Estrogen receptor beta: Difference between revisions

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{{Infobox_gene}}
{{Infobox_gene}}
'''Estrogen receptor beta''' ('''ER-β'''), also known as '''NR3A2''' (nuclear receptor subfamily 3, group A, member 2), is one of two main types of [[estrogen receptor]], a [[nuclear receptor]] which is activated by the sex hormone [[estrogen]].<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 = Proc. Natl. Acad. Sci. U.S.A. | volume = 93 | issue = 12 | pages = 5925–30 | date = June 1996 | pmid = 8650195 | pmc = 39164 | doi = 10.1073/pnas.93.12.5925 }}</ref>  In humans, ER-β is encoded by the ''ESR2'' [[gene]].<ref name="pmid8769313">{{cite journal | vauthors = Mosselman S, Polman J, Dijkema R | title = ER beta: identification and characterization of a novel human estrogen receptor | journal = FEBS Lett. | volume = 392 | issue = 1 | pages = 49–53 | date = August 1996 | pmid = 8769313 | doi = 10.1016/0014-5793(96)00782-X }}</ref>
'''Estrogen receptor beta''' ('''ER-β'''), also known as '''NR3A2''' (nuclear receptor subfamily 3, group A, member 2), is one of two main types of [[estrogen receptor]], a [[nuclear receptor]] which is activated by the sex hormone [[estrogen]].<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 = June 1996 | pmid = 8650195 | pmc = 39164 | doi = 10.1073/pnas.93.12.5925 }}</ref>  In humans, ER-β is encoded by the ''ESR2'' [[gene]].<ref name="pmid8769313">{{cite journal | vauthors = Mosselman S, Polman J, Dijkema R | title = ER beta: identification and characterization of a novel human estrogen receptor | journal = FEBS Letters | volume = 392 | issue = 1 | pages = 49–53 | date = August 1996 | pmid = 8769313 | doi = 10.1016/0014-5793(96)00782-X }}</ref>


== Function ==
== Function ==
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ER-β is a member of the family of [[estrogen receptor]]s and the superfamily of [[nuclear receptor]] transcription factors. The gene product contains an [[N-terminus|N-terminal]] [[DNA binding domain]] and [[C-terminus|C-terminal]] ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17-β-estradiol, estriol or related ligands, the encoded protein forms homo-dimers or hetero-dimers with [[estrogen receptor alpha|estrogen receptor α]]  that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized.<ref name="entrez">{{cite web | title = Entrez Gene: ESR2 estrogen receptor 2 (ER beta)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2100 }}</ref>
ER-β is a member of the family of [[estrogen receptor]]s and the superfamily of [[nuclear receptor]] transcription factors. The gene product contains an [[N-terminus|N-terminal]] [[DNA binding domain]] and [[C-terminus|C-terminal]] ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17-β-estradiol, estriol or related ligands, the encoded protein forms homo-dimers or hetero-dimers with [[estrogen receptor alpha|estrogen receptor α]]  that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized.<ref name="entrez">{{cite web | title = Entrez Gene: ESR2 estrogen receptor 2 (ER beta)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2100 }}</ref>


ER-β may have anti-proliferative effects and therefore oppose the actions of ERα in reproductive tissue.<ref name="pmid10823946">{{cite journal | vauthors = Weihua Z, Saji S, Mäkinen S, Cheng G, Jensen EV, Warner M, Gustafsson JA | title = Estrogen receptor (ER) β, a modulator of ERα in the uterus | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 11 | pages = 5936–41 | year = 2000 | pmid = 10823946 | pmc = 18537 | doi = 10.1073/pnas.97.11.5936 }}</ref> ER-β may also have an important role in adaptive function of the lung during pregnancy.<ref name="pmid17575008">{{cite journal | vauthors = Carey MA, Card JW, Voltz JW, Germolec DR, Korach KS, Zeldin DC | title = The impact of sex and sex hormones on lung physiology and disease: lessons from animal studies | journal = Am. J. Physiol. Lung Cell Mol. Physiol. | volume = 293 | issue = 2 | pages = L272–8 | year = 2007 | pmid = 17575008 | doi = 10.1152/ajplung.00174.2007 }}</ref>
ER-β may have anti-proliferative effects and therefore oppose the actions of ERα in reproductive tissue.<ref name="pmid10823946">{{cite journal | vauthors = Weihua Z, Saji S, Mäkinen S, Cheng G, Jensen EV, Warner M, Gustafsson JA | title = Estrogen receptor (ER) beta, a modulator of ERalpha in the uterus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 11 | pages = 5936–41 | date = May 2000 | pmid = 10823946 | pmc = 18537 | doi = 10.1073/pnas.97.11.5936 }}</ref> ER-β may also have an important role in adaptive function of the lung during pregnancy.<ref name="pmid17575008">{{cite journal | vauthors = Carey MA, Card JW, Voltz JW, Germolec DR, Korach KS, Zeldin DC | title = The impact of sex and sex hormones on lung physiology and disease: lessons from animal studies | journal = American Journal of Physiology. Lung Cellular and Molecular Physiology | volume = 293 | issue = 2 | pages = L272-8 | date = August 2007 | pmid = 17575008 | doi = 10.1152/ajplung.00174.2007 }}</ref>


ER-β is a potent [[tumor suppressor gene|tumor suppressor]] and plays a crucial role in many cancer types such as [[prostate cancer]].<ref name="pmid17913855">{{cite journal | vauthors = Stettner M, Kaulfuss S, Burfeind P, Schweyer S, Strauss A, Ringert RH, Thelen P | title = The relevance of estrogen receptor-beta expression to the antiproliferative effects observed with histone deacetylase inhibitors and phytoestrogens in prostate cancer treatment | journal = Mol Cancer Ther | volume = 6| issue = 10 | pages = 2626–33 | year = 2007 | pmid = 17913855 | doi = 10.1158/1535-7163.MCT-07-0197 }}</ref><ref name="pmid26861465">{{cite journal | vauthors = Kyriakidis I, Papaioannidou P | title = Estrogen receptor beta and ovarian cancer: a key to pathogenesis and response to therapy | journal = Arch Gynecol Obstet | volume = 293 | issue = 6 | pages = 1161–8 | year = June 2016 | pmid = 26861465 | doi = 10.1007/s00404-016-4027-8}}</ref>
ER-β is a potent [[tumor suppressor gene|tumor suppressor]] and plays a crucial role in many cancer types such as [[prostate cancer]].<ref name="pmid17913855">{{cite journal | vauthors = Stettner M, Kaulfuss S, Burfeind P, Schweyer S, Strauss A, Ringert RH, Thelen P | title = The relevance of estrogen receptor-beta expression to the antiproliferative effects observed with histone deacetylase inhibitors and phytoestrogens in prostate cancer treatment | journal = Molecular Cancer Therapeutics | volume = 6 | issue = 10 | pages = 2626–33 | date = October 2007 | pmid = 17913855 | doi = 10.1158/1535-7163.MCT-07-0197 }}</ref><ref name="pmid26861465">{{cite journal | vauthors = Kyriakidis I, Papaioannidou P | title = Estrogen receptor beta and ovarian cancer: a key to pathogenesis and response to therapy | journal = Archives of Gynecology and Obstetrics | volume = 293 | issue = 6 | pages = 1161–8 | date = June 2016 | pmid = 26861465 | doi = 10.1007/s00404-016-4027-8 }}</ref>


== Tissue distribution ==
== Tissue distribution ==


ER-β is expressed by many tissues including the [[uterus]],<ref name="HapangamaKamal2014">{{cite journal | vauthors = Hapangama DK, Kamal AM, Bulmer JN | title = Estrogen receptor β: the guardian of the endometrium | journal = Human Reproduction Update | volume = 21 | issue = 2 | pages = 174–193 | date = Mar 2015 | pmid = 25305176 | doi = 10.1093/humupd/dmu053 }}</ref> blood monocytes and tissue macrophages, colonic and pulmonary epithelial cells and in prostatic epithelium and in malignant counterparts of these tissues. Also, ER-β is found throughout the brain at different concentrations in different neuron clusters.<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 (ERα) and estrogen receptor-beta (ER-β) messenger ribonucleic acid in the wild-type and ERα-knockout mouse | journal = Endocrinology | volume = 138 | issue = 11 | pages = 4613–21 | year = 1997 | pmid = 9348186 | doi = 10.1210/en.138.11.4613 }}</ref><ref name="pmid15857973">{{cite journal | vauthors = Koehler KF, Helguero LA, Haldosén LA, Warner M, Gustafsson JA | title = Reflections on the discovery and significance of estrogen receptor β | journal = Endocr. Rev. | volume = 26 | issue = 3 | pages = 465–78 | year = 2005 | pmid = 15857973 | doi = 10.1210/er.2004-0027 }}</ref>
ER-β is expressed by many tissues including the [[uterus]],<ref name="HapangamaKamal2014">{{cite journal | vauthors = Hapangama DK, Kamal AM, Bulmer JN | title = Estrogen receptor β: the guardian of the endometrium | journal = Human Reproduction Update | volume = 21 | issue = 2 | pages = 174–93 | date = Mar 2015 | pmid = 25305176 | doi = 10.1093/humupd/dmu053 }}</ref> blood monocytes and tissue macrophages, colonic and pulmonary epithelial cells and in prostatic epithelium and in malignant counterparts of these tissues. Also, ER-β is found throughout the brain at different concentrations in different neuron clusters.<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 = November 1997 | pmid = 9348186 | doi = 10.1210/en.138.11.4613 }}</ref><ref name="pmid15857973">{{cite journal | vauthors = Koehler KF, Helguero LA, Haldosén LA, Warner M, Gustafsson JA | title = Reflections on the discovery and significance of estrogen receptor beta | journal = Endocrine Reviews | volume = 26 | issue = 3 | pages = 465–78 | date = May 2005 | pmid = 15857973 | doi = 10.1210/er.2004-0027 }}</ref>


== ER-β abnormalities ==
== ER-β abnormalities ==


ER-β function is related to various cardiovascular targets including [[ABCA1|ATP-binding cassette transporter A1 (ABCA1)]] and [[apolipoprotein AI|apolipoprotein A1 (ApoA-1)]]. Polymorphism may affect ER-β function and lead to altered responses in postmenopausal women receiving [[Hormone replacement therapy (menopause)|hormone replacement therapy]]. <ref>{{cite journal | vauthors = Darabi M, Ani M, Panjehpour M, Rabbani M, Movahedian A, Zarean E | title = Effect of estrogen receptor beta A1730G polymorphism on ABCA1 gene expression response to postmenopausal hormone replacement therapy | journal = Genetic testing and molecular biomarkers | volume = 15 | issue = 1–2 | pages = 11–15 | date = January–February 2011 | pmid = 21117950 | doi = 10.1089/gtmb.2010.0106 }}</ref> Abnormalities in gene expression associated with ER-β have also been linked to [[autism spectrum disorder]]. <ref>{{cite journal | vauthors = Crider A, Thakkar R, Ahmed A, Pillai A | title = Dysregulation of estrogen receptor beta (ERβ), aromatase (CYP19A1), and ER co-activators in the middle frontal gyrus of autism spectrum disorder subjects | journal = Molecular Autism | volume = 5 | issue = 46 | date = 9 September 2014 | doi = 10.1186/2040-2392-5-46 }}</ref>
ER-β function is related to various cardiovascular targets including [[ABCA1|ATP-binding cassette transporter A1 (ABCA1)]] and [[apolipoprotein AI|apolipoprotein A1 (ApoA-1)]]. Polymorphism may affect ER-β function and lead to altered responses in postmenopausal women receiving [[Hormone replacement therapy (menopause)|hormone replacement therapy]].<ref>{{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 | date = January–February 2011 | pmid = 21117950 | doi = 10.1089/gtmb.2010.0106 }}</ref> Abnormalities in gene expression associated with ER-β have also been linked to [[autism spectrum disorder]].<ref>{{cite journal | vauthors = Crider A, Thakkar R, Ahmed AO, Pillai A | title = Dysregulation of estrogen receptor beta (ERβ), aromatase (CYP19A1), and ER co-activators in the middle frontal gyrus of autism spectrum disorder subjects | journal = Molecular Autism | volume = 5 | issue = 1 | pages = 46 | date = 9 September 2014 | pmid = 25221668 | doi = 10.1186/2040-2392-5-46 }}</ref>


==Disease==
==Disease==


===Cardiovascular Disease===
===Cardiovascular Disease===
Mutations in ERβ have been shown to influence [[cardiomyocytes]], the cells that comprise the largest part of the heart, and can lead to an increased risk of [[cardiovascular disease]] (CVD). There is a disparity in prevalence of CVD between pre- and post-menopausal women, and the difference can be attributed to estrogen levels. Many types of ERβ receptors exist in order to help regulate gene expression and subsequent health in the body, but binding of 17βE2 (a naturally occurring estrogen) specifically improves cardiac metabolism. The heart utilizes a lot of energy in the form of [[Adenosine triphosphate|ATP]] to properly pump blood and maintain physiological requirements in order to live, and 17βE2 helps by increasing these myocardial ATP levels and respiratory function<ref>{{Cite journal|last=Luo|first=Tao|last2=Kim|first2=Jin Kyung|date=August 2016|title=The Role of Estrogen and Estrogen Receptors on Cardiomyocytes: An Overview|url=https://www.ncbi.nlm.nih.gov/pubmed/26860777|journal=The Canadian Journal of Cardiology|volume=32|issue=8|pages=1017–1025|doi=10.1016/j.cjca.2015.10.021|issn=1916-7075|pmc=4853290|pmid=26860777}}</ref>.
Mutations in ERβ have been shown to influence [[cardiomyocytes]], the cells that comprise the largest part of the heart, and can lead to an increased risk of [[cardiovascular disease]] (CVD). There is a disparity in prevalence of CVD between pre- and post-menopausal women, and the difference can be attributed to estrogen levels. Many types of ERβ receptors exist in order to help regulate gene expression and subsequent health in the body, but binding of 17βE2 (a naturally occurring estrogen) specifically improves cardiac metabolism. The heart utilizes a lot of energy in the form of [[Adenosine triphosphate|ATP]] to properly pump blood and maintain physiological requirements in order to live, and 17βE2 helps by increasing these myocardial ATP levels and respiratory function.<ref>{{cite journal | vauthors = Luo T, Kim JK | title = The Role of Estrogen and Estrogen Receptors on Cardiomyocytes: An Overview | journal = The Canadian Journal of Cardiology | volume = 32 | issue = 8 | pages = 1017–25 | date = August 2016 | pmid = 26860777 | pmc = 4853290 | doi = 10.1016/j.cjca.2015.10.021 }}</ref>


In addition, 17βE2 can alter myocardial signaling pathways and stimulate myocyte regeneration, which can aid in inhibiting myocyte cell death. The ERβ signaling pathway plays a role in both [[vasodilation]] and [[Artery|arterial]] dilation, which contributes to an individual having a healthy heart rate and a decrease in blood pressure. This regulation can increase [[Endothelium|endothelial]] function and [[Perfusion|arterial perfusion]], both of which are important to myocyte health. Thus, alterations in this signaling pathways due to ERβ mutation could lead to myocyte cell death from physiological stress. While ERα has a more profound role in regeneration after myocyte cell death, ERβ can still help by increasing [[endothelial progenitor cell]] activation and subsequent cardiac function<ref>{{Cite journal|last=Muka|first=Taulant|last2=Vargas|first2=Kris G.|last3=Jaspers|first3=Loes|last4=Wen|first4=Ke-xin|last5=Dhana|first5=Klodian|last6=Vitezova|first6=Anna|last7=Nano|first7=Jana|last8=Brahimaj|first8=Adela|last9=Colpani|first9=Veronica|date=April 2016|title=Estrogen receptor β actions in the female cardiovascular system: A systematic review of animal and human studies|url=https://www.ncbi.nlm.nih.gov/pubmed/26921926|journal=Maturitas|volume=86|pages=28–43|doi=10.1016/j.maturitas.2016.01.009|issn=1873-4111|pmid=26921926}}</ref>.
In addition, 17βE2 can alter myocardial signaling pathways and stimulate myocyte regeneration, which can aid in inhibiting myocyte cell death. The ERβ signaling pathway plays a role in both [[vasodilation]] and [[Artery|arterial]] dilation, which contributes to an individual having a healthy heart rate and a decrease in blood pressure. This regulation can increase [[Endothelium|endothelial]] function and [[Perfusion|arterial perfusion]], both of which are important to myocyte health. Thus, alterations in this signaling pathways due to ERβ mutation could lead to myocyte cell death from physiological stress. While ERα has a more profound role in regeneration after myocyte cell death, ERβ can still help by increasing [[endothelial progenitor cell]] activation and subsequent cardiac function.<ref>{{cite journal | vauthors = Muka T, Vargas KG, Jaspers L, Wen KX, Dhana K, Vitezova A, Nano J, Brahimaj A, Colpani V, Bano A, Kraja B, Zaciragic A, Bramer WM, van Dijk GM, Kavousi M, Franco OH | title = Estrogen receptor β actions in the female cardiovascular system: A systematic review of animal and human studies | journal = Maturitas | volume = 86 | pages = 28–43 | date = April 2016 | pmid = 26921926 | doi = 10.1016/j.maturitas.2016.01.009 }}</ref>


=== Alzheimer's Disease ===
=== Alzheimer's Disease ===
Genetic variation in ERβ is both sex and age dependent and ERβ polymorphism can lead to accelerated brain aging, cognitive impairment, and development of AD pathology. Similar to CVD, post-menopausal women have an increased risk of developing [[Alzheimer's disease|Alzheimer’s disease]] (AD) due to a loss of estrogen, which affects proper aging of the [[hippocampus]], neural survival and [[Neural regeneration|regeneration]], and [[Amyloid|amyloid metabolism]]. ERβ mRNA is highly expressed in hippocampal formation, an area of the brain that is associated with memory. This expression contributes to increased neuronal survival and helps protect against neurodegenerative diseases such as AD. The pathology of AD is also associated with accumulation of [[Amyloid-beta peptide|amyloid beta peptide]] (Aβ). While a proper concentration of Aβ in the brain is important for healthy functioning, too much can lead to cognitive impairment. Thus, ERβ helps control Aβ levels by maintaining the protein it is derived from, β-amyloid precursor protein. ERβ helps by up-regulating [[insulin-degrading enzyme]] (IDE), which leads to β-amyloid degradation when accumulation levels begin to rise. However, in AD, lack of ERβ causes a decrease in this degradation and an increase in plaque build-up<ref>{{Cite journal|last=Li|first=Rena|last2=Cui|first2=Jie|last3=Shen|first3=Yong|date=2014-05-25|title=Brain sex matters: estrogen in cognition and Alzheimer's disease|url=https://www.ncbi.nlm.nih.gov/pubmed/24418360|journal=Molecular and Cellular Endocrinology|volume=389|issue=1-2|pages=13–21|doi=10.1016/j.mce.2013.12.018|issn=1872-8057|pmc=4040318|pmid=24418360}}</ref>.
Genetic variation in ERβ is both sex and age dependent and ERβ polymorphism can lead to accelerated brain aging, cognitive impairment, and development of AD pathology. Similar to CVD, post-menopausal women have an increased risk of developing [[Alzheimer's disease|Alzheimer’s disease]] (AD) due to a loss of estrogen, which affects proper aging of the [[hippocampus]], neural survival and [[Neural regeneration|regeneration]], and [[Amyloid|amyloid metabolism]]. ERβ mRNA is highly expressed in hippocampal formation, an area of the brain that is associated with memory. This expression contributes to increased neuronal survival and helps protect against neurodegenerative diseases such as AD. The pathology of AD is also associated with accumulation of [[Amyloid-beta peptide|amyloid beta peptide]] (Aβ). While a proper concentration of Aβ in the brain is important for healthy functioning, too much can lead to cognitive impairment. Thus, ERβ helps control Aβ levels by maintaining the protein it is derived from, β-amyloid precursor protein. ERβ helps by up-regulating [[insulin-degrading enzyme]] (IDE), which leads to β-amyloid degradation when accumulation levels begin to rise. However, in AD, lack of ERβ causes a decrease in this degradation and an increase in plaque build-up.<ref>{{cite journal | vauthors = Li R, Cui J, Shen Y | title = Brain sex matters: estrogen in cognition and Alzheimer's disease | journal = Molecular and Cellular Endocrinology | volume = 389 | issue = 1-2 | pages = 13–21 | date = May 2014 | pmid = 24418360 | pmc = 4040318 | doi = 10.1016/j.mce.2013.12.018 }}</ref>


ERβ also plays a role in regulating [[Apolipoprotein E|APOE]], a risk factor for AD that redistributes lipids across cells. APOE expression in the hippocampus is specifically regulated by 17βE2, affecting learning and memory in individuals afflicted with AD. Thus, estrogen therapy via an ERβ-targeted approach can be used as a prevention method for AD either before or at the onset of menopause. Interactions between ERα and ERβ can lead to antagonistic actions in the brain, so an ERβ-targeted approach can increase therapeutic neural responses independently of ERα. Therapeutically, ERβ can be used in both men and women in order to regulate plaque formation in the brain<ref>{{Cite journal|last=Zhao|first=Liqin|last2=Woody|first2=Sarah K.|last3=Chhibber|first3=Anindit|date=November 2015|title=Estrogen receptor β in Alzheimer's disease: From mechanisms to therapeutics|url=https://www.ncbi.nlm.nih.gov/pubmed/26307455|journal=Ageing Research Reviews|volume=24|issue=Pt B|pages=178–190|doi=10.1016/j.arr.2015.08.001|issn=1872-9649|pmc=4661108|pmid=26307455}}</ref>.
ERβ also plays a role in regulating [[Apolipoprotein E|APOE]], a risk factor for AD that redistributes lipids across cells. APOE expression in the hippocampus is specifically regulated by 17βE2, affecting learning and memory in individuals afflicted with AD. Thus, estrogen therapy via an ERβ-targeted approach can be used as a prevention method for AD either before or at the onset of menopause. Interactions between ERα and ERβ can lead to antagonistic actions in the brain, so an ERβ-targeted approach can increase therapeutic neural responses independently of ERα. Therapeutically, ERβ can be used in both men and women in order to regulate plaque formation in the brain.<ref>{{cite journal | vauthors = Zhao L, Woody SK, Chhibber A | title = Estrogen receptor β in Alzheimer's disease: From mechanisms to therapeutics | journal = Ageing Research Reviews | volume = 24 | issue = Pt B | pages = 178–90 | date = November 2015 | pmid = 26307455 | pmc = 4661108 | doi = 10.1016/j.arr.2015.08.001 }}</ref>


==Neuroprotective Benefits==
==Neuroprotective Benefits==


===Synaptic Strength and Plasticity===
===Synaptic Strength and Plasticity===
ERβ levels can dictate both synaptic strength and [[neuroplasticity]] through neural structure modifications. Variations in endogenous estrogen levels cause changes in [[Dendrite|dendritic architecture]] in the hippocampus, which affects neural signaling and plasticity. Specifically, lower estrogen levels lead to decreased dendritic spines and improper signaling, inhibiting plasticity of the brain. However, treatment of 17βE2 can reverse this affect, giving it the ability to modify hippocampal structure. As a result of the relationship between dendritic architecture and [[long-term potentiation]] (LTP), ERβ can enhance LTP and lead to an increase in synaptic strength.  Furthermore, 17βE2 promotes [[neurogenesis]] in developing hippocampal neurons and neurons in the [[subventricular zone]] and [[dentate gyrus]] of the adult human brain. Specifically, ERβ increases the proliferation of progenitor cells to create new neurons and can be increased later in life through 17βE2 treatment<ref>{{Cite journal|last=Engler-Chiurazzi|first=E.B.|last2=Brown|first2=C.M.|last3=Povroznik|first3=J.M.|last4=Simpkins|first4=J.W.|title=Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury|url=http://linkinghub.elsevier.com/retrieve/pii/S0301008215300630|journal=Progress in Neurobiology|volume=157|pages=188–211|doi=10.1016/j.pneurobio.2015.12.008}}</ref><ref>{{Cite journal|last=Vargas|first=Kris G.|last2=Milic|first2=Jelena|last3=Zaciragic|first3=Asija|last4=Wen|first4=Ke-Xin|last5=Jaspers|first5=Loes|last6=Nano|first6=Jana|last7=Dhana|first7=Klodian|last8=Bramer|first8=Wichor M.|last9=Kraja|first9=Bledar|date=November 2016|title=The functions of estrogen receptor beta in the female brain: A systematic review|url=https://www.ncbi.nlm.nih.gov/pubmed/27338976|journal=Maturitas|volume=93|pages=41–57|doi=10.1016/j.maturitas.2016.05.014|issn=1873-4111|pmid=27338976}}</ref>.
ERβ levels can dictate both synaptic strength and [[neuroplasticity]] through neural structure modifications. Variations in endogenous estrogen levels cause changes in [[Dendrite|dendritic architecture]] in the hippocampus, which affects neural signaling and plasticity. Specifically, lower estrogen levels lead to decreased dendritic spines and improper signaling, inhibiting plasticity of the brain. However, treatment of 17βE2 can reverse this affect, giving it the ability to modify hippocampal structure. As a result of the relationship between dendritic architecture and [[long-term potentiation]] (LTP), ERβ can enhance LTP and lead to an increase in synaptic strength.  Furthermore, 17βE2 promotes [[neurogenesis]] in developing hippocampal neurons and neurons in the [[subventricular zone]] and [[dentate gyrus]] of the adult human brain. Specifically, ERβ increases the proliferation of progenitor cells to create new neurons and can be increased later in life through 17βE2 treatment.<ref>{{cite journal | vauthors = Engler-Chiurazzi EB, Brown CM, Povroznik JM, Simpkins JW | title = Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury | journal = Progress in Neurobiology | volume = 157 | pages = 188–211 | date = October 2017 | pmid = 26891883 | doi = 10.1016/j.pneurobio.2015.12.008 | url = http://linkinghub.elsevier.com/retrieve/pii/S0301008215300630 }}</ref><ref>{{cite journal | vauthors = Vargas KG, Milic J, Zaciragic A, Wen KX, Jaspers L, Nano J, Dhana K, Bramer WM, Kraja B, van Beeck E, Ikram MA, Muka T, Franco OH | title = The functions of estrogen receptor beta in the female brain: A systematic review | journal = Maturitas | volume = 93 | pages = 41–57 | date = November 2016 | pmid = 27338976 | doi = 10.1016/j.maturitas.2016.05.014 }}</ref>


==Ligands==
==Ligands==
Line 41: Line 41:
====Non-selective====
====Non-selective====
* [[Endogenous]] [[estrogen]]s (e.g., [[estradiol]], [[estrone]], [[estriol]], [[estetrol]])
* [[Endogenous]] [[estrogen]]s (e.g., [[estradiol]], [[estrone]], [[estriol]], [[estetrol]])
* [[Natural product|Natural]] [[estrogen]]s (e.g., [[conjugated equine estrogen]]s)
* [[Natural product|Natural]] [[estrogen]]s (e.g., [[conjugated estrogens]])
* [[Synthetic compound|Synthetic]] [[estrogen]]s (e.g., [[ethinylestradiol]], [[diethylstilbestrol]])
* [[Synthetic compound|Synthetic]] [[estrogen]]s (e.g., [[ethinylestradiol]], [[diethylstilbestrol]])


Line 51: Line 51:
* [[8β-VE2|8β-VE<sub>2</sub>]]
* [[8β-VE2|8β-VE<sub>2</sub>]]
* [[AC-186]]
* [[AC-186]]
* [[Apigenin]] – [[phytoestrogen]]<ref name="HajirahimkhanDietz2013">{{cite journal | vauthors = Hajirahimkhan A, Dietz BM, Bolton JL | title = Botanical modulation of menopausal symptoms: mechanisms of action? | journal = Planta Medica | volume = 79 | issue = 7 | pages = 538–53 | date = May 2013 | pmid = 23408273 | doi = 10.1055/s-0032-1328187 | pmc=3800090}}</ref>
* [[Apigenin]] – [[phytoestrogen]]<ref name="HajirahimkhanDietz2013">{{cite journal | vauthors = Hajirahimkhan A, Dietz BM, Bolton JL | title = Botanical modulation of menopausal symptoms: mechanisms of action? | journal = Planta Medica | volume = 79 | issue = 7 | pages = 538–53 | date = May 2013 | pmid = 23408273 | pmc = 3800090 | doi = 10.1055/s-0032-1328187 }}</ref>
* [[Daidzein]] – phytoestrogen<ref name="HajirahimkhanDietz2013" />
* [[Daidzein]] – phytoestrogen<ref name="HajirahimkhanDietz2013" />
* [[DCW234]]
* [[DCW234]]
Line 59: Line 59:
* [[ERB-196]] (WAY-202196)
* [[ERB-196]] (WAY-202196)
* [[Erteberel]] (SERBA-1, LY-500307)
* [[Erteberel]] (SERBA-1, LY-500307)
* [[FERb 033]] – 62-fold selectivity for ER-β over ERα<ref name="pmid19128016">{{cite journal | vauthors = Minutolo F, Bertini S, Granchi C, Marchitiello T, Prota G, Rapposelli S, Tuccinardi T, Martinelli A, Gunther JR, Carlson KE, Katzenellenbogen JA, Macchia M | title = Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor beta | journal = J. Med. Chem. | volume = 52 | issue = 3 | pages = 858–67 | year = 2009 | pmid = 19128016 | doi = 10.1021/jm801458t }}</ref>
* [[FERb 033]] – 62-fold selectivity for ER-β over ERα<ref name="pmid19128016">{{cite journal | vauthors = Minutolo F, Bertini S, Granchi C, Marchitiello T, Prota G, Rapposelli S, Tuccinardi T, Martinelli A, Gunther JR, Carlson KE, Katzenellenbogen JA, Macchia M | title = Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor beta | journal = Journal of Medicinal Chemistry | volume = 52 | issue = 3 | pages = 858–67 | date = February 2009 | pmid = 19128016 | doi = 10.1021/jm801458t }}</ref>
* [[Genistein]] – phytoestrogen; 16-fold selectivity for ER-β over ERα<ref name="HajirahimkhanDietz2013" />
* [[Genistein]] – phytoestrogen; 16-fold selectivity for ER-β over ERα<ref name="HajirahimkhanDietz2013" />
* [[Kaempferol]] – phytoestrogen<ref name="HajirahimkhanDietz2013" />
* [[Kaempferol]] – phytoestrogen<ref name="HajirahimkhanDietz2013" />
Line 74: Line 74:


====Non-selective====
====Non-selective====
* [[Selective estrogen receptor modulator]]s (e.g., [[tamoxifen]], [[raloxifene]])<ref name="pmid9658195">{{cite journal | vauthors = Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson J, Nilsson S | title = Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists | journal = Mol. Pharmacol. | volume = 54 | issue = 1 | pages = 105–12 | year = 1998 | pmid = 9658195 | doi = | url = }}</ref>
* [[Selective estrogen receptor modulator]]s (e.g., [[tamoxifen]], [[raloxifene]])<ref name="pmid9658195">{{cite journal | vauthors = Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson J, Nilsson S | title = Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists | journal = Molecular Pharmacology | volume = 54 | issue = 1 | pages = 105–12 | date = July 1998 | pmid = 9658195 | doi = }}</ref>
* [[Antiestrogen]]s (e.g., [[fulvestrant]], [[ICI-164384]])
* [[Antiestrogen]]s (e.g., [[fulvestrant]], [[ICI-164384]])


Line 87: Line 87:
Estrogen receptor beta has been shown to [[Protein-protein interaction|interact]] with:
Estrogen receptor beta has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
{{div col|colwidth=20em}}
* [[Cyclin D1|CCND1]],<ref name="pmid23060014">{{cite journal | vauthors = Nakamura Y, Felizola SJ, Kurotaki Y, Fujishima F, McNamara KM, Suzuki T, Arai Y, Sasano H | title = Cyclin D1 (CCND1) expression is involved in estrogen receptor beta (ER-β) in human prostate cancer | journal = Prostate | volume = 73| issue = 6 | pages = 590–5 | date = May 2013 | pmid = 23060014 | doi = 10.1002/pros.22599 }}</ref>
* [[Cyclin D1|CCND1]],<ref name="pmid23060014">{{cite journal | vauthors = Nakamura Y, Felizola SJ, Kurotaki Y, Fujishima F, McNamara KM, Suzuki T, Arai Y, Sasano H | title = Cyclin D1 (CCND1) expression is involved in estrogen receptor beta (ERβ) in human prostate cancer | journal = The Prostate | volume = 73 | issue = 6 | pages = 590–5 | date = May 2013 | pmid = 23060014 | doi = 10.1002/pros.22599 }}</ref>
* [[Estrogen receptor alpha|ESR1]]<ref name="pmid9473491">{{cite journal | vauthors = Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, Hosoi T, Ouchi Y, Muramatsu M | title = The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro | journal = Biochem. Biophys. Res. Commun. | volume = 243 | issue = 1 | pages = 122–6 | date = February 1998 | pmid = 9473491 | doi = 10.1006/bbrc.1997.7893 }}</ref><ref name="pmid10706629">{{cite journal | vauthors = Poelzl G, Kasai Y, Mochizuki N, Shaul PW, Brown M, Mendelsohn ME | title = Specific association of estrogen receptor β with the cell cycle spindle assembly checkpoint protein, MAD2 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 6 | pages = 2836–9 | date = March 2000 | pmid = 10706629 | pmc = 16016 | doi = 10.1073/pnas.050580997 }}</ref>
* [[Estrogen receptor alpha|ESR1]]<ref name="pmid9473491">{{cite journal | vauthors = Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, Hosoi T, Ouchi Y, Muramatsu M | title = The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro | journal = Biochemical and Biophysical Research Communications | volume = 243 | issue = 1 | pages = 122–6 | date = February 1998 | pmid = 9473491 | doi = 10.1006/bbrc.1997.7893 }}</ref><ref name="pmid10706629">{{cite journal | vauthors = Poelzl G, Kasai Y, Mochizuki N, Shaul PW, Brown M, Mendelsohn ME | title = Specific association of estrogen receptor beta with the cell cycle spindle assembly checkpoint protein, MAD2 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 6 | pages = 2836–9 | date = March 2000 | pmid = 10706629 | pmc = 16016 | doi = 10.1073/pnas.050580997 }}</ref>
* [[MAD2L1]],<ref name=pmid10706629/>
* [[MAD2L1]],<ref name=pmid10706629/>
* [[Nuclear receptor coactivator 3|NCOA3]],<ref name="pmid11389589">{{cite journal | vauthors = Wong CW, Komm B, Cheskis BJ | title = Structure-function evaluation of ER alpha and beta interplay with SRC family coactivators. ER selective ligands | journal = Biochemistry | volume = 40 | issue = 23 | pages = 6756–65 | date = June 2001 | pmid = 11389589 | doi = 10.1021/bi010379h }}</ref><ref name="pmid10681591">{{cite journal | vauthors = Leo C, Li H, Chen JD | title = Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3 | journal = J. Biol. Chem. | volume = 275 | issue = 8 | pages = 5976–82 | date = February 2000 | pmid = 10681591 | doi = 10.1074/jbc.275.8.5976 }}</ref>
* [[Nuclear receptor coactivator 3|NCOA3]],<ref name="pmid11389589">{{cite journal | vauthors = Wong CW, Komm B, Cheskis BJ | title = Structure-function evaluation of ER alpha and beta interplay with SRC family coactivators. ER selective ligands | journal = Biochemistry | volume = 40 | issue = 23 | pages = 6756–65 | date = June 2001 | pmid = 11389589 | doi = 10.1021/bi010379h }}</ref><ref name="pmid10681591">{{cite journal | vauthors = Leo C, Li H, Chen JD | title = Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3 | journal = The Journal of Biological Chemistry | volume = 275 | issue = 8 | pages = 5976–82 | date = February 2000 | pmid = 10681591 | doi = 10.1074/jbc.275.8.5976 }}</ref>
* [[NCOA6]],<ref name="pmid11158331">{{cite journal | vauthors = Lee SK, Jung SY, Kim YS, Na SY, Lee YC, Lee JW | title = Two distinct nuclear receptor-interaction domains and CREB-binding protein-dependent transactivation function of activating signal cointegrator-2 | journal = Mol. Endocrinol. | volume = 15 | issue = 2 | pages = 241–54 | date = February 2001 | pmid = 11158331 | doi = 10.1210/me.15.2.241 }}</ref><ref name="pmid11773444">{{cite journal | vauthors = Ko L, Cardona GR, Iwasaki T, Bramlett KS, Burris TP, Chin WW | title = Ser-884 adjacent to the LXXLL motif of coactivator TRBP defines selectivity for ERs and TRs | journal = Mol. Endocrinol. | volume = 16 | issue = 1 | pages = 128–40 | date = January 2002 | pmid = 11773444 | doi = 10.1210/mend.16.1.0755 }}</ref>
* [[NCOA6]],<ref name="pmid11158331">{{cite journal | vauthors = Lee SK, Jung SY, Kim YS, Na SY, Lee YC, Lee JW | title = Two distinct nuclear receptor-interaction domains and CREB-binding protein-dependent transactivation function of activating signal cointegrator-2 | journal = Molecular Endocrinology | volume = 15 | issue = 2 | pages = 241–54 | date = February 2001 | pmid = 11158331 | doi = 10.1210/me.15.2.241 }}</ref><ref name="pmid11773444">{{cite journal | vauthors = Ko L, Cardona GR, Iwasaki T, Bramlett KS, Burris TP, Chin WW | title = Ser-884 adjacent to the LXXLL motif of coactivator TRBP defines selectivity for ERs and TRs | journal = Molecular Endocrinology | volume = 16 | issue = 1 | pages = 128–40 | date = January 2002 | pmid = 11773444 | doi = 10.1210/mend.16.1.0755 }}</ref>
* [[RBM39]],<ref name="pmid11704680">{{cite journal | vauthors = Jung DJ, Na SY, Na DS, Lee JW | title = Molecular cloning and characterization of CAPER, a novel coactivator of activating protein-1 and estrogen receptors | journal = J. Biol. Chem. | volume = 277 | issue = 2 | pages = 1229–34 | date = January 2002 | pmid = 11704680 | doi = 10.1074/jbc.M110417200 }}</ref> and
* [[RBM39]],<ref name="pmid11704680">{{cite journal | vauthors = Jung DJ, Na SY, Na DS, Lee JW | title = Molecular cloning and characterization of CAPER, a novel coactivator of activating protein-1 and estrogen receptors | journal = The Journal of Biological Chemistry | volume = 277 | issue = 2 | pages = 1229–34 | date = January 2002 | pmid = 11704680 | doi = 10.1074/jbc.M110417200 }}</ref> and
* [[Src (gene)|SRC]].<ref name="pmid11032808">{{cite journal | vauthors = Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio A, Lombardi M, Barone MV, Ametrano D, Zannini MS, Abbondanza C, Auricchio F | title = Steroid-induced androgen receptor–oestradiol receptor β–Src complex triggers prostate cancer cell proliferation | journal = EMBO J. | volume = 19 | issue = 20 | pages = 5406–17 | date = October 2000 | pmid = 11032808 | pmc = 314017 | doi = 10.1093/emboj/19.20.5406 }}</ref><ref name="pmid11013076">{{cite journal | vauthors = Slentz-Kesler K, Moore JT, Lombard M, Zhang J, Hollingsworth R, Weiner MP | title = Identification of the human Mnk2 gene (MKNK2) through protein interaction with estrogen receptor beta | journal = Genomics | volume = 69 | issue = 1 | pages = 63–71 | date = October 2000 | pmid = 11013076 | doi = 10.1006/geno.2000.6299 }}</ref>
* [[Src (gene)|SRC]].<ref name="pmid11032808">{{cite journal | vauthors = Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio A, Lombardi M, Barone MV, Ametrano D, Zannini MS, Abbondanza C, Auricchio F | title = Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation | journal = The EMBO Journal | volume = 19 | issue = 20 | pages = 5406–17 | date = October 2000 | pmid = 11032808 | pmc = 314017 | doi = 10.1093/emboj/19.20.5406 }}</ref><ref name="pmid11013076">{{cite journal | vauthors = Slentz-Kesler K, Moore JT, Lombard M, Zhang J, Hollingsworth R, Weiner MP | title = Identification of the human Mnk2 gene (MKNK2) through protein interaction with estrogen receptor beta | journal = Genomics | volume = 69 | issue = 1 | pages = 63–71 | date = October 2000 | pmid = 11013076 | doi = 10.1006/geno.2000.6299 }}</ref>
{{Div col end}}
{{Div col end}}
{{clear}}
{{clear}}
Line 102: Line 102:
== Further reading ==
== Further reading ==
{{refbegin|33em}}
{{refbegin|33em}}
* {{cite journal | vauthors = Pettersson K, Gustafsson JA | title = Role of estrogen receptor beta in estrogen action | journal = Annu. Rev. Physiol. | volume = 63 | issue =  | pages = 165–92 | year = 2001 | pmid = 11181953 | doi = 10.1146/annurev.physiol.63.1.165 }}
* {{cite journal | vauthors = Pettersson K, Gustafsson JA | title = Role of estrogen receptor beta in estrogen action | journal = Annual Review of Physiology | volume = 63 | issue =  | pages = 165–92 | year = 2001 | pmid = 11181953 | doi = 10.1146/annurev.physiol.63.1.165 }}
* {{cite journal | vauthors = Warner M, Saji S, Gustafsson JA | title = The normal and malignant mammary gland: a fresh look with ER beta onboard | journal = Journal of Mammary Gland Biology and Neoplasia | volume = 5 | issue = 3 | pages = 289–94 | year = 2004 | pmid = 14973391 | doi = 10.1023/A:1009598828267 }}
* {{cite journal | vauthors = Warner M, Saji S, Gustafsson JA | title = The normal and malignant mammary gland: a fresh look with ER beta onboard | journal = Journal of Mammary Gland Biology and Neoplasia | volume = 5 | issue = 3 | pages = 289–94 | date = July 2000 | pmid = 14973391 | doi = 10.1023/A:1009598828267 }}
* {{cite journal | vauthors = Saxon LK, Turner CH | title = Estrogen receptor beta: the antimechanostat? | journal = Bone | volume = 36 | issue = 2 | pages = 185–92 | year = 2005 | pmid = 15780944 | doi = 10.1016/j.bone.2004.08.003 }}
* {{cite journal | vauthors = Saxon LK, Turner CH | title = Estrogen receptor beta: the antimechanostat? | journal = Bone | volume = 36 | issue = 2 | pages = 185–92 | date = February 2005 | pmid = 15780944 | doi = 10.1016/j.bone.2004.08.003 }}
* {{cite journal | vauthors = Halachmi S, Marden E, Martin G, MacKay H, Abbondanza C, Brown M | title = Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription | journal = Science | volume = 264 | issue = 5164 | pages = 1455–8 | year = 1994 | pmid = 8197458 | doi = 10.1126/science.8197458 }}
* {{cite journal | vauthors = Halachmi S, Marden E, Martin G, MacKay H, Abbondanza C, Brown M | title = Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription | journal = Science | volume = 264 | issue = 5164 | pages = 1455–8 | date = June 1994 | pmid = 8197458 | doi = 10.1126/science.8197458 }}
* {{cite journal | vauthors = Schwabe JW, Chapman L, Finch JT, Rhodes D | title = The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: how receptors discriminate between their response elements | journal = Cell | volume = 75 | issue = 3 | pages = 567–78 | year = 1993 | pmid = 8221895 | doi = 10.1016/0092-8674(93)90390-C }}
* {{cite journal | vauthors = Schwabe JW, Chapman L, Finch JT, Rhodes D | title = The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: how receptors discriminate between their response elements | journal = Cell | volume = 75 | issue = 3 | pages = 567–78 | date = November 1993 | pmid = 8221895 | doi = 10.1016/0092-8674(93)90390-C }}
* {{cite journal | vauthors = Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM | title = Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300 | journal = Cell | volume = 90 | issue = 3 | pages = 569–80 | year = 1997 | pmid = 9267036 | doi = 10.1016/S0092-8674(00)80516-4 }}
* {{cite journal | vauthors = Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM | title = Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300 | journal = Cell | volume = 90 | issue = 3 | pages = 569–80 | date = August 1997 | pmid = 9267036 | doi = 10.1016/S0092-8674(00)80516-4 }}
* {{cite journal | vauthors = Pace P, Taylor J, Suntharalingam S, Coombes RC, Ali S | title = Human estrogen receptor beta binds DNA in a manner similar to and dimerizes with estrogen receptor alpha | journal = J. Biol. Chem. | volume = 272 | issue = 41 | pages = 25832–8 | year = 1997 | pmid = 9325313 | doi = 10.1074/jbc.272.41.25832 }}
* {{cite journal | vauthors = Pace P, Taylor J, Suntharalingam S, Coombes RC, Ali S | title = Human estrogen receptor beta binds DNA in a manner similar to and dimerizes with estrogen receptor alpha | journal = The Journal of Biological Chemistry | volume = 272 | issue = 41 | pages = 25832–8 | date = October 1997 | pmid = 9325313 | doi = 10.1074/jbc.272.41.25832 }}
* {{cite journal | vauthors = Brandenberger AW, Tee MK, Lee JY, Chao V, Jaffe RB | title = Tissue distribution of estrogen receptors alpha (ER-alpha) and beta (ER-beta) mRNA in the midgestational human fetus | journal = J. Clin. Endocrinol. Metab. | volume = 82 | issue = 10 | pages = 3509–12 | year = 1997 | pmid = 9329394 | doi = 10.1210/jc.82.10.3509 }}
* {{cite journal | vauthors = Brandenberger AW, Tee MK, Lee JY, Chao V, Jaffe RB | title = Tissue distribution of estrogen receptors alpha (ER-alpha) and beta (ER-beta) mRNA in the midgestational human fetus | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 82 | issue = 10 | pages = 3509–12 | date = October 1997 | pmid = 9329394 | doi = 10.1210/jc.82.10.3509 }}
* {{cite journal | vauthors = Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G, Nordenskjöld M, Gustafsson JA | title = Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern | journal = J. Clin. Endocrinol. Metab. | volume = 82 | issue = 12 | pages = 4258–65 | year = 1998 | pmid = 9398750 | doi = 10.1210/jc.82.12.4258 }}
* {{cite journal | vauthors = Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G, Nordenskjöld M, Gustafsson JA | title = Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 82 | issue = 12 | pages = 4258–65 | date = December 1997 | pmid = 9398750 | doi = 10.1210/jc.82.12.4258 }}
* {{cite journal | vauthors = Vladusic EA, Hornby AE, Guerra-Vladusic FK, Lupu R | title = Expression of estrogen receptor beta messenger RNA variant in breast cancer | journal = Cancer Res. | volume = 58 | issue = 2 | pages = 210–4 | year = 1998 | pmid = 9443393 | doi =  }}
* {{cite journal | vauthors = Vladusic EA, Hornby AE, Guerra-Vladusic FK, Lupu R | title = Expression of estrogen receptor beta messenger RNA variant in breast cancer | journal = Cancer Research | volume = 58 | issue = 2 | pages = 210–4 | date = January 1998 | pmid = 9443393 | doi =  }}
* {{cite journal | vauthors = Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, Hosoi T, Ouchi Y, Muramatsu M | title = The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro | journal = Biochem. Biophys. Res. Commun. | volume = 243 | issue = 1 | pages = 122–6 | year = 1998 | pmid = 9473491 | doi = 10.1006/bbrc.1997.7893 }}
* {{cite journal | vauthors = Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, Hosoi T, Ouchi Y, Muramatsu M | title = The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro | journal = Biochemical and Biophysical Research Communications | volume = 243 | issue = 1 | pages = 122–6 | date = February 1998 | pmid = 9473491 | doi = 10.1006/bbrc.1997.7893 }}
* {{cite journal | vauthors = Alves SE, Lopez V, McEwen BS, Weiland NG | title = Differential colocalization of estrogen receptor β (ER-β) with oxytocin and vasopressin in the paraventricular and supraoptic nuclei of the female rat brain: An immunocytochemical study | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 6 | pages = 3281–6 | year = 1998 | pmid = 9501254 | pmc = 19733 | doi = 10.1073/pnas.95.6.3281 }}
* {{cite journal | vauthors = Alves SE, Lopez V, McEwen BS, Weiland NG | title = Differential colocalization of estrogen receptor beta (ERbeta) with oxytocin and vasopressin in the paraventricular and supraoptic nuclei of the female rat brain: an immunocytochemical study | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 6 | pages = 3281–6 | date = March 1998 | pmid = 9501254 | pmc = 19733 | doi = 10.1073/pnas.95.6.3281 }}
* {{cite journal | vauthors = Brandenberger AW, Tee MK, Jaffe RB | title = Estrogen receptor alpha (ER-alpha) and beta (ER-beta) mRNAs in normal ovary, ovarian serous cystadenocarcinoma and ovarian cancer cell lines: down-regulation of ER-beta in neoplastic tissues | journal = J. Clin. Endocrinol. Metab. | volume = 83 | issue = 3 | pages = 1025–8 | year = 1998 | pmid = 9506768 | doi = 10.1210/jc.83.3.1025 }}
* {{cite journal | vauthors = Brandenberger AW, Tee MK, Jaffe RB | title = Estrogen receptor alpha (ER-alpha) and beta (ER-beta) mRNAs in normal ovary, ovarian serous cystadenocarcinoma and ovarian cancer cell lines: down-regulation of ER-beta in neoplastic tissues | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 83 | issue = 3 | pages = 1025–8 | date = March 1998 | pmid = 9506768 | doi = 10.1210/jc.83.3.1025 }}
* {{cite journal | vauthors = Moore JT, McKee DD, Slentz-Kesler K, Moore LB, Jones SA, Horne EL, Su JL, Kliewer SA, Lehmann JM, Willson TM | title = Cloning and characterization of human estrogen receptor beta isoforms | journal = Biochem. Biophys. Res. Commun. | volume = 247 | issue = 1 | pages = 75–8 | year = 1998 | pmid = 9636657 | doi = 10.1006/bbrc.1998.8738 }}
* {{cite journal | vauthors = Moore JT, McKee DD, Slentz-Kesler K, Moore LB, Jones SA, Horne EL, Su JL, Kliewer SA, Lehmann JM, Willson TM | title = Cloning and characterization of human estrogen receptor beta isoforms | journal = Biochemical and Biophysical Research Communications | volume = 247 | issue = 1 | pages = 75–8 | date = June 1998 | pmid = 9636657 | doi = 10.1006/bbrc.1998.8738 }}
* {{cite journal | vauthors = Ogawa S, Inoue S, Watanabe T, Orimo A, Hosoi T, Ouchi Y, Muramatsu M | title = Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor ofestrogen action in human | journal = Nucleic Acids Res. | volume = 26 | issue = 15 | pages = 3505–12 | year = 1998 | pmid = 9671811 | pmc = 147730 | doi = 10.1093/nar/26.15.3505 }}
* {{cite journal | vauthors = Ogawa S, Inoue S, Watanabe T, Orimo A, Hosoi T, Ouchi Y, Muramatsu M | title = Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor ofestrogen action in human | journal = Nucleic Acids Research | volume = 26 | issue = 15 | pages = 3505–12 | date = August 1998 | pmid = 9671811 | pmc = 147730 | doi = 10.1093/nar/26.15.3505 }}
* {{cite journal | vauthors = Lu B, Leygue E, Dotzlaw H, Murphy LJ, Murphy LC, Watson PH | title = Estrogen receptor-beta mRNA variants in human and murine tissues | journal = Mol. Cell. Endocrinol. | volume = 138 | issue = 1–2 | pages = 199–203 | year = 1998 | pmid = 9685228 | doi = 10.1016/S0303-7207(98)00050-1 }}
* {{cite journal | vauthors = Lu B, Leygue E, Dotzlaw H, Murphy LJ, Murphy LC, Watson PH | title = Estrogen receptor-beta mRNA variants in human and murine tissues | journal = Molecular and Cellular Endocrinology | volume = 138 | issue = 1-2 | pages = 199–203 | date = March 1998 | pmid = 9685228 | doi = 10.1016/S0303-7207(98)00050-1 }}
* {{cite journal | vauthors = Seol W, Hanstein B, Brown M, Moore DD | title = Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner) | journal = Mol. Endocrinol. | volume = 12 | issue = 10 | pages = 1551–7 | year = 1998 | pmid = 9773978 | doi = 10.1210/me.12.10.1551 }}
* {{cite journal | vauthors = Seol W, Hanstein B, Brown M, Moore DD | title = Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner) | journal = Molecular Endocrinology | volume = 12 | issue = 10 | pages = 1551–7 | date = October 1998 | pmid = 9773978 | doi = 10.1210/me.12.10.1551 }}
* {{cite journal | vauthors = Hanstein B, Liu H, Yancisin MC, Brown M | title = Functional analysis of a novel estrogen receptor-beta isoform | journal = Mol. Endocrinol. | volume = 13 | issue = 1 | pages = 129–37 | year = 1999 | pmid = 9892018 | doi = 10.1210/me.13.1.129 }}
* {{cite journal | vauthors = Hanstein B, Liu H, Yancisin MC, Brown M | title = Functional analysis of a novel estrogen receptor-beta isoform | journal = Molecular Endocrinology | volume = 13 | issue = 1 | pages = 129–37 | date = January 1999 | pmid = 9892018 | doi = 10.1210/me.13.1.129 }}
* {{cite journal | vauthors = Vidal O, Kindblom LG, Ohlsson C | title = Expression and localization of estrogen receptor-beta in murine and human bone | journal = J. Bone Miner. Res. | volume = 14 | issue = 6 | pages = 923–9 | year = 1999 | pmid = 10352100 | doi = 10.1359/jbmr.1999.14.6.923 }}
* {{cite journal | vauthors = Vidal O, Kindblom LG, Ohlsson C | title = Expression and localization of estrogen receptor-beta in murine and human bone | journal = Journal of Bone and Mineral Research | volume = 14 | issue = 6 | pages = 923–9 | date = June 1999 | pmid = 10352100 | doi = 10.1359/jbmr.1999.14.6.923 }}
{{refend}}
{{refend}}


Revision as of 04:51, 19 May 2018

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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Estrogen receptor beta (ER-β), also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2), is one of two main types of estrogen receptor, a nuclear receptor which is activated by the sex hormone estrogen.[1] In humans, ER-β is encoded by the ESR2 gene.[2]

Function

ER-β is a member of the family of estrogen receptors and the superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17-β-estradiol, estriol or related ligands, the encoded protein forms homo-dimers or hetero-dimers with estrogen receptor α that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized.[3]

ER-β may have anti-proliferative effects and therefore oppose the actions of ERα in reproductive tissue.[4] ER-β may also have an important role in adaptive function of the lung during pregnancy.[5]

ER-β is a potent tumor suppressor and plays a crucial role in many cancer types such as prostate cancer.[6][7]

Tissue distribution

ER-β is expressed by many tissues including the uterus,[8] blood monocytes and tissue macrophages, colonic and pulmonary epithelial cells and in prostatic epithelium and in malignant counterparts of these tissues. Also, ER-β is found throughout the brain at different concentrations in different neuron clusters.[9][10]

ER-β abnormalities

ER-β function is related to various cardiovascular targets including ATP-binding cassette transporter A1 (ABCA1) and apolipoprotein A1 (ApoA-1). Polymorphism may affect ER-β function and lead to altered responses in postmenopausal women receiving hormone replacement therapy.[11] Abnormalities in gene expression associated with ER-β have also been linked to autism spectrum disorder.[12]

Disease

Cardiovascular Disease

Mutations in ERβ have been shown to influence cardiomyocytes, the cells that comprise the largest part of the heart, and can lead to an increased risk of cardiovascular disease (CVD). There is a disparity in prevalence of CVD between pre- and post-menopausal women, and the difference can be attributed to estrogen levels. Many types of ERβ receptors exist in order to help regulate gene expression and subsequent health in the body, but binding of 17βE2 (a naturally occurring estrogen) specifically improves cardiac metabolism. The heart utilizes a lot of energy in the form of ATP to properly pump blood and maintain physiological requirements in order to live, and 17βE2 helps by increasing these myocardial ATP levels and respiratory function.[13]

In addition, 17βE2 can alter myocardial signaling pathways and stimulate myocyte regeneration, which can aid in inhibiting myocyte cell death. The ERβ signaling pathway plays a role in both vasodilation and arterial dilation, which contributes to an individual having a healthy heart rate and a decrease in blood pressure. This regulation can increase endothelial function and arterial perfusion, both of which are important to myocyte health. Thus, alterations in this signaling pathways due to ERβ mutation could lead to myocyte cell death from physiological stress. While ERα has a more profound role in regeneration after myocyte cell death, ERβ can still help by increasing endothelial progenitor cell activation and subsequent cardiac function.[14]

Alzheimer's Disease

Genetic variation in ERβ is both sex and age dependent and ERβ polymorphism can lead to accelerated brain aging, cognitive impairment, and development of AD pathology. Similar to CVD, post-menopausal women have an increased risk of developing Alzheimer’s disease (AD) due to a loss of estrogen, which affects proper aging of the hippocampus, neural survival and regeneration, and amyloid metabolism. ERβ mRNA is highly expressed in hippocampal formation, an area of the brain that is associated with memory. This expression contributes to increased neuronal survival and helps protect against neurodegenerative diseases such as AD. The pathology of AD is also associated with accumulation of amyloid beta peptide (Aβ). While a proper concentration of Aβ in the brain is important for healthy functioning, too much can lead to cognitive impairment. Thus, ERβ helps control Aβ levels by maintaining the protein it is derived from, β-amyloid precursor protein. ERβ helps by up-regulating insulin-degrading enzyme (IDE), which leads to β-amyloid degradation when accumulation levels begin to rise. However, in AD, lack of ERβ causes a decrease in this degradation and an increase in plaque build-up.[15]

ERβ also plays a role in regulating APOE, a risk factor for AD that redistributes lipids across cells. APOE expression in the hippocampus is specifically regulated by 17βE2, affecting learning and memory in individuals afflicted with AD. Thus, estrogen therapy via an ERβ-targeted approach can be used as a prevention method for AD either before or at the onset of menopause. Interactions between ERα and ERβ can lead to antagonistic actions in the brain, so an ERβ-targeted approach can increase therapeutic neural responses independently of ERα. Therapeutically, ERβ can be used in both men and women in order to regulate plaque formation in the brain.[16]

Neuroprotective Benefits

Synaptic Strength and Plasticity

ERβ levels can dictate both synaptic strength and neuroplasticity through neural structure modifications. Variations in endogenous estrogen levels cause changes in dendritic architecture in the hippocampus, which affects neural signaling and plasticity. Specifically, lower estrogen levels lead to decreased dendritic spines and improper signaling, inhibiting plasticity of the brain. However, treatment of 17βE2 can reverse this affect, giving it the ability to modify hippocampal structure. As a result of the relationship between dendritic architecture and long-term potentiation (LTP), ERβ can enhance LTP and lead to an increase in synaptic strength. Furthermore, 17βE2 promotes neurogenesis in developing hippocampal neurons and neurons in the subventricular zone and dentate gyrus of the adult human brain. Specifically, ERβ increases the proliferation of progenitor cells to create new neurons and can be increased later in life through 17βE2 treatment.[17][18]

Ligands

Agonists

Non-selective

Selective

Agonists of ER-β selective over ERα include:

Antagonists

Non-selective

Selective

Antagonists of ER-β selective over ERα include:

Interactions

Estrogen receptor beta has been shown to interact with:

References

  1. ↑ Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA (June 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.
  2. ↑ Mosselman S, Polman J, Dijkema R (August 1996). "ER beta: identification and characterization of a novel human estrogen receptor". FEBS Letters. 392 (1): 49–53. doi:10.1016/0014-5793(96)00782-X. PMID 8769313.
  3. ↑ "Entrez Gene: ESR2 estrogen receptor 2 (ER beta)".
  4. ↑ Weihua Z, Saji S, Mäkinen S, Cheng G, Jensen EV, Warner M, Gustafsson JA (May 2000). "Estrogen receptor (ER) beta, a modulator of ERalpha in the uterus". Proceedings of the National Academy of Sciences of the United States of America. 97 (11): 5936–41. doi:10.1073/pnas.97.11.5936. PMC 18537. PMID 10823946.
  5. ↑ Carey MA, Card JW, Voltz JW, Germolec DR, Korach KS, Zeldin DC (August 2007). "The impact of sex and sex hormones on lung physiology and disease: lessons from animal studies". American Journal of Physiology. Lung Cellular and Molecular Physiology. 293 (2): L272–8. doi:10.1152/ajplung.00174.2007. PMID 17575008.
  6. ↑ Stettner M, Kaulfuss S, Burfeind P, Schweyer S, Strauss A, Ringert RH, Thelen P (October 2007). "The relevance of estrogen receptor-beta expression to the antiproliferative effects observed with histone deacetylase inhibitors and phytoestrogens in prostate cancer treatment". Molecular Cancer Therapeutics. 6 (10): 2626–33. doi:10.1158/1535-7163.MCT-07-0197. PMID 17913855.
  7. ↑ Kyriakidis I, Papaioannidou P (June 2016). "Estrogen receptor beta and ovarian cancer: a key to pathogenesis and response to therapy". Archives of Gynecology and Obstetrics. 293 (6): 1161–8. doi:10.1007/s00404-016-4027-8. PMID 26861465.
  8. ↑ Hapangama DK, Kamal AM, Bulmer JN (Mar 2015). "Estrogen receptor β: the guardian of the endometrium". Human Reproduction Update. 21 (2): 174–93. doi:10.1093/humupd/dmu053. PMID 25305176.
  9. ↑ Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS (November 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.
  10. ↑ Koehler KF, Helguero LA, Haldosén LA, Warner M, Gustafsson JA (May 2005). "Reflections on the discovery and significance of estrogen receptor beta". Endocrine Reviews. 26 (3): 465–78. doi:10.1210/er.2004-0027. PMID 15857973.
  11. ↑ Darabi M, Ani M, Panjehpour M, Rabbani M, Movahedian A, Zarean E (January–February 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.
  12. ↑ Crider A, Thakkar R, Ahmed AO, Pillai A (9 September 2014). "Dysregulation of estrogen receptor beta (ERβ), aromatase (CYP19A1), and ER co-activators in the middle frontal gyrus of autism spectrum disorder subjects". Molecular Autism. 5 (1): 46. doi:10.1186/2040-2392-5-46. PMID 25221668.
  13. ↑ Luo T, Kim JK (August 2016). "The Role of Estrogen and Estrogen Receptors on Cardiomyocytes: An Overview". The Canadian Journal of Cardiology. 32 (8): 1017–25. doi:10.1016/j.cjca.2015.10.021. PMC 4853290. PMID 26860777.
  14. ↑ Muka T, Vargas KG, Jaspers L, Wen KX, Dhana K, Vitezova A, Nano J, Brahimaj A, Colpani V, Bano A, Kraja B, Zaciragic A, Bramer WM, van Dijk GM, Kavousi M, Franco OH (April 2016). "Estrogen receptor β actions in the female cardiovascular system: A systematic review of animal and human studies". Maturitas. 86: 28–43. doi:10.1016/j.maturitas.2016.01.009. PMID 26921926.
  15. ↑ Li R, Cui J, Shen Y (May 2014). "Brain sex matters: estrogen in cognition and Alzheimer's disease". Molecular and Cellular Endocrinology. 389 (1–2): 13–21. doi:10.1016/j.mce.2013.12.018. PMC 4040318. PMID 24418360.
  16. ↑ Zhao L, Woody SK, Chhibber A (November 2015). "Estrogen receptor β in Alzheimer's disease: From mechanisms to therapeutics". Ageing Research Reviews. 24 (Pt B): 178–90. doi:10.1016/j.arr.2015.08.001. PMC 4661108. PMID 26307455.
  17. ↑ Engler-Chiurazzi EB, Brown CM, Povroznik JM, Simpkins JW (October 2017). "Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury". Progress in Neurobiology. 157: 188–211. doi:10.1016/j.pneurobio.2015.12.008. PMID 26891883.
  18. ↑ Vargas KG, Milic J, Zaciragic A, Wen KX, Jaspers L, Nano J, Dhana K, Bramer WM, Kraja B, van Beeck E, Ikram MA, Muka T, Franco OH (November 2016). "The functions of estrogen receptor beta in the female brain: A systematic review". Maturitas. 93: 41–57. doi:10.1016/j.maturitas.2016.05.014. PMID 27338976.
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 19.6 Hajirahimkhan A, Dietz BM, Bolton JL (May 2013). "Botanical modulation of menopausal symptoms: mechanisms of action?". Planta Medica. 79 (7): 538–53. doi:10.1055/s-0032-1328187. PMC 3800090. PMID 23408273.
  20. ↑ Minutolo F, Bertini S, Granchi C, Marchitiello T, Prota G, Rapposelli S, Tuccinardi T, Martinelli A, Gunther JR, Carlson KE, Katzenellenbogen JA, Macchia M (February 2009). "Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor beta". Journal of Medicinal Chemistry. 52 (3): 858–67. doi:10.1021/jm801458t. PMID 19128016.
  21. ↑ Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson J, Nilsson S (July 1998). "Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists". Molecular Pharmacology. 54 (1): 105–12. PMID 9658195.
  22. ↑ Nakamura Y, Felizola SJ, Kurotaki Y, Fujishima F, McNamara KM, Suzuki T, Arai Y, Sasano H (May 2013). "Cyclin D1 (CCND1) expression is involved in estrogen receptor beta (ERβ) in human prostate cancer". The Prostate. 73 (6): 590–5. doi:10.1002/pros.22599. PMID 23060014.
  23. ↑ Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, Hosoi T, Ouchi Y, Muramatsu M (February 1998). "The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro". Biochemical and Biophysical Research Communications. 243 (1): 122–6. doi:10.1006/bbrc.1997.7893. PMID 9473491.
  24. ↑ 24.0 24.1 Poelzl G, Kasai Y, Mochizuki N, Shaul PW, Brown M, Mendelsohn ME (March 2000). "Specific association of estrogen receptor beta with the cell cycle spindle assembly checkpoint protein, MAD2". Proceedings of the National Academy of Sciences of the United States of America. 97 (6): 2836–9. doi:10.1073/pnas.050580997. PMC 16016. PMID 10706629.
  25. ↑ Wong CW, Komm B, Cheskis BJ (June 2001). "Structure-function evaluation of ER alpha and beta interplay with SRC family coactivators. ER selective ligands". Biochemistry. 40 (23): 6756–65. doi:10.1021/bi010379h. PMID 11389589.
  26. ↑ Leo C, Li H, Chen JD (February 2000). "Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3". The Journal of Biological Chemistry. 275 (8): 5976–82. doi:10.1074/jbc.275.8.5976. PMID 10681591.
  27. ↑ Lee SK, Jung SY, Kim YS, Na SY, Lee YC, Lee JW (February 2001). "Two distinct nuclear receptor-interaction domains and CREB-binding protein-dependent transactivation function of activating signal cointegrator-2". Molecular Endocrinology. 15 (2): 241–54. doi:10.1210/me.15.2.241. PMID 11158331.
  28. ↑ Ko L, Cardona GR, Iwasaki T, Bramlett KS, Burris TP, Chin WW (January 2002). "Ser-884 adjacent to the LXXLL motif of coactivator TRBP defines selectivity for ERs and TRs". Molecular Endocrinology. 16 (1): 128–40. doi:10.1210/mend.16.1.0755. PMID 11773444.
  29. ↑ Jung DJ, Na SY, Na DS, Lee JW (January 2002). "Molecular cloning and characterization of CAPER, a novel coactivator of activating protein-1 and estrogen receptors". The Journal of Biological Chemistry. 277 (2): 1229–34. doi:10.1074/jbc.M110417200. PMID 11704680.
  30. ↑ Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio A, Lombardi M, Barone MV, Ametrano D, Zannini MS, Abbondanza C, Auricchio F (October 2000). "Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation". The EMBO Journal. 19 (20): 5406–17. doi:10.1093/emboj/19.20.5406. PMC 314017. PMID 11032808.
  31. ↑ Slentz-Kesler K, Moore JT, Lombard M, Zhang J, Hollingsworth R, Weiner MP (October 2000). "Identification of the human Mnk2 gene (MKNK2) through protein interaction with estrogen receptor beta". Genomics. 69 (1): 63–71. doi:10.1006/geno.2000.6299. PMID 11013076.

Further reading

  • Pettersson K, Gustafsson JA (2001). "Role of estrogen receptor beta in estrogen action". Annual Review of Physiology. 63: 165–92. doi:10.1146/annurev.physiol.63.1.165. PMID 11181953.
  • Warner M, Saji S, Gustafsson JA (July 2000). "The normal and malignant mammary gland: a fresh look with ER beta onboard". Journal of Mammary Gland Biology and Neoplasia. 5 (3): 289–94. doi:10.1023/A:1009598828267. PMID 14973391.
  • Saxon LK, Turner CH (February 2005). "Estrogen receptor beta: the antimechanostat?". Bone. 36 (2): 185–92. doi:10.1016/j.bone.2004.08.003. PMID 15780944.
  • Halachmi S, Marden E, Martin G, MacKay H, Abbondanza C, Brown M (June 1994). "Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription". Science. 264 (5164): 1455–8. doi:10.1126/science.8197458. PMID 8197458.
  • Schwabe JW, Chapman L, Finch JT, Rhodes D (November 1993). "The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: how receptors discriminate between their response elements". Cell. 75 (3): 567–78. doi:10.1016/0092-8674(93)90390-C. PMID 8221895.
  • Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM (August 1997). "Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300". Cell. 90 (3): 569–80. doi:10.1016/S0092-8674(00)80516-4. PMID 9267036.
  • Pace P, Taylor J, Suntharalingam S, Coombes RC, Ali S (October 1997). "Human estrogen receptor beta binds DNA in a manner similar to and dimerizes with estrogen receptor alpha". The Journal of Biological Chemistry. 272 (41): 25832–8. doi:10.1074/jbc.272.41.25832. PMID 9325313.
  • Brandenberger AW, Tee MK, Lee JY, Chao V, Jaffe RB (October 1997). "Tissue distribution of estrogen receptors alpha (ER-alpha) and beta (ER-beta) mRNA in the midgestational human fetus". The Journal of Clinical Endocrinology and Metabolism. 82 (10): 3509–12. doi:10.1210/jc.82.10.3509. PMID 9329394.
  • Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G, Nordenskjöld M, Gustafsson JA (December 1997). "Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern". The Journal of Clinical Endocrinology and Metabolism. 82 (12): 4258–65. doi:10.1210/jc.82.12.4258. PMID 9398750.
  • Vladusic EA, Hornby AE, Guerra-Vladusic FK, Lupu R (January 1998). "Expression of estrogen receptor beta messenger RNA variant in breast cancer". Cancer Research. 58 (2): 210–4. PMID 9443393.
  • Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, Hosoi T, Ouchi Y, Muramatsu M (February 1998). "The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro". Biochemical and Biophysical Research Communications. 243 (1): 122–6. doi:10.1006/bbrc.1997.7893. PMID 9473491.
  • Alves SE, Lopez V, McEwen BS, Weiland NG (March 1998). "Differential colocalization of estrogen receptor beta (ERbeta) with oxytocin and vasopressin in the paraventricular and supraoptic nuclei of the female rat brain: an immunocytochemical study". Proceedings of the National Academy of Sciences of the United States of America. 95 (6): 3281–6. doi:10.1073/pnas.95.6.3281. PMC 19733. PMID 9501254.
  • Brandenberger AW, Tee MK, Jaffe RB (March 1998). "Estrogen receptor alpha (ER-alpha) and beta (ER-beta) mRNAs in normal ovary, ovarian serous cystadenocarcinoma and ovarian cancer cell lines: down-regulation of ER-beta in neoplastic tissues". The Journal of Clinical Endocrinology and Metabolism. 83 (3): 1025–8. doi:10.1210/jc.83.3.1025. PMID 9506768.
  • Moore JT, McKee DD, Slentz-Kesler K, Moore LB, Jones SA, Horne EL, Su JL, Kliewer SA, Lehmann JM, Willson TM (June 1998). "Cloning and characterization of human estrogen receptor beta isoforms". Biochemical and Biophysical Research Communications. 247 (1): 75–8. doi:10.1006/bbrc.1998.8738. PMID 9636657.
  • Ogawa S, Inoue S, Watanabe T, Orimo A, Hosoi T, Ouchi Y, Muramatsu M (August 1998). "Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor ofestrogen action in human". Nucleic Acids Research. 26 (15): 3505–12. doi:10.1093/nar/26.15.3505. PMC 147730. PMID 9671811.
  • Lu B, Leygue E, Dotzlaw H, Murphy LJ, Murphy LC, Watson PH (March 1998). "Estrogen receptor-beta mRNA variants in human and murine tissues". Molecular and Cellular Endocrinology. 138 (1–2): 199–203. doi:10.1016/S0303-7207(98)00050-1. PMID 9685228.
  • Seol W, Hanstein B, Brown M, Moore DD (October 1998). "Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner)". Molecular Endocrinology. 12 (10): 1551–7. doi:10.1210/me.12.10.1551. PMID 9773978.
  • Hanstein B, Liu H, Yancisin MC, Brown M (January 1999). "Functional analysis of a novel estrogen receptor-beta isoform". Molecular Endocrinology. 13 (1): 129–37. doi:10.1210/me.13.1.129. PMID 9892018.
  • Vidal O, Kindblom LG, Ohlsson C (June 1999). "Expression and localization of estrogen receptor-beta in murine and human bone". Journal of Bone and Mineral Research. 14 (6): 923–9. doi:10.1359/jbmr.1999.14.6.923. PMID 10352100.

External links

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