ArticleThe Journal of biological chemistry2013
Estrogen receptor α L543A,L544A mutation changes antagonists to agonists, correlating with the ligand binding domain dimerization associated with DNA binding activity.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 29 citations in OpenAlex.
- Expression Dynamics and Estrogen Response of Estrogen Receptors in Duolang Sheep During Puberty.Genes · 2025Article
- An Inverse Agonist GSK5182 Increases Protein Stability of the Orphan Nuclear Receptor ERRγ via Inhibition of Ubiquitination.International journal of molecular sciences · 2022Article
- Estrogen Receptor Alpha and ESR1 Mutations in Breast Cancer.Advances in experimental medicine and biology · 2022Article
- Estrogen Receptor Function: Impact on the Human Endometrium.Frontiers in endocrinology · 2022Review
- The physiological role of estrogen receptor functional domains.Essays in biochemistry · 2021Review
- ERpred: a web server for the prediction of subtype-specific estrogen receptor antagonists.PeerJ · 2021Article
- The genomic regulatory elements for estrogen receptor alpha transactivation-function-1 regulated genes.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Lavender Products Associated With Premature Thelarche and Prepubertal Gynecomastia: Case Reports and Endocrine-Disrupting Chemical Activities.The Journal of clinical endocrinology and metabolism · 2019Article
- Transactivation Function-1-Mediated Partial Agonist Activity of Selective Estrogen Receptor Modulator Requires Homo-Dimerization of the Estrogen Receptor α Ligand Binding Domain.International journal of molecular sciences · 2019Review
- Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay.Journal of visualized experiments : JoVE · 2018Article
- N-terminal transactivation function, AF-1, of estrogen receptor alpha controls obesity through enhancement of energy expenditure.Molecular metabolism · 2018Article
- The F domain of estrogen receptor α is involved in species-specific, tamoxifen-mediated transactivation.The Journal of biological chemistry · 2018Article
- Molecular mechanism of estrogen-estrogen receptor signaling.Reproductive medicine and biology · 2017Review
- Estrogen Hormone Biology.Current topics in developmental biology · 2017Review
- What's new in estrogen receptor action in the female reproductive tract.Journal of molecular endocrinology · 2016Review
- Transactivation Function-2 of Estrogen Receptor α Contains Transactivation Function-1-regulating Element.The Journal of biological chemistry · 2015Article
- The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- The Transactivating Function 2 (AF-2) of Estrogen Receptor (ER) α is Indispensable for ERα-mediated Physiological Responses and AF-1 Activity.Open journal of endocrine and metabolic diseases · 2013Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
A ligand-dependent nuclear transcription factor, ERα has two transactivating functional domains (AF), AF-1 and AF-2. AF-1 is localized in the N-terminal region, and AF-2 is distributed in the C-terminal ligand-binding domain (LBD) of the ERα protein. Helix 12 (H12) in the LBD is a component of the AF-2, and the configuration of H12 is ligand-inducible to an active or inactive form. We demonstrated previously that the ERα mutant (AF2ER) possessing L543A,L544A mutations in H12 disrupts AF-2 function and reverses antagonists such as fulvestrant/ICI182780 (ICI) or 4-hydoxytamoxifen (OHT) into agonists in the AF2ER knock-in mouse. Our previous in vitro studies suggested that the mode of AF2ER activation is similar to the partial agonist activity of OHT for WT-ERα. However, it is still unclear how antagonists activate ERα. To understand the molecular mechanism of antagonist reversal activity, we analyzed the correlation between the ICI-dependent estrogen-responsive element-mediated transcription activity of AF2ER and AF2ER-LBD dimerization activity. We report here that ICI-dependent AF2ER activation correlated with the activity of AF2ER-LBD homodimerization. Prevention of dimerization impaired the ICI-dependent ERE binding and transcription activity of AF2ER. The dislocation of H12 caused ICI-dependent LBD homodimerization involving the F-domain, the adjoining region of H12. Furthermore, F-domain truncation also strongly depressed the dimerization of WT-ERα-LBD with antagonists but not with E2. AF2ER activation levels with ICI, OHT, and raloxifene were parallel with the degree of AF2ER-LBD homodimerization, supporting a mechanism that antagonist-dependent LBD homodimerization involving the F-domain results in antagonist reversal activity of H12-mutated ERα.
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