Different versions of the ''ESR1'' gene have been identified (with [[single-nucleotide polymorphism]]s) and are associated with different risks of developing breast cancer.<ref name="pmid16511588"/>
Studies in female mice have shown that estrogen receptor-alpha declines in the pre-optic [[hypothalamus]] as they grow old.  Female mice that were given a [[calorically restricted]] diet during the majority of their lives, maintained higher levels of ERα in the pre-optic hypothalamus than their non-calorically restricted counterparts.<ref name="pmid15990721">{{cite journal | author = Yaghmaie F, Saeed O, Garan SA, Freitag W, Timiras PS, Sternberg H | title = Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice | journal = Neuro Endocrinol. Lett. | volume = 26 | issue = 3 | pages = 197-203 | year = 2005 | pmid = 15990721 | doi = | url = http://www.nel.edu/pdf_/26_3/260305A01_15990721_Yaghmaie_.pdf}}</ref>


=== Cancer ===
Estrogen and the ERs have also been implicated in [[breast cancer]], [[ovarian cancer]], [[colon cancer]], [[prostate cancer]], and [[endometrial cancer]]. Advanced colon cancer is associated with a loss of ERβ, the predominant ER in colon tissue, and colon cancer is treated with ERβ-specific agonists.<ref name="pmid14500559">{{cite journal | vauthors = Harris HA, Albert LM, Leathurby Y, Malamas MS, Mewshaw RE, Miller CP, Kharode YP, Marzolf J, Komm BS, Winneker RC, Frail DE, Henderson RA, Zhu Y, Keith JC | title = Evaluation of an estrogen receptor-beta agonist in animal models of human disease | journal = Endocrinology | volume = 144 | issue = 10 | pages = 4241–9 | date = Oct 2003 | pmid = 14500559 | doi = 10.1210/en.2003-0550 }}</ref>
Estrogen receptors are overexpressed in around 70% of [[breast cancer]] cases, referred to as "ER positive".  Two hypotheses have been proposed to explain why this causes [[tumorigenesis]], and the available evidence suggests that both mechanisms contribute:
* Firstly, binding of estrogen to the ER stimulates proliferation of [[Mammary gland|mammary cell]]s, with the resulting increase in [[cell division]] and [[DNA replication]] leading to mutations.
* Secondly, estrogen metabolism produces [[genotoxic]] waste.


The result of both processes is disruption of [[cell cycle]], [[apoptosis]] and [[DNA repair]] and therefore tumour formation. ERα is certainly associated with more differentiated tumours, while evidence that ERβ is involved is controversial.  Different versions of the ''ESR1'' gene have been identified (with [[single-nucleotide polymorphism]]s) and are associated with different risks of developing breast cancer.<ref name="pmid16511588">
[[Endocrine]] therapy for breast cancer involves [[selective estrogen receptor modulator]]s (SERMS), such as [[tamoxifen]], which behave as ER antagonists in breast tissue, or [[aromatase inhibitors]], such as [[anastrozole]]. ER status is used to determine sensitivity of [[breast cancer]] lesions to tamoxifen and aromatase inhibitors.<ref name="pmid12363457">{{cite journal | vauthors = Clemons M, Danson S, Howell A | title = Tamoxifen ("Nolvadex"): a review | journal = Cancer Treatment Reviews | volume = 28 | issue = 4 | pages = 165–80 | date = Aug 2002 | pmid = 12363457 | doi = 10.1016/s0305-7372(02)00036-1 }}</ref> Another SERM, [[raloxifene]], has been used as a preventive chemotherapy for women judged to have a high risk of developing breast cancer.<ref name="pmid15755972">{{cite journal | vauthors = Fabian CJ, Kimler BF | title = Selective estrogen-receptor modulators for primary prevention of breast cancer | journal = Journal of Clinical Oncology | volume = 23 | issue = 8 | pages = 1644–55 | date = Mar 2005 | pmid = 15755972 | doi = 10.1200/JCO.2005.11.005 }}</ref>    Another chemotherapeutic anti-estrogen, [[ICI 182,780]] (Faslodex), which acts as a complete antagonist, also promotes degradation of the estrogen receptor.


[[Endocrine]] therpapy for breast cancer involves [[selective estrogen receptor modulator]]s (SERMS) which behave as ER antagonists in breast tissue or [[aromatase inhibitors]]. ER status is used to determine sensitivity of [[breast cancer]] lesions to [[tamoxifen]] and aromatase inhibitors<ref>M Clemons, S Danson, A Howell, 2002. "Tamoxifen (Nolvadox): A Review," Cancer Treat. Rev. 28, 165-180.</ref>.  Another SERM, [[raloxifene]], has been used as a preventative chemotherapy for women judged to have a high risk of developing breast cancer.<ref name="pmid15755972">{{cite journal | author = Fabian CJ, Kimler BF | title = Selective estrogen-receptor modulators for primary prevention of breast cancer | journal = J. Clin. Oncol. | volume = 23 | issue = 8 | pages = 1644-55 | year = 2005 | pmid = 15755972 | doi = 10.1200/JCO.2005.11.005 | issn = }}</ref>   Another chemotherapeutic anti-estrogen, [[ICI 182,780]] (Faslodex) which acts as a complete antagonist also promotes degradation of the estrogen receptor.
However, ''[[Mutation|de novo]]'' resistance to endocrine therapy undermines the efficacy of using competitive inhibitors like tamoxifen. Hormone deprivation through the use of aromatase inhibitors is also rendered futile.<ref>{{cite journal | vauthors = Oesterreich S, Davidson NE | title = The search for ESR1 mutations in breast cancer | journal = Nature Genetics | volume = 45 | issue = 12 | pages = 1415–6 | date = Dec 2013 | pmid = 24270445 | pmc = 4934882 | doi = 10.1038/ng.2831 }}</ref> Massively parallel genome sequencing has revealed the common presence of point mutations on ''[[ESR1]]'' that are drivers for resistance, and promote the agonist conformation of ERα without the bound [[ligand]]. Such constitutive, estrogen-independent activity is driven by specific mutations, such as the D538G or Y537S/C/N mutations, in the ligand binding domain of ''ESR1'' and promote cell proliferation and tumor progression without hormone stimulation.<ref>{{cite journal | vauthors = Li S, Shen D, Shao J, Crowder R, Liu W, Prat A, He X, Liu S, Hoog J, Lu C, Ding L, Griffith OL, Miller C, Larson D, Fulton RS, Harrison M, Mooney T, McMichael JF, Luo J, Tao Y, Goncalves R, Schlosberg C, Hiken JF, Saied L, Sanchez C, Giuntoli T, Bumb C, Cooper C, Kitchens RT, Lin A, Phommaly C, Davies SR, Zhang J, Kavuri MS, McEachern D, Dong YY, Ma C, Pluard T, Naughton M, Bose R, Suresh R, McDowell R, Michel L, Aft R, Gillanders W, DeSchryver K, Wilson RK, Wang S, Mills GB, Gonzalez-Angulo A, Edwards JR, Maher C, Perou CM, Mardis ER, Ellis MJ | display-authors = 6 | title = Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts | journal = Cell Reports | volume = 4 | issue = 6 | pages = 1116–30 | date = Sep 2013 | pmid = 24055055 | pmc = 3881975 | doi = 10.1016/j.celrep.2013.08.022 }}</ref>


Estrogen and the ERs have also been implicated in [[breast cancer]], [[ovarian cancer]], [[colon cancer]], [[prostate cancer]] and [[endometrial cancer]].  Advanced colon cancer is associated with a loss of ERβ, the predominant ER in colon tissue, and colon cancer is treated with ERβ specific agonists.<ref name="pmid14500559">{{cite journal | author = Harris HA, Albert LM, Leathurby Y, Malamas MS, Mewshaw RE, Miller CP, Kharode YP, Marzolf J, Komm BS, Winneker RC, Frail DE, Henderson RA, Zhu Y, Keith JC | title = Evaluation of an estrogen receptor-beta agonist in animal models of human disease | journal = Endocrinology | volume = 144 | issue = 10 | pages = 4241-9 | year = 2003 | pmid = 14500559 | doi = 10.1210/en.2003-0550 | issn = }}</ref>
=== Menopause ===
The metabolic effects of estrogen in postmenopausal women has been linked to the genetic polymorphism of [[Estrogen receptor beta|estrogen receptor beta  (ER-β)]].<ref name="pmid21117950">{{cite journal | vauthors = Darabi M, Ani M, Panjehpour M, Rabbani M, Movahedian A, Zarean E | title = Effect of estrogen receptor β A1730G polymorphism on ABCA1 gene expression response to postmenopausal hormone replacement therapy | journal = Genetic Testing and Molecular Biomarkers | volume = 15 | issue = 1–2 | pages = 11–5 | year = 2011 | pmid = 21117950 | doi = 10.1089/gtmb.2010.0106 }}</ref>
 
=== Aging ===
Studies in female mice have shown that estrogen receptor-alpha declines in the pre-optic [[hypothalamus]] as they grow old. Female mice that were given a [[calorically restricted]] diet during the majority of their lives maintained higher levels of ERα in the pre-optic hypothalamus than their non-calorically restricted counterparts.<ref name="pmid15990721"/>


=== Obesity ===
=== Obesity ===
A dramatic demonstration of the importance of estrogens in the regulation of fat deposition comes from [[Genetically modified organism|transgenic mice]] that were genetically engineered to lack a functional [[aromatase]] gene. These mice have very low levels of estrogen and are obese.<ref name="pmid12933663">{{cite journal | author = Hewitt KN, Boon WC, Murata Y, Jones ME, Simpson ER | title = The aromatase knockout mouse presents with a sexually dimorphic disruption to cholesterol homeostasis | journal = Endocrinology | volume = 144 | issue = 9 | pages = 3895-903 | year = 2003 | pmid = 12933663 | doi = | issn = }}</ref> Obesity was also observed in estrogen deficient female mice lacking the [[follicle-stimulating hormone]] receptor.<ref name="pmid11089565">{{cite journal | author = Danilovich N, Babu PS, Xing W, Gerdes M, Krishnamurthy H, Sairam MR | title = Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice | journal = Endocrinology | volume = 141 | issue = 11 | pages = 4295-308 | year = 2000 | pmid = 11089565 | doi = 10.1210/en.141.11.4295 | issn = }}</ref> The effect of low estrogen on increased obesity has been linked to estrogen receptor alpha.<ref name="pmid11095962">{{cite journal | author = Ohlsson C, Hellberg N, Parini P, Vidal O, Bohlooly-Y M, Bohlooly M, Rudling M, Lindberg MK, Warner M, Angelin B, Gustafsson JA | title = Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice | journal = Biochem. Biophys. Res. Commun. | volume = 278 | issue = 3 | pages = 640-5 | year = 2000 | pmid = 11095962 | doi = 10.1006/bbrc.2000.3827 | issn = }}</ref>
A dramatic demonstration of the importance of estrogens in the regulation of fat deposition comes from [[Genetically modified organism|transgenic mice]] that were genetically engineered to lack a functional [[aromatase]] gene. These mice have very low levels of estrogen and are obese.<ref name="pmid12933663">{{cite journal | vauthors = Hewitt KN, Boon WC, Murata Y, Jones ME, Simpson ER | title = The aromatase knockout mouse presents with a sexually dimorphic disruption to cholesterol homeostasis | journal = Endocrinology | volume = 144 | issue = 9 | pages = 3895–903 | date = Sep 2003 | pmid = 12933663 | doi = 10.1210/en.2003-0244 }}</ref> Obesity was also observed in estrogen deficient female mice lacking the [[follicle-stimulating hormone receptor]].<ref name="pmid11089565">{{cite journal | vauthors = Danilovich N, Babu PS, Xing W, Gerdes M, Krishnamurthy H, Sairam MR | title = Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice | journal = Endocrinology | volume = 141 | issue = 11 | pages = 4295–308 | date = Nov 2000 | pmid = 11089565 | doi = 10.1210/en.141.11.4295 }}</ref> The effect of low estrogen on increased obesity has been linked to estrogen receptor alpha.<ref name="pmid11095962">{{cite journal | vauthors = Ohlsson C, Hellberg N, Parini P, Vidal O, Bohlooly-Y M, Bohlooly M, Rudling M, Lindberg MK, Warner M, Angelin B, Gustafsson JA | title = Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice | journal = Biochemical and Biophysical Research Communications | volume = 278 | issue = 3 | pages = 640–5 | date = Nov 2000 | pmid = 11095962 | doi = 10.1006/bbrc.2000.3827 }}</ref>


==Research history==
== Discovery ==
Estrogen receptors were first identified by [[Elwood V. Jensen]] at the University of Chicago in the 1950s,<ref name="pmid12796359">{{cite journal | author = Jensen EV, Jordan VC | title = The estrogen receptor: a model for molecular medicine | journal = Clin. Cancer Res. | volume = 9 | issue = 6 | pages = 1980-9 | year = 2003 | pmid = 12796359 | doi = | issn = | url = http://clincancerres.aacrjournals.org/cgi/content/abstract/9/6/1980}}</ref> for which Jensen was awarded the [[Lasker Award]]<ref>David Bracey, 2004 "[http://www.uc.edu/news/NR.asp?id=1993 UC Scientist Wins 'American Nobel' Research Award]." University of Cincinnati press release.</ref>. The gene for a second estrogen receptor (ERβ) was identified in 1996.<ref name="pmid8650195">{{cite journal | author = Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA | title = Cloning of a novel receptor expressed in rat prostate and ovary | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 93 | issue = 12 | pages = 5925-30 | year = 1996 | pmid = 8650195 | doi = 10.1073/pnas.93.12.5925| issn = }}</ref>
Estrogen receptors were first identified by [[Elwood V. Jensen]] at the [[University of Chicago]] in 1958,<ref name="pmid12796359">{{cite journal | vauthors = Jensen EV, Jordan VC | title = The estrogen receptor: a model for molecular medicine | journal = Clinical Cancer Research | volume = 9 | issue = 6 | pages = 1980–9 | date = Jun 2003 | pmid = 12796359 | url = http://clincancerres.aacrjournals.org/cgi/content/abstract/9/6/1980 | format = abstract }}</ref><ref name="pmid21888507">{{cite journal | vauthors = Jensen E | title = A conversation with Elwood Jensen. Interview by David D. Moore | journal = Annual Review of Physiology | volume = 74 | issue =  | pages = 1–11 | year = 2011 | pmid = 21888507 | pmc =  | doi = 10.1146/annurev-physiol-020911-153327 }}</ref> for which Jensen was awarded the [[Lasker Award]].<ref>David Bracey, 2004 "[http://www.uc.edu/news/NR.asp?id=1993 UC Scientist Wins 'American Nobel' Research Award]." University of Cincinnati press release.</ref> The gene for a second estrogen receptor (ERβ) was identified in 1996 by Kuiper et al. in rat prostate and ovary using degenerate ERalpha primers.<ref name="pmid8650195">{{cite journal | vauthors = Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA | title = Cloning of a novel receptor expressed in rat prostate and ovary | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 12 | pages = 5925–30 | date = Jun 1996 | pmid = 8650195 | pmc = 39164 | doi = 10.1073/pnas.93.12.5925 }}</ref>


==References==
== See also ==
* [[Membrane estrogen receptor]]
* [[Estrogen insensitivity syndrome]]
* [[Aromatase deficiency]]
* [[Aromatase excess syndrome]]
 
== References ==
{{Reflist|2}}
{{Reflist|2}}


==External links==
== External links ==
* {{MeshName|Estrogen+Receptors}}
* {{MeshName|Estrogen Receptors}}
* [http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb45_1.html Molecule of the month] February 2006 at the [[Protein Data Bank]].
* {{cite web | url = http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb45_1.html | title = Estrogen Receptor | accessdate = 2008-03-15 | author = David S. Goodsell | date = 2003-09-01 | work = | publisher = [[Protein Data Bank]], Research Collaboratory for Structural Bioinformatics (RCSB) | pages = | archiveurl = | archivedate = | quote = }}
 
{{Transcription factors|g2}}
{{Estrogenics}}


{{Transcription factors}}
{{DEFAULTSORT:Estrogen Receptor}}
{{Sex hormones}}
[[Category:Intracellular receptors]]
[[Category:Intracellular receptors]]
[[Category:Endocrinology]]
[[Category:Transcription factors]]
[[de:Östrogenrezeptor]]
[[Category:Human female endocrine system]]
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Latest revision as of 06:32, 10 January 2019

estrogen receptor 1 (ER-alpha)
A dimer of the ligand-binding region of ERα (PDB rendering based on 3erd​).
Identifiers
SymbolESR1
Alt. symbolsER-α, NR3A1
Entrez2099
HUGO3467
OMIM133430
PDB1ERE
RefSeqNM_000125
UniProtP03372
Other data
LocusChr. 6 q24-q27
estrogen receptor 2 (ER-beta)
A dimer of the ligand-binding region of ERβ (PDB rendering based on 1u3s​).
Identifiers
SymbolESR2
Alt. symbolsER-β, NR3A2
Entrez2100
HUGO3468
OMIM601663
PDB1QKM
RefSeqNM_001040275
UniProtQ92731
Other data
LocusChr. 14 q21-q22

Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol).[1] Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs) (GPER (GPR30), ER-X, and Gq-mER), which are mostly G protein-coupled receptors. This article refers to the former (ER).

Once activated by estrogen, the ER is able to translocate into the nucleus and bind to DNA to regulate the activity of different genes (i.e. it is a DNA-binding transcription factor). However, it also has additional functions independent of DNA binding.[2]

As hormone receptors for sex steroids (steroid hormone receptors), ERs, androgen receptors (ARs), and progesterone receptors (PRs) are important in sexual maturation and gestation.

Proteomics

There are two different forms of the estrogen receptor, usually referred to as α and β, each encoded by a separate gene (ESR1 and ESR2, respectively). Hormone-activated estrogen receptors form dimers, and, since the two forms are coexpressed in many cell types, the receptors may form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers.[3] Estrogen receptor alpha and beta show significant overall sequence homology, and both are composed of five domains designated A/B through F (listed from the N- to C-terminus; amino acid sequence numbers refer to human ER).

The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand-independent regulation.

The N-terminal A/B domain is able to transactivate gene transcription in the absence of bound ligand (e.g., the estrogen hormone). While this region is able to activate gene transcription without ligand, this activation is weak and more selective compared to the activation provided by the E domain. The C domain, also known as the DNA-binding domain, binds to estrogen response elements in DNA. The D domain is a hinge region that connects the C and E domains. The E domain contains the ligand binding cavity as well as binding sites for coactivator and corepressor proteins. The E-domain in the presence of bound ligand is able to activate gene transcription. The C-terminal F domain function is not entirely clear and is variable in length.

Estrogen receptor alpha
N-terminal AF1 domain
Identifiers
SymbolOest_recep
PfamPF02159
InterProIPR001292
SCOP1hcp
SUPERFAMILY1hcp
Estrogen and estrogen related receptor C-terminal domain
Identifiers
SymbolESR1_C
PfamPF12743

Due to alternative RNA splicing, several ER isoforms are known to exist. At least three ERα and five ERβ isoforms have been identified. The ERβ isoforms receptor subtypes can transactivate transcription only when a heterodimer with the functional ERß1 receptor of 59 kDa is formed. The ERß3 receptor was detected at high levels in the testis. The two other ERα isoforms are 36 and 46kDa.[4][5]

Only in fish, but not in humans, an ERγ receptor has been described.[6]

Genetics

In humans, the two forms of the estrogen receptor are encoded by different genes, ESR1 and ESR2 on the sixth and fourteenth chromosome (6q25.1 and 14q23.2), respectively.

Distribution

Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns:[7]

The ERs are regarded to be cytoplasmic receptors in their unliganded state, but visualization research has shown that only a small fraction of the ERs reside in the cytoplasm, with most ER constitutively in the nucleus.[11] The "ERα" primary transcript gives rise to several alternatively spliced variants of unknown function.[12]

Ligands

Agonists

Mixed

Antagonists

Binding and functional selectivity

The ER's helix 12 domain plays a crucial role in determining interactions with coactivators and corepressors and, therefore, the respective agonist or antagonist effect of the ligand.[13][14]

Different ligands may differ in their affinity for alpha and beta isoforms of the estrogen receptor:

Subtype selective estrogen receptor modulators preferentially bind to either the α- or the β-subtype of the receptor. In addition, the different estrogen receptor combinations may respond differently to various ligands, which may translate into tissue selective agonistic and antagonistic effects.[16] The ratio of α- to β- subtype concentration has been proposed to play a role in certain diseases.[17]

The concept of selective estrogen receptor modulators is based on the ability to promote ER interactions with different proteins such as transcriptional coactivator or corepressors. Furthermore, the ratio of coactivator to corepressor protein varies in different tissues.[18] As a consequence, the same ligand may be an agonist in some tissue (where coactivators predominate) while antagonistic in other tissues (where corepressors dominate). Tamoxifen, for example, is an antagonist in breast and is, therefore, used as a breast cancer treatment[19] but an ER agonist in bone (thereby preventing osteoporosis) and a partial agonist in the endometrium (increasing the risk of uterine cancer).

Signal transduction

Since estrogen is a steroidal hormone, it can pass through the phospholipid membranes of the cell, and receptors therefore do not need to be membrane-bound in order to bind with estrogen.

Genomic

In the absence of hormone, estrogen receptors are largely located in the cytosol. Hormone binding to the receptor triggers a number of events starting with migration of the receptor from the cytosol into the nucleus, dimerization of the receptor, and subsequent binding of the receptor dimer to specific sequences of DNA known as hormone response elements. The DNA/receptor complex then recruits other proteins that are responsible for the transcription of downstream DNA into mRNA and finally protein that results in a change in cell function. Estrogen receptors also occur within the cell nucleus, and both estrogen receptor subtypes have a DNA-binding domain and can function as transcription factors to regulate the production of proteins.

The receptor also interacts with activator protein 1 and Sp-1 to promote transcription, via several coactivators such as PELP-1.[2]

Direct acetylation of the estrogen receptor alpha at the lysine residues in hinge region by p300 regulates transactivation and hormone sensitivity.[20]

Non-genomic

Some estrogen receptors associate with the cell surface membrane and can be rapidly activated by exposure of cells to estrogen.[21][22]

In addition, some ER may associate with cell membranes by attachment to caveolin-1 and form complexes with G proteins, striatin, receptor tyrosine kinases (e.g., EGFR and IGF-1), and non-receptor tyrosine kinases (e.g., Src).[2][21] Through striatin, some of this membrane bound ER may lead to increased levels of Ca2+ and nitric oxide (NO).[23] Through the receptor tyrosine kinases, signals are sent to the nucleus through the mitogen-activated protein kinase (MAPK/ERK) pathway and phosphoinositide 3-kinase (Pl3K/AKT) pathway.[24] Glycogen synthase kinase-3 (GSK)-3β inhibits transcription by nuclear ER by inhibiting phosphorylation of serine 118 of nuclear ERα. Phosphorylation of GSK-3β removes its inhibitory effect, and this can be achieved by the PI3K/AKT pathway and the MAPK/ERK pathway, via rsk.

17β-Estradiol has been shown to activate the G protein-coupled receptor GPR30.[25] However the subcellular localization and role of this receptor are still object of controversy.[26]

Disease

File:Nolvadex.jpg
Nolvadex (tamoxifen) 20 mg
File:Arimidex.jpg
Arimidex (anastrozole) 1 mg

Cancer

Estrogen receptors are over-expressed in around 70% of breast cancer cases, referred to as "ER-positive", and can be demonstrated in such tissues using immunohistochemistry. Two hypotheses have been proposed to explain why this causes tumorigenesis, and the available evidence suggests that both mechanisms contribute:

The result of both processes is disruption of cell cycle, apoptosis and DNA repair, and, therefore, tumour formation. ERα is certainly associated with more differentiated tumours, while evidence that ERβ is involved is controversial. Different versions of the ESR1 gene have been identified (with single-nucleotide polymorphisms) and are associated with different risks of developing breast cancer.[19]

Estrogen and the ERs have also been implicated in breast cancer, ovarian cancer, colon cancer, prostate cancer, and endometrial cancer. Advanced colon cancer is associated with a loss of ERβ, the predominant ER in colon tissue, and colon cancer is treated with ERβ-specific agonists.[27]

Endocrine therapy for breast cancer involves selective estrogen receptor modulators (SERMS), such as tamoxifen, which behave as ER antagonists in breast tissue, or aromatase inhibitors, such as anastrozole. ER status is used to determine sensitivity of breast cancer lesions to tamoxifen and aromatase inhibitors.[28] Another SERM, raloxifene, has been used as a preventive chemotherapy for women judged to have a high risk of developing breast cancer.[29] Another chemotherapeutic anti-estrogen, ICI 182,780 (Faslodex), which acts as a complete antagonist, also promotes degradation of the estrogen receptor.

However, de novo resistance to endocrine therapy undermines the efficacy of using competitive inhibitors like tamoxifen. Hormone deprivation through the use of aromatase inhibitors is also rendered futile.[30] Massively parallel genome sequencing has revealed the common presence of point mutations on ESR1 that are drivers for resistance, and promote the agonist conformation of ERα without the bound ligand. Such constitutive, estrogen-independent activity is driven by specific mutations, such as the D538G or Y537S/C/N mutations, in the ligand binding domain of ESR1 and promote cell proliferation and tumor progression without hormone stimulation.[31]

Menopause

The metabolic effects of estrogen in postmenopausal women has been linked to the genetic polymorphism of estrogen receptor beta (ER-β).[32]

Aging

Studies in female mice have shown that estrogen receptor-alpha declines in the pre-optic hypothalamus as they grow old. Female mice that were given a calorically restricted diet during the majority of their lives maintained higher levels of ERα in the pre-optic hypothalamus than their non-calorically restricted counterparts.[8]

Obesity

A dramatic demonstration of the importance of estrogens in the regulation of fat deposition comes from transgenic mice that were genetically engineered to lack a functional aromatase gene. These mice have very low levels of estrogen and are obese.[33] Obesity was also observed in estrogen deficient female mice lacking the follicle-stimulating hormone receptor.[34] The effect of low estrogen on increased obesity has been linked to estrogen receptor alpha.[35]

Discovery

Estrogen receptors were first identified by Elwood V. Jensen at the University of Chicago in 1958,[36][37] for which Jensen was awarded the Lasker Award.[38] The gene for a second estrogen receptor (ERβ) was identified in 1996 by Kuiper et al. in rat prostate and ovary using degenerate ERalpha primers.[39]

See also

References

  1. ↑ Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA (Dec 2006). "International Union of Pharmacology. LXIV. Estrogen receptors". Pharmacological Reviews. 58 (4): 773–81. doi:10.1124/pr.58.4.8. PMID 17132854.
  2. ↑ 2.0 2.1 2.2 Levin ER (Aug 2005). "Integration of the extranuclear and nuclear actions of estrogen". Molecular Endocrinology. 19 (8): 1951–9. doi:10.1210/me.2004-0390. PMC 1249516. PMID 15705661.
  3. ↑ Li X, Huang J, Yi P, Bambara RA, Hilf R, Muyan M (Sep 2004). "Single-chain estrogen receptors (ERs) reveal that the ERalpha/beta heterodimer emulates functions of the ERalpha dimer in genomic estrogen signaling pathways". Molecular and Cellular Biology. 24 (17): 7681–94. doi:10.1128/MCB.24.17.7681-7694.2004. PMC 506997. PMID 15314175.
  4. ↑ Nilsson S, Mäkelä S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JA (Oct 2001). "Mechanisms of estrogen action". Physiological Reviews. 81 (4): 1535–65. PMID 11581496.
  5. ↑ Leung YK, Mak P, Hassan S, Ho SM (Aug 2006). "Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling". Proceedings of the National Academy of Sciences of the United States of America. 103 (35): 13162–7. doi:10.1073/pnas.0605676103. PMC 1552044. PMID 16938840.
  6. ↑ Hawkins MB, Thornton JW, Crews D, Skipper JK, Dotte A, Thomas P (Sep 2000). "Identification of a third distinct estrogen receptor and reclassification of estrogen receptors in teleosts". Proceedings of the National Academy of Sciences of the United States of America. 97 (20): 10751–6. doi:10.1073/pnas.97.20.10751. PMC 27095. PMID 11005855.
  7. ↑ Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS (Nov 1997). "Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse". Endocrinology. 138 (11): 4613–21. doi:10.1210/en.138.11.4613. PMID 9348186.
  8. ↑ 8.0 8.1 Yaghmaie F, Saeed O, Garan SA, Freitag W, Timiras PS, Sternberg H (Jun 2005). "Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice" (PDF). Neuro Endocrinology Letters. 26 (3): 197–203. PMID 15990721.
  9. ↑ Hess RA (Jul 2003). "Estrogen in the adult male reproductive tract: a review". Reproductive Biology and Endocrinology. 1 (52): 52. doi:10.1186/1477-7827-1-52. PMC 179885. PMID 12904263.
  10. ↑ Babiker FA, De Windt LJ, van Eickels M, Grohe C, Meyer R, Doevendans PA (Feb 2002). "Estrogenic hormone action in the heart: regulatory network and function". Cardiovascular Research. 53 (3): 709–19. doi:10.1016/S0008-6363(01)00526-0. PMID 11861041.
  11. ↑ Htun H, Holth LT, Walker D, Davie JR, Hager GL (Feb 1999). "Direct visualization of the human estrogen receptor alpha reveals a role for ligand in the nuclear distribution of the receptor". Molecular Biology of the Cell. 10 (2): 471–86. doi:10.1091/mbc.10.2.471. PMC 25181. PMID 9950689.
  12. ↑ Pfeffer U, Fecarotta E, Vidali G (May 1995). "Coexpression of multiple estrogen receptor variant messenger RNAs in normal and neoplastic breast tissues and in MCF-7 cells". Cancer Research. 55 (10): 2158–65. PMID 7743517.
  13. ↑ Ascenzi P, Bocedi A, Marino M (Aug 2006). "Structure-function relationship of estrogen receptor alpha and beta: impact on human health". Molecular Aspects of Medicine. 27 (4): 299–402. doi:10.1016/j.mam.2006.07.001. PMID 16914190.
  14. ↑ Bourguet W, Germain P, Gronemeyer H (Oct 2000). "Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications". Trends in Pharmacological Sciences. 21 (10): 381–8. doi:10.1016/S0165-6147(00)01548-0. PMID 11050318.
  15. ↑ 15.0 15.1 15.2 Zhu BT, Han GZ, Shim JY, Wen Y, Jiang XR (Sep 2006). "Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor alpha and beta subtypes: Insights into the structural determinants favoring a differential subtype binding". Endocrinology. 147 (9): 4132–50. doi:10.1210/en.2006-0113. PMID 16728493.
  16. ↑ Kansra S, Yamagata S, Sneade L, Foster L, Ben-Jonathan N (Jul 2005). "Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release". Molecular and Cellular Endocrinology. 239 (1–2): 27–36. doi:10.1016/j.mce.2005.04.008. PMID 15950373.
  17. ↑ Bakas P, Liapis A, Vlahopoulos S, Giner M, Logotheti S, Creatsas G, Meligova AK, Alexis MN, Zoumpourlis V (Nov 2008). "Estrogen receptor alpha and beta in uterine fibroids: a basis for altered estrogen responsiveness". Fertility and Sterility. 90 (5): 1878–85. doi:10.1016/j.fertnstert.2007.09.019. PMID 18166184.
  18. ↑ Shang Y, Brown M (Mar 2002). "Molecular determinants for the tissue specificity of SERMs". Science. 295 (5564): 2465–8. doi:10.1126/science.1068537. PMID 11923541.
  19. ↑ 19.0 19.1 Deroo BJ, Korach KS (Mar 2006). "Estrogen receptors and human disease". The Journal of Clinical Investigation. 116 (3): 561–70. doi:10.1172/JCI27987. PMC 2373424. PMID 16511588.
  20. ↑ Wang C, Fu M, Angeletti RH, Siconolfi-Baez L, Reutens AT, Albanese C, Lisanti MP, Katzenellenbogen BS, Kato S, Hopp T, Fuqua SA, Lopez GN, Kushner PJ, Pestell RG (May 2001). "Direct acetylation of the estrogen receptor alpha hinge region by p300 regulates transactivation and hormone sensitivity". The Journal of Biological Chemistry. 276 (21): 18375–83. doi:10.1074/jbc.M100800200. PMID 11279135.
  21. ↑ 21.0 21.1 Zivadinovic D, Gametchu B, Watson CS (2005). "Membrane estrogen receptor-alpha levels in MCF-7 breast cancer cells predict cAMP and proliferation responses". Breast Cancer Research. 7 (1): R101–12. doi:10.1186/bcr958. PMC 1064104. PMID 15642158.
  22. ↑ Björnström L, Sjöberg M (Jun 2004). "Estrogen receptor-dependent activation of AP-1 via non-genomic signalling". Nuclear Receptor. 2 (1): 3. doi:10.1186/1478-1336-2-3. PMC 434532. PMID 15196329.
  23. ↑ Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, Karas RH (Dec 2004). "Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha". Proceedings of the National Academy of Sciences of the United States of America. 101 (49): 17126–31. doi:10.1073/pnas.0407492101. PMC 534607. PMID 15569929.
  24. ↑ Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D, Chambon P (Dec 1995). "Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase". Science. 270 (5241): 1491–4. doi:10.1126/science.270.5241.1491. PMID 7491495.
  25. ↑ Prossnitz ER, Arterburn JB, Sklar LA (Feb 2007). "GPR30: A G protein-coupled receptor for estrogen". Molecular and Cellular Endocrinology. 265-266: 138–42. doi:10.1016/j.mce.2006.12.010. PMC 1847610. PMID 17222505.
  26. ↑ Otto C, Rohde-Schulz B, Schwarz G, Fuchs I, Klewer M, Brittain D, Langer G, Bader B, Prelle K, Nubbemeyer R, Fritzemeier KH (Oct 2008). "G protein-coupled receptor 30 localizes to the endoplasmic reticulum and is not activated by estradiol". Endocrinology. 149 (10): 4846–56. doi:10.1210/en.2008-0269. PMID 18566127.
  27. ↑ Harris HA, Albert LM, Leathurby Y, Malamas MS, Mewshaw RE, Miller CP, Kharode YP, Marzolf J, Komm BS, Winneker RC, Frail DE, Henderson RA, Zhu Y, Keith JC (Oct 2003). "Evaluation of an estrogen receptor-beta agonist in animal models of human disease". Endocrinology. 144 (10): 4241–9. doi:10.1210/en.2003-0550. PMID 14500559.
  28. ↑ Clemons M, Danson S, Howell A (Aug 2002). "Tamoxifen ("Nolvadex"): a review". Cancer Treatment Reviews. 28 (4): 165–80. doi:10.1016/s0305-7372(02)00036-1. PMID 12363457.
  29. ↑ Fabian CJ, Kimler BF (Mar 2005). "Selective estrogen-receptor modulators for primary prevention of breast cancer". Journal of Clinical Oncology. 23 (8): 1644–55. doi:10.1200/JCO.2005.11.005. PMID 15755972.
  30. ↑ Oesterreich S, Davidson NE (Dec 2013). "The search for ESR1 mutations in breast cancer". Nature Genetics. 45 (12): 1415–6. doi:10.1038/ng.2831. PMC 4934882. PMID 24270445.
  31. ↑ Li S, Shen D, Shao J, Crowder R, Liu W, Prat A, et al. (Sep 2013). "Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts". Cell Reports. 4 (6): 1116–30. doi:10.1016/j.celrep.2013.08.022. PMC 3881975. PMID 24055055.
  32. ↑ Darabi M, Ani M, Panjehpour M, Rabbani M, Movahedian A, Zarean E (2011). "Effect of estrogen receptor β A1730G polymorphism on ABCA1 gene expression response to postmenopausal hormone replacement therapy". Genetic Testing and Molecular Biomarkers. 15 (1–2): 11–5. doi:10.1089/gtmb.2010.0106. PMID 21117950.
  33. ↑ Hewitt KN, Boon WC, Murata Y, Jones ME, Simpson ER (Sep 2003). "The aromatase knockout mouse presents with a sexually dimorphic disruption to cholesterol homeostasis". Endocrinology. 144 (9): 3895–903. doi:10.1210/en.2003-0244. PMID 12933663.
  34. ↑ Danilovich N, Babu PS, Xing W, Gerdes M, Krishnamurthy H, Sairam MR (Nov 2000). "Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice". Endocrinology. 141 (11): 4295–308. doi:10.1210/en.141.11.4295. PMID 11089565.
  35. ↑ Ohlsson C, Hellberg N, Parini P, Vidal O, Bohlooly-Y M, Bohlooly M, Rudling M, Lindberg MK, Warner M, Angelin B, Gustafsson JA (Nov 2000). "Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice". Biochemical and Biophysical Research Communications. 278 (3): 640–5. doi:10.1006/bbrc.2000.3827. PMID 11095962.
  36. ↑ Jensen EV, Jordan VC (Jun 2003). "The estrogen receptor: a model for molecular medicine" (abstract). Clinical Cancer Research. 9 (6): 1980–9. PMID 12796359.
  37. ↑ Jensen E (2011). "A conversation with Elwood Jensen. Interview by David D. Moore". Annual Review of Physiology. 74: 1–11. doi:10.1146/annurev-physiol-020911-153327. PMID 21888507.
  38. ↑ David Bracey, 2004 "UC Scientist Wins 'American Nobel' Research Award." University of Cincinnati press release.
  39. ↑ Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA (Jun 1996). "Cloning of a novel receptor expressed in rat prostate and ovary". Proceedings of the National Academy of Sciences of the United States of America. 93 (12): 5925–30. doi:10.1073/pnas.93.12.5925. PMC 39164. PMID 8650195.

External links

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