Estrogen receptor
From Wikipedia, the free encyclopedia
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| A dimer of the ligand-binding region of the estrogen receptor | |
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estrogen receptor 1
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| Identifiers | |
| Symbol | ESR1 ESR |
| HUGO | 3467 |
| Entrez | 2099 |
| OMIM | 133430 |
| RefSeq | NM_000125 |
| UniProt | P03372 |
| Other data | |
| Locus | Chr. 6 q24-q27 |
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estrogen receptor 2
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| Identifiers | |
| Symbol | ESR2 |
| HUGO | 3468 |
| Entrez | 2100 |
| OMIM | 601663 |
| RefSeq | NM_001040275 |
| UniProt | Q92731 |
| Other data | |
| Locus | Chr. 14 q21-q22 |
An estrogen receptor (ER) is a nuclear receptor for estrogens such as estradiol (the main endogenous human estrogen). Estrogen receptors are intracellular proteins like other steroid hormone receptors. Some estrogen receptors associate with the cell surface membrane and can be rapidly activated by exposure of cells to estrogen[1]. 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. Both receptors also have functions independent of DNA binding[2].
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[edit] Proteomics
The two different estrogen receptor proteins produced from the ESR1 and ESR2 genes are usually called the α and β receptors. The estrogen receptors form dimers, and there the two different receptor subtypes can form mixed dimers in the presence of ligands. Hence, there are three combinations: ERα (αα), ERβ (ββ) and ERαβ (αβ)[3]. Different tissues express the subtypes in different proportions, and therefore have different responses to stimulation.
Both receptors show some overall homology, and are composed of seven domains (listed from N- to C-; numbers refer to human ER, and may vary):
| Name | Start ERα | Start ERβ | Homology % | |
| A/B. | AF1 / Growth Hormone binding | 1 | 1 | 18 |
| C. | DNA binding | 180 | 144 | 97 |
| D. | Hinge | 263 | 227 | 30 |
| E. | AF2 / Ligand binding | 302 | 255 | 59 |
| F. | 552 | 504 | 18 |
[edit] Genetics
The two chains are coded by different genes, ESR1 and ESR2 on the sixth and fourteenth chromosome (6q25.1 and 14q), respectively.
[edit] Distribution
All the ERs are widely distributed.
- The ERα is found in endometrium, breast cancer cells, ovarian stroma cells and the hypothalamus[4].
- The ERβ has been documented in kidney, brain, bone, heart[5], lungs, intestinal mucosa, prostate, and endothelial cells.
[edit] Binding affinity
Different estrogenic compounds have different binding affinities for alpha and beta ERs:
- 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.
The concept of selective estrogen receptor modulators is based on the ability to selectively activate (or block) one type of ER or to promote ER interactions with different proteins such as transcriptional co-activator or co-repressor proteins.
Additionally, the different estrogen receptor combinations respond differently to various antagonists, and some compounds have partially agonistic and antagonistic effects, depending on the tissue[6]. Tamoxifen, for example, is an ER agonist in bone and uterus, but antagonist in breast tissue, and is therefore used as a breast cancer treatment[7].
[edit] 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.
[edit] Nuclear
One of the major mechanisms of estrogen is to initiate the production of proteins. Estrogen receptors are therefore located in the nucleus where, when bound with estrogen as an estrogen-ER complex, bind to the estrogen response element to promote transcription.
The receptor also interacts with activator protein 1 and Sp-1 to promote transcription, via several coactivators such as PELP-1.[8]
[edit] Cytosolic
Some ER is attached to the cell membrane by caveolin-1, and forms complexes with G proteins, striatin, receptor tyrosine kinases (e.g. EGFR and IGF-1), and non-receptor tyrosine kinases (e.g. Src)[1][8]. Through striatin, some of this membrane bound ER may lead to increased levels of Ca2+ and nitric oxide (NO)[9]. 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 [10][8]. Glycogen synthase kinase-3 (GSK)-3β inhibits transcription by nuclear ER by inhibiting phosphorylation of serine 118 of nuclear ERα. The Pl3K/AKT pathway leads to phosphorylation of GSK-3β, thus removing this inhibition of transcription.
[edit] Aging
Studies in female mice have shown that estrogen receptor-alpha declines in the pre-optic hypothalamus as they grow old. The 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.[11].
[edit] Disease
[edit] Cancer
Estrogen is involved in the development of breast cancer. Two hypotheses have been proposed to explain this, and evidence supports a combination of both:
- Firstly, binding of estrogen to the ER stimulates proliferation of mammary cells, 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 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.[7]
Endocrine therapy for breast cancer involves SERMs and aromatase inhibitors. ER status is used to determine sensitivity of breast cancer lesions to tamoxifen and aromatase inhibitors[12]. Another SERM, raloxifene, has been used as a preventative chemotherapy for women judged to have a high risk of developing breast cancer[13] Another chemotheraputic anti-estrogen, ICI 182,780 (Faslodex), degrades the estrogen receptor.
Estrogen and the ERs have also been implicated in 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 [14].
[edit] 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 [15]. Obesity was also observed in estrogen deficient female mice lacking the follicle-stimulating hormone receptor [16]. The effect of low estrogen on increased obesity has been linked to estrogen receptor alpha [17]
[edit] Research history
Estrogen receptors were first identified by Elwood V. Jensen at the University of Chicago in the 1950s[18], for which Jensen was awarded the Lasker Award[19]. The gene for a second estrogen receptor (ERβ) was identified in 1996[20].
[edit] References
- ^ a b Dragoslava Zivadinovic and Cheryl S. Watson, 2005. "Membrane estrogen receptor-α levels predict estrogen-induced ERK1/2 activation in MCF-7 cells". Breast Cancer Research (2005) 7(1): R130–R144. DOI:10.1186/bcr959
- ^ "Integration of the Extranuclear and Nuclear Actions of Estrogen" by Ellis R. Levin in Molecular Endocrinology (2005) Volume 19, pages 1951–1959. DOI:10.1210/me.2004-0390
- ^ Single-Chain Estrogen Receptors (ERs) Reveal that the ERα/β Heterodimer Emulates Functions of the ERα Dimer in Genomic Estrogen Signaling Pathways" by Xiaodong Li, Jing Huang, Ping Yi, Robert A. Bambara, Russell Hilf and Mesut Muyan in Molecular and Cellular Biology (2004) Volume 24, pages 7681–7694. DOI:10.1128/MCB.24.17.7681-7694.2004
- ^ Yaghmaie F, Saeed O, Garan SA, Freitag W, Timiras PS, Sternberg H., 2005. Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice. Neuro Endocrinol Lett. 2005 Jun;26(3):197-203.PubMed
- ^ F.A. Babiker, L.J. De Windt, M. van Eickels, C. Grohe, R. Meyer, and P.A. Doevendans, 2002. Estrogenic hormone action in the heart: regulatory network and function. Cardiovasc Res. 53:709-719.
- ^ S. Kansra, S. Yamagata, L. Sneade, L. Foster & N. Ben-Jonathan, 2005. "Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release." Mol Cell Endocrinol. 2005 Jul 15;239(1-2):27-36.
- ^ a b Bonnie J. Deroo & Kenneth S. Korach, 2006. "Estrogen receptors and human disease." J Clin Invest 2006 March 01; 116(3): 561-570. PubMed
- ^ a b c Ellis R. Levin, 2005. "Integration of the extranuclear and nuclear actions of estrogen." Mol Endocrinol 19(8):1951-1959.
- ^ Lu Q et al, 2004. "Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha." PNAS, 2004 Dec 7;101(49):17126-31. Epub 2004 Nov 29. PubMed.
- ^ S. Kato et al, 1995. "Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase." Science. 1995 Dec 1;270(5241):1491-4. PubMed.
- ^ Yaghmaie F, Saeed O, Garan SA, Freitag W, Timiras PS, Sternberg H., 2005. Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice. Neuro Endocrinol Lett. 2005 Jun;26(3):197-203.PubMed
- ^ M Clemons, S Danson, A Howell, 2002. "Tamoxifen (Nolvadox): A Review," Cancer Treat. Rev. 28, 165-180.
- ^ C.J. Fabian & B.F. Kimler, 2005. "Selective estrogen-receptor modulators for primary prevention of breast cancer." J. Clin. Oncol. 2005;23:1644-1655.
- ^ H.A. Harris, et al, 2003. "Evaluation of an estrogen receptor-beta agonist in animal models of human disease." Endocrinology 2003;144:4241-4249.
- ^ K. N. Hewitt, et al, 2003. "The aromatase knockout mouse presents with a sexually dimorphic disruption to cholesterol homeostasis." Endocrinology 2003;144:3895-3903.
- ^ N. Danilovich , et al, 2000. "Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice" Endocrinology 2000;141:4295-4308.
- ^ C. Ohlsson, et al, 2000. "Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice" Biochem Biophys Res Commun. 2000;278:640-645.
- ^ Reviewed in "The Estrogen Receptor: A Model for Molecular Medicine" by Elwood V. Jensen and V. Craig Jordan in Clinical Cancer Research (20030 volume 9, pages 1980-1989. full text online
- ^ David Bracey, 2004 "UC Scientist Wins 'American Nobel' Research Award." University of Cincinnati press release.
- ^ "Cloning of a novel receptor expressed in rat prostate and ovary" by G. G. Kuiper, E. Enmark, M. Pelto-Huikko, S. Nilsson, J. A. Gustafsson in Proc Natl Acad Sci U S A (1996) volume 93 pages 5925-5930. Full text at PMC: 39164
[edit] See also
[edit] External links
- MeSH Estrogen+Receptors
- Lu Q, Pallas D, Surks H, Baur W, Mendelsohn M, Karas R (2004). "Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha". Proc Natl Acad Sci U S A 101 (49): 17126-31. PMID 15569929.
- Molecule of the month February 2006 at the Protein Data Bank.
CAP - CBF - E2F - KlF - Nanog - NF-kB - Oct-4 - P300/CBP - PIT-1 - Rho/Sigma - R-SMAD - Sox2 - Sp1 - STAT (STAT1, STAT3, STAT5)
Basic-helix-loop-helix: AhR - HIF - MYC - Twist - Myogenic regulatory factors (MyoD, Myogenin, MYF5, MYF6)
Basic leucine zipper: C/EBP - CREB - AP-1
Basic helix-loop-helix leucine zipper: MITF - SREBP
Nuclear receptors: subfamily 1 (Thyroid hormone, RAR, PPAR, LXR, FXR, Calcitriol, PXR, CAR) - subfamily 2 (HNF4, RXR) - subfamily 3/Steroid hormone (Estrogen, Estrogen related, Glucocorticoid,Mineralocorticoid, Progesterone, Androgen) - subfamily 0 (NR0B1)
