The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation
Abstract Estetrol (E4) is a natural estrogen with a long half‐life produced only by the human fetal liver during pregnancy. The crystal structures of the estrogen receptor α (ERα) ligand‐binding domain bound to 17β‐estradiol (E2) and E4 are very similar, as well as their capacity to activate the two...
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2014-10-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201404112 |
| _version_ | 1797280687133294592 |
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| author | Anne Abot Coralie Fontaine Mélissa Buscato Romain Solinhac Gilles Flouriot Aurélie Fabre Anne Drougard Shyamala Rajan Muriel Laine Alain Milon Isabelle Muller Daniel Henrion Marine Adlanmerini Marie‐Cécile Valéra Anne Gompel Céline Gerard Christel Péqueux Mélanie Mestdagt Isabelle Raymond‐Letron Claude Knauf François Ferriere Philippe Valet Pierre Gourdy Benita S Katzenellenbogen John A Katzenellenbogen Françoise Lenfant Geoffrey L Greene Jean‐Michel Foidart Jean‐François Arnal |
| author_facet | Anne Abot Coralie Fontaine Mélissa Buscato Romain Solinhac Gilles Flouriot Aurélie Fabre Anne Drougard Shyamala Rajan Muriel Laine Alain Milon Isabelle Muller Daniel Henrion Marine Adlanmerini Marie‐Cécile Valéra Anne Gompel Céline Gerard Christel Péqueux Mélanie Mestdagt Isabelle Raymond‐Letron Claude Knauf François Ferriere Philippe Valet Pierre Gourdy Benita S Katzenellenbogen John A Katzenellenbogen Françoise Lenfant Geoffrey L Greene Jean‐Michel Foidart Jean‐François Arnal |
| author_sort | Anne Abot |
| collection | DOAJ |
| description | Abstract Estetrol (E4) is a natural estrogen with a long half‐life produced only by the human fetal liver during pregnancy. The crystal structures of the estrogen receptor α (ERα) ligand‐binding domain bound to 17β‐estradiol (E2) and E4 are very similar, as well as their capacity to activate the two activation functions AF‐1 and AF‐2 and to recruit the coactivator SRC3. In vivo administration of high doses of E4 stimulated uterine gene expression, epithelial proliferation, and prevented atheroma, three recognized nuclear ERα actions. However, E4 failed to promote endothelial NO synthase activation and acceleration of endothelial healing, two processes clearly dependent on membrane‐initiated steroid signaling (MISS). Furthermore, E4 antagonized E2 MISS‐dependent effects in endothelium but also in MCF‐7 breast cancer cell line. This profile of ERα activation by E4, uncoupling nuclear and membrane activation, characterizes E4 as a selective ER modulator which could have medical applications that should now be considered further. |
| first_indexed | 2024-03-07T16:44:52Z |
| format | Article |
| id | doaj.art-f81d485b302d454596333e69beb5f6bc |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T16:44:52Z |
| publishDate | 2014-10-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-f81d485b302d454596333e69beb5f6bc2024-03-03T07:05:15ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842014-10-016101328134610.15252/emmm.201404112The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activationAnne Abot0Coralie Fontaine1Mélissa Buscato2Romain Solinhac3Gilles Flouriot4Aurélie Fabre5Anne Drougard6Shyamala Rajan7Muriel Laine8Alain Milon9Isabelle Muller10Daniel Henrion11Marine Adlanmerini12Marie‐Cécile Valéra13Anne Gompel14Céline Gerard15Christel Péqueux16Mélanie Mestdagt17Isabelle Raymond‐Letron18Claude Knauf19François Ferriere20Philippe Valet21Pierre Gourdy22Benita S Katzenellenbogen23John A Katzenellenbogen24Françoise Lenfant25Geoffrey L Greene26Jean‐Michel Foidart27Jean‐François Arnal28INSERM U1048 Institut des Maladies Métaboliques et Cardiovasculaires Université de Toulouse – UPS Toulouse FranceINSERM U1048 Institut des Maladies Métaboliques et Cardiovasculaires Université de Toulouse – UPS Toulouse FranceINSERM U1048 Institut des Maladies Métaboliques et Cardiovasculaires Université de Toulouse – UPS Toulouse FranceINSERM U1048 Institut des Maladies Métaboliques et Cardiovasculaires Université de Toulouse – UPS Toulouse FranceInstitut de Recherche en Santé Environnement et Travail IRSET INSERM U1085 Team TREC Biosit Université de Rennes I Rennes FranceINSERM U1048 Institut des Maladies Métaboliques et Cardiovasculaires Université de Toulouse – UPS Toulouse FranceINSERM U1048 Institut des Maladies Métaboliques et Cardiovasculaires Université de Toulouse – UPS Toulouse FranceDepartment for Cancer Research University of Chicago Chicago IL USADepartment for Cancer Research University of Chicago Chicago IL USACNRS and Université de Toulouse IPBS Toulouse FranceCNRS and Université de Toulouse IPBS Toulouse FranceINSERM U1083 CNRS UMR 6214 Université d'Angers Angers FranceINSERM U1048 Institut des Maladies Métaboliques et Cardiovasculaires Université de Toulouse – UPS Toulouse FranceINSERM U1048 Institut des Maladies Métaboliques et Cardiovasculaires Université de Toulouse – UPS Toulouse FranceAPHP Unité de Gynécologie Endocrinienne Université Paris Descartes Paris FranceGroupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA‐cancer) Université de Liège Liège BelgiqueGroupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA‐cancer) Université de Liège Liège BelgiqueGroupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA‐cancer) Université de Liège Liège BelgiqueINP ENVT Université de Toulouse Toulouse FranceINSERM U1048 Institut des Maladies Métaboliques et Cardiovasculaires Université de Toulouse – UPS Toulouse FranceInstitut de Recherche en Santé Environnement et Travail IRSET INSERM U1085 Team TREC Biosit Université de Rennes I Rennes FranceINSERM U1048 Institut des Maladies Métaboliques et Cardiovasculaires Université de Toulouse – UPS Toulouse FranceINSERM U1048 Institut des Maladies Métaboliques et Cardiovasculaires Université de Toulouse – UPS Toulouse FranceDepartments of Molecular and Integrative Biology and Chemistry University of Illinois at Urbana‐Champaign Urbana IL USADepartments of Molecular and Integrative Biology and Chemistry University of Illinois at Urbana‐Champaign Urbana IL USAINSERM U1048 Institut des Maladies Métaboliques et Cardiovasculaires Université de Toulouse – UPS Toulouse FranceDepartment for Cancer Research University of Chicago Chicago IL USAGroupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA‐cancer) Université de Liège Liège BelgiqueINSERM U1048 Institut des Maladies Métaboliques et Cardiovasculaires Université de Toulouse – UPS Toulouse FranceAbstract Estetrol (E4) is a natural estrogen with a long half‐life produced only by the human fetal liver during pregnancy. The crystal structures of the estrogen receptor α (ERα) ligand‐binding domain bound to 17β‐estradiol (E2) and E4 are very similar, as well as their capacity to activate the two activation functions AF‐1 and AF‐2 and to recruit the coactivator SRC3. In vivo administration of high doses of E4 stimulated uterine gene expression, epithelial proliferation, and prevented atheroma, three recognized nuclear ERα actions. However, E4 failed to promote endothelial NO synthase activation and acceleration of endothelial healing, two processes clearly dependent on membrane‐initiated steroid signaling (MISS). Furthermore, E4 antagonized E2 MISS‐dependent effects in endothelium but also in MCF‐7 breast cancer cell line. This profile of ERα activation by E4, uncoupling nuclear and membrane activation, characterizes E4 as a selective ER modulator which could have medical applications that should now be considered further.https://doi.org/10.15252/emmm.201404112endotheliumestetrolestrogen receptoruterus |
| spellingShingle | Anne Abot Coralie Fontaine Mélissa Buscato Romain Solinhac Gilles Flouriot Aurélie Fabre Anne Drougard Shyamala Rajan Muriel Laine Alain Milon Isabelle Muller Daniel Henrion Marine Adlanmerini Marie‐Cécile Valéra Anne Gompel Céline Gerard Christel Péqueux Mélanie Mestdagt Isabelle Raymond‐Letron Claude Knauf François Ferriere Philippe Valet Pierre Gourdy Benita S Katzenellenbogen John A Katzenellenbogen Françoise Lenfant Geoffrey L Greene Jean‐Michel Foidart Jean‐François Arnal The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation EMBO Molecular Medicine endothelium estetrol estrogen receptor uterus |
| title | The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation |
| title_full | The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation |
| title_fullStr | The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation |
| title_full_unstemmed | The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation |
| title_short | The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation |
| title_sort | uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation uncoupling nuclear and membrane activation |
| topic | endothelium estetrol estrogen receptor uterus |
| url | https://doi.org/10.15252/emmm.201404112 |
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