Estrogen receptor
1581134
225658766
2008-07-14T19:46:05Z
Boghog2
2428506
added group abbreviation to transcription factor navbox
{{protein
| Name = [[estrogen receptor 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
| width =
| HGNCid = 3467
| Symbol = ERα
| AltSymbols = (''ESR1'', ''ESR'')
| EntrezGene = 2099
| OMIM = 133430
| RefSeq = NM_000125
| UniProt = P03372
| PDB = 1ERE
| ECnumber =
| Chromosome = 6
| Arm = q
| Band = 24
| LocusSupplementaryData = -q27
}}
{{protein
| Name = [[estrogen receptor beta]]
| caption = A dimer of the ligand-binding region of ERβ ([[Protein Data Bank|PDB]] rendering based on {{PDB2|1u3s}}).
| image = Estrogen receptor beta 1U3S.png
| width = 200
| HGNCid = 3468
| Symbol = [[ESR2|ERβ]]
| AltSymbols = (''ESR2'')
| EntrezGene = 2100
| OMIM = 601663
| RefSeq = NM_001040275
| UniProt = Q92731
| PDB = 1QKM
| ECnumber =
| Chromosome = 14
| Arm = q
| Band = 21
| LocusSupplementaryData = -q22
}}
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>
==Proteomics==
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 [[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>
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):
[[Image:Er domains.svg|thumb|none|400px|The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand independent regulation.]]
==Genetics==
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.
==Distribution==
Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns:
* 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>
* 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 = 10.1016/S0008-6363(01)00526-0| url = http://linkinghub.elsevier.com/retrieve/pii/s0008636301005260}}</ref> [[lungs]], [[intestine|intestinal]] mucosa, [[prostate]], and [[endothelium|endothelial]] cells.
==Binding and functional selectivity==
[[Image:Estrogen receptor bound to estradiol and tamoxifen.png|thumb|Estrogen receptor bound to the estradiol hormone (top; {{PDB|1QKU}}) and to anticancer drug tamoxifen (bottom; {{PDB2|3ERT}}). 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.]]
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
* [[estrone]] and [[raloxifene]] bind preferentially to the alpha receptor
* [[estriol]] and [[genistein]] to the beta receptor
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> The ratio of α- to β- subtype concentration has been proposed to play a role in certain diseases<ref>Bakas P, Liapis A, Vlahopoulos S, Giner M, Logotheti S, Creatsas G, Meligova AK, Alexis MN, Zoumpourlis V. Estrogen receptor alpha and beta in uterine fibroids: a basis for altered estrogen responsiveness. Fertil Steril. 2007 Dec 29. [Epub ahead of print] PMID: 18166184 [PubMed - as supplied by publisher]</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]]) .
==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.
===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.
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>
===Nongenomic===
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]].
Finally, estrogens have been shown to activate a [[G protein-coupled receptor]], [[GPR30]].<ref name="pmid17222505">{{cite journal | author = Prossnitz ER, Arterburn JB, Sklar LA | title = GPR30: A G protein-coupled receptor for estrogen | journal = Mol. Cell. Endocrinol. | volume = 265-266 | issue = | pages = 138–42 | year = 2007 | pmid = 17222505 | doi = 10.1016/j.mce.2006.12.010 }}</ref>
== Disease ==
=== 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">{{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 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]] 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 }}</ref> Another chemotherapeutic anti-estrogen, [[ICI 182,780]] (Faslodex) which acts as a complete antagonist also promotes degradation of the estrogen receptor.
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 }}</ref>
=== 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 = 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 | 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 }}</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 }}</ref>
==Research history==
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 | format = abstract}}</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 }}</ref>
==References==
{{Reflist|2}}
==External links==
* {{MeshName|Estrogen+Receptors}}
* {{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 | authorlink = | coauthors = | date = 2003-09-01 | format = | work = | publisher = [[Protein Data Bank]], Research Collaboratory for Structural Bioinformatics (RCSB) | pages = | language = | archiveurl = | archivedate = | quote = }}
{{Transcription factors|g2}}
{{Sex hormones}}
[[Category:Intracellular receptors]]
[[Category:Transcription factors]]
[[de:Estrogenrezeptor]]
[[fr:Récepteur des œstrogènes]]