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Estrogen receptor



PDB rendering based on 3erd.
estrogen receptor alpha
Identifiers
Symbol ERα
Alt. Symbols (ESR1, ESR)
Entrez 2099
HUGO 3467
OMIM 133430
PDB 1ERE
RefSeq NM_000125
UniProt P03372
Other data
Locus Chr. 6 q24-q27
A dimer of the ligand-binding region of ERβ
estrogen receptor beta
Identifiers
Symbol ERβ
Alt. Symbols (ESR2)
Entrez 2100
HUGO 3468
OMIM 601663
PDB 1QKM
RefSeq NM_001040275
UniProt Q92731
Other data
Locus Chr. 14 q21-q22

The estrogen receptor (ER) is a member of the nuclear hormone family of intracellular receptors which is activated by the hormone 17β-estradiol.[1] 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.[2]

Additional recommended knowledge

Contents

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 seven domains (listed from the N- to C-terminus; amino acid sequence numbers refer to human ER):


















Genetics

The two forms of the estrogen receptor are encoded by different genes, ESR1 and 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.[4]
  • The expression of the ERβ protein has been documented in kidney, brain, bone, heart,[5] lungs, intestinal mucosa, prostate, and endothelial cells.

Binding and Functional Selectivity

 

Different ligands 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 modulators 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.[6]

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.[7] 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[8] 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 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 subsequently binding of the receptor dimer to specific sequences of DNA known as hormone response elements. The DNA/receptor complex then recruits other proteins which are responsible for the 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 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]

Nongenomic

Some estrogen receptors associate with the cell surface membrane and can be rapidly activated by exposure of cells to estrogen.[9][10]

Additionally 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)[9][2]. Through striatin, some of this membrane bound ER may lead to increased levels of Ca2+ and nitric oxide (NO).[11] 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.[12] 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.

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.[4]

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 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 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.[8]. Another SERM, raloxifene, has been used as a preventative chemotherapy for women judged to have a high risk of developing breast cancer.[13] 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.[14]

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]

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]

References

  1. ^ Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA (2006). "International Union of Pharmacology. LXIV. Estrogen receptors". Pharmacol. Rev. 58 (4): 773-81. doi:10.1124/pr.58.4.8. PMID 17132854.
  2. ^ a b c Levin ER (2005). "Integration of the extranuclear and nuclear actions of estrogen". Mol. Endocrinol. 19 (8): 1951-9. doi:10.1210/me.2004-0390. PMID 15705661.
  3. ^ Li X, Huang J, Yi P, Bambara RA, Hilf R, Muyan M (2004). "Single-chain estrogen receptors (ERs) reveal that the ERalpha/beta heterodimer emulates functions of the ERalpha dimer in genomic estrogen signaling pathways". Mol. Cell. Biol. 24 (17): 7681-94. doi:10.1128/MCB.24.17.7681-7694.2004. PMID 15314175.
  4. ^ a b 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. 26 (3): 197-203. PMID 15990721.
  5. ^ Babiker FA, De Windt LJ, van Eickels M, Grohe C, Meyer R, Doevendans PA (2002). "Estrogenic hormone action in the heart: regulatory network and function". Cardiovasc. Res. 53 (3): 709-19. PMID 11861041.
  6. ^ Kansra S, Yamagata S, Sneade L, Foster L, Ben-Jonathan N (2005). "Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release". Mol. Cell. Endocrinol. 239 (1-2): 27-36. doi:10.1016/j.mce.2005.04.008. PMID 15950373.
  7. ^ Shang Y, Brown M (2002). "Molecular determinants for the tissue specificity of SERMs". Science 295 (5564): 2465-8. doi:10.1126/science.1068537. PMID 11923541.
  8. ^ a b Deroo BJ, Korach KS (2006). "Estrogen receptors and human disease". J. Clin. Invest. 116 (3): 561-70. doi:10.1172/JCI27987. PMID 16511588.
  9. ^ a b 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 Res. 7 (1): R101-12. doi:10.1186/bcr958. PMID 15642158.
  10. ^ Björnström L, Sjöberg M (2004). "Estrogen receptor-dependent activation of AP-1 via non-genomic signalling". Nucl Recept 2 (1): 3. doi:10.1186/1478-1336-2-3. PMID 15196329.
  11. ^ Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, Karas RH (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. doi:10.1073/pnas.0407492101. PMID 15569929.
  12. ^ Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D, Chambon P (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.
  13. ^ Fabian CJ, Kimler BF (2005). "Selective estrogen-receptor modulators for primary prevention of breast cancer". J. Clin. Oncol. 23 (8): 1644-55. doi:10.1200/JCO.2005.11.005. PMID 15755972.
  14. ^ 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 (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.
  15. ^ Hewitt KN, Boon WC, Murata Y, Jones ME, Simpson ER (2003). "The aromatase knockout mouse presents with a sexually dimorphic disruption to cholesterol homeostasis". Endocrinology 144 (9): 3895-903. PMID 12933663.
  16. ^ Danilovich N, Babu PS, Xing W, Gerdes M, Krishnamurthy H, Sairam MR (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.
  17. ^ Ohlsson C, Hellberg N, Parini P, Vidal O, Bohlooly-Y M, Bohlooly M, Rudling M, Lindberg MK, Warner M, Angelin B, Gustafsson JA (2000). "Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice". Biochem. Biophys. Res. Commun. 278 (3): 640-5. doi:10.1006/bbrc.2000.3827. PMID 11095962.
  18. ^ Jensen EV, Jordan VC (2003). "The estrogen receptor: a model for molecular medicine". Clin. Cancer Res. 9 (6): 1980-9. PMID 12796359.
  19. ^ David Bracey, 2004 "UC Scientist Wins 'American Nobel' Research Award." University of Cincinnati press release.
  20. ^ Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA (1996). "Cloning of a novel receptor expressed in rat prostate and ovary". Proc. Natl. Acad. Sci. U.S.A. 93 (12): 5925-30. doi:10.1073/pnas.93.12.5925. PMID 8650195.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Estrogen_receptor". A list of authors is available in Wikipedia.
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