المؤلفون: Adlanmerini, Marine, Solinhac, Romain, Abot, Anne, Fabre, Aurelie J, Raymond-Letron, Isabelle, Guihot, Anne-Laure, Boudou, Frédéric, Sautier, Lucile, Vessières, Emilie, Kim, Sung Hoon, Lière, Philippe, Fontaine, Coralie, Krust, Andrée, Chambon, Pierre, Katzenellenbogen, John, A., Gourdy, Pierre, Shaul, Philip, W., Henrion, Daniel, Arnal, Jean-François, Lenfant, Françoise

المساهمون: Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANEXPLO, Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées Auzeville (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry, University of Illinois at Urbana-Champaign Urbana (UIUC), University of Illinois System-University of Illinois System, Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, The work at I2MC-INSERM U1048 is supported by Institut National de la Santé et de la Recherche Médicale, Université et CHU de Toulouse, Faculté de Médecine Toulouse-Rangueil, Fondation pour la Recherche Médicale, Fondation de France, Fondation de l'Avenir, Conseil Régional Midi-Pyrénées, and AVIESAN-Astra-Zeneca. The work at INSERM U1083-Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 6214 is supported by INSERM, CNRS, Centre Hospitalier Universitaire and Université d'Angers, Fondation de France, Fondation de l'Avenir and Conseil Régional Pays de la Loire, Conseil Régional Midi-Pyrénées, and Fondation pour la Recherche Médicale. M.A. and A.A. were supported by grants from the Ministère de la Recherche and Groupe de Réflexion sur la Recherche Cardiovasculaire, respectively. This work was supported by National Institutes of Health Grants DK015556 and HL087564 (to J.A.K. and P.W.S., respectively)., ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010)

المصدر: ISSN: 0027-8424.

مصطلحات موضوعية: fertility, vascular effects nongenomic effects, genomic actions, MESH: Analysis of Variance, MESH: Animals, MESH: Image Processing, Computer-Assisted, MESH: Immunohistochemistry, MESH: Lipoylation, MESH: Mice, Transgenic, MESH: Microarray Analysis, MESH: Ovary, MESH: Point Mutation, MESH: Receptor Cross-Talk, MESH: Uterus, MESH: Blotting, Western, MESH: Cell Membrane, MESH: Cell Movement, MESH: Cell Nucleus, MESH: Computational Biology, MESH: Endothelial Cells, MESH: Estrogen Receptor alpha, MESH: Female

الوصف: International audience ; Estrogen receptor alpha (ERα) activation functions AF-1 and AF-2 classically mediate gene transcription in response to estradiol (E2). A fraction of ERα is targeted to plasma membrane and elicits membrane-initiated steroid signaling (MISS), but the physiological roles of MISS in vivo are poorly understood. We therefore generated a mouse with a point mutation of the palmitoylation site of ERα (C451A-ERα) to obtain membrane-specific loss of function of ERα. The abrogation of membrane localization of ERα in vivo was confirmed in primary hepatocytes, and it resulted in female infertility with abnormal ovaries lacking corpora lutea and increase in luteinizing hormone levels. In contrast, E2 action in the uterus was preserved in C451A-ERα mice and endometrial epithelial proliferation was similar to wild type. However, E2 vascular actions such as rapid dilatation, acceleration of endothelial repair, and endothelial NO synthase phosphorylation were abrogated in C451A-ERα mice. A complementary mutant mouse lacking the transactivation function AF-2 of ERα (ERα-AF2(0)) provided selective loss of function of nuclear ERα actions. In ERα-AF2(0), the acceleration of endothelial repair in response to estrogen-dendrimer conjugate, which is a membrane-selective ER ligand, was unaltered, demonstrating integrity of MISS actions. In genome-wide analysis of uterine gene expression, the vast majority of E2-dependent gene regulation was abrogated in ERα-AF2(0), whereas in C451A-ERα it was nearly fully preserved, indicating that membrane-to-nuclear receptor cross-talk in vivo is modest in the uterus. Thus, this work genetically segregated membrane versus nuclear actions of a steroid hormone receptor and demonstrated their in vivo tissue-specific roles.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/24371309; inserm-01015486; https://inserm.hal.science/inserm-01015486Test; PUBMED: 24371309; PUBMEDCENTRAL: PMC3896153

الإتاحة: https://doi.org/10.1073/pnas.1322057111Test
https://inserm.hal.science/inserm-01015486Test

المؤلفون: Adlanmerini, Marine, Solinhac, Romain, Abot, Anne, Fabre, Aurelie J, Raymond-Letron, Isabelle, Guihot, Anne-Laure, Boudou, Frédéric, Sautier, Lucile, Vessières, Emilie, Kim, Sung Hoon, Lière, Philippe, Fontaine, Coralie, Krust, Andrée, Chambon, Pierre, Katzenellenbogen, John, A., Gourdy, Pierre, Shaul, Philip, W., Henrion, Daniel, Arnal, Jean-François, Lenfant, Françoise

المساهمون: Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANEXPLO, Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées Auzeville (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry, University of Illinois at Urbana-Champaign Urbana (UIUC), University of Illinois System-University of Illinois System, Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, The work at I2MC-INSERM U1048 is supported by Institut National de la Santé et de la Recherche Médicale, Université et CHU de Toulouse, Faculté de Médecine Toulouse-Rangueil, Fondation pour la Recherche Médicale, Fondation de France, Fondation de l'Avenir, Conseil Régional Midi-Pyrénées, and AVIESAN-Astra-Zeneca. The work at INSERM U1083-Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 6214 is supported by INSERM, CNRS, Centre Hospitalier Universitaire and Université d'Angers, Fondation de France, Fondation de l'Avenir and Conseil Régional Pays de la Loire, Conseil Régional Midi-Pyrénées, and Fondation pour la Recherche Médicale. M.A. and A.A. were supported by grants from the Ministère de la Recherche and Groupe de Réflexion sur la Recherche Cardiovasculaire, respectively. This work was supported by National Institutes of Health Grants DK015556 and HL087564 (to J.A.K. and P.W.S., respectively)., ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010)

المصدر: ISSN: 0027-8424.

مصطلحات موضوعية: fertility, vascular effects nongenomic effects, genomic actions, MESH: Analysis of Variance, MESH: Animals, MESH: Image Processing, Computer-Assisted, MESH: Immunohistochemistry, MESH: Lipoylation, MESH: Mice, Transgenic, MESH: Microarray Analysis, MESH: Ovary, MESH: Point Mutation, MESH: Receptor Cross-Talk, MESH: Uterus, MESH: Blotting, Western, MESH: Cell Membrane, MESH: Cell Movement, MESH: Cell Nucleus, MESH: Computational Biology, MESH: Endothelial Cells, MESH: Estrogen Receptor alpha, MESH: Female

الوصف: International audience ; Estrogen receptor alpha (ERα) activation functions AF-1 and AF-2 classically mediate gene transcription in response to estradiol (E2). A fraction of ERα is targeted to plasma membrane and elicits membrane-initiated steroid signaling (MISS), but the physiological roles of MISS in vivo are poorly understood. We therefore generated a mouse with a point mutation of the palmitoylation site of ERα (C451A-ERα) to obtain membrane-specific loss of function of ERα. The abrogation of membrane localization of ERα in vivo was confirmed in primary hepatocytes, and it resulted in female infertility with abnormal ovaries lacking corpora lutea and increase in luteinizing hormone levels. In contrast, E2 action in the uterus was preserved in C451A-ERα mice and endometrial epithelial proliferation was similar to wild type. However, E2 vascular actions such as rapid dilatation, acceleration of endothelial repair, and endothelial NO synthase phosphorylation were abrogated in C451A-ERα mice. A complementary mutant mouse lacking the transactivation function AF-2 of ERα (ERα-AF2(0)) provided selective loss of function of nuclear ERα actions. In ERα-AF2(0), the acceleration of endothelial repair in response to estrogen-dendrimer conjugate, which is a membrane-selective ER ligand, was unaltered, demonstrating integrity of MISS actions. In genome-wide analysis of uterine gene expression, the vast majority of E2-dependent gene regulation was abrogated in ERα-AF2(0), whereas in C451A-ERα it was nearly fully preserved, indicating that membrane-to-nuclear receptor cross-talk in vivo is modest in the uterus. Thus, this work genetically segregated membrane versus nuclear actions of a steroid hormone receptor and demonstrated their in vivo tissue-specific roles.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/24371309; inserm-01015486; https://inserm.hal.science/inserm-01015486Test; PUBMED: 24371309; PUBMEDCENTRAL: PMC3896153

الإتاحة: https://doi.org/10.1073/pnas.1322057111Test
https://inserm.hal.science/inserm-01015486Test

المؤلفون: Adlanmerini, Marine, Solinhac, Romain, Abot, Anne, Fabre, Aurelie J, Raymond-Letron, Isabelle, Guihot, Anne-Laure, Boudou, Frédéric, Sautier, Lucile, Vessières, Emilie, Kim, Sung Hoon, Lière, Philippe, Fontaine, Coralie, Krust, Andrée, Chambon, Pierre, Katzenellenbogen, John, A., Gourdy, Pierre, Shaul, Philip, W., Henrion, Daniel, Arnal, Jean-François, Lenfant, Françoise

المساهمون: Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANEXPLO, Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées Auzeville (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry, University of Illinois at Urbana-Champaign Urbana (UIUC), University of Illinois System-University of Illinois System, Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, The work at I2MC-INSERM U1048 is supported by Institut National de la Santé et de la Recherche Médicale, Université et CHU de Toulouse, Faculté de Médecine Toulouse-Rangueil, Fondation pour la Recherche Médicale, Fondation de France, Fondation de l'Avenir, Conseil Régional Midi-Pyrénées, and AVIESAN-Astra-Zeneca. The work at INSERM U1083-Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 6214 is supported by INSERM, CNRS, Centre Hospitalier Universitaire and Université d'Angers, Fondation de France, Fondation de l'Avenir and Conseil Régional Pays de la Loire, Conseil Régional Midi-Pyrénées, and Fondation pour la Recherche Médicale. M.A. and A.A. were supported by grants from the Ministère de la Recherche and Groupe de Réflexion sur la Recherche Cardiovasculaire, respectively. This work was supported by National Institutes of Health Grants DK015556 and HL087564 (to J.A.K. and P.W.S., respectively)., ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010)

المصدر: ISSN: 0027-8424.

مصطلحات موضوعية: fertility, vascular effects nongenomic effects, genomic actions, MESH: Analysis of Variance, MESH: Animals, MESH: Image Processing, Computer-Assisted, MESH: Immunohistochemistry, MESH: Lipoylation, MESH: Mice, Transgenic, MESH: Microarray Analysis, MESH: Ovary, MESH: Point Mutation, MESH: Receptor Cross-Talk, MESH: Uterus, MESH: Blotting, Western, MESH: Cell Membrane, MESH: Cell Movement, MESH: Cell Nucleus, MESH: Computational Biology, MESH: Endothelial Cells, MESH: Estrogen Receptor alpha, MESH: Female

الوصف: International audience ; Estrogen receptor alpha (ERα) activation functions AF-1 and AF-2 classically mediate gene transcription in response to estradiol (E2). A fraction of ERα is targeted to plasma membrane and elicits membrane-initiated steroid signaling (MISS), but the physiological roles of MISS in vivo are poorly understood. We therefore generated a mouse with a point mutation of the palmitoylation site of ERα (C451A-ERα) to obtain membrane-specific loss of function of ERα. The abrogation of membrane localization of ERα in vivo was confirmed in primary hepatocytes, and it resulted in female infertility with abnormal ovaries lacking corpora lutea and increase in luteinizing hormone levels. In contrast, E2 action in the uterus was preserved in C451A-ERα mice and endometrial epithelial proliferation was similar to wild type. However, E2 vascular actions such as rapid dilatation, acceleration of endothelial repair, and endothelial NO synthase phosphorylation were abrogated in C451A-ERα mice. A complementary mutant mouse lacking the transactivation function AF-2 of ERα (ERα-AF2(0)) provided selective loss of function of nuclear ERα actions. In ERα-AF2(0), the acceleration of endothelial repair in response to estrogen-dendrimer conjugate, which is a membrane-selective ER ligand, was unaltered, demonstrating integrity of MISS actions. In genome-wide analysis of uterine gene expression, the vast majority of E2-dependent gene regulation was abrogated in ERα-AF2(0), whereas in C451A-ERα it was nearly fully preserved, indicating that membrane-to-nuclear receptor cross-talk in vivo is modest in the uterus. Thus, this work genetically segregated membrane versus nuclear actions of a steroid hormone receptor and demonstrated their in vivo tissue-specific roles.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/24371309; inserm-01015486; https://inserm.hal.science/inserm-01015486Test; PUBMED: 24371309; PUBMEDCENTRAL: PMC3896153

الإتاحة: https://doi.org/10.1073/pnas.1322057111Test
https://inserm.hal.science/inserm-01015486Test

المؤلفون: Adlanmerini, Marine, Solinhac, Romain, Abot, Anne, Fabre, Aurelie J, Raymond-Letron, Isabelle, Guihot, Anne-Laure, Boudou, Frédéric, Sautier, Lucile, Vessières, Emilie, Kim, Sung Hoon, Lière, Philippe, Fontaine, Coralie, Krust, Andrée, Chambon, Pierre, Katzenellenbogen, John, A., Gourdy, Pierre, Shaul, Philip, W., Henrion, Daniel, Arnal, Jean-François, Lenfant, Françoise

المساهمون: Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANEXPLO, Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées Auzeville (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry, University of Illinois at Urbana-Champaign Urbana (UIUC), University of Illinois System-University of Illinois System, Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, The work at I2MC-INSERM U1048 is supported by Institut National de la Santé et de la Recherche Médicale, Université et CHU de Toulouse, Faculté de Médecine Toulouse-Rangueil, Fondation pour la Recherche Médicale, Fondation de France, Fondation de l'Avenir, Conseil Régional Midi-Pyrénées, and AVIESAN-Astra-Zeneca. The work at INSERM U1083-Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 6214 is supported by INSERM, CNRS, Centre Hospitalier Universitaire and Université d'Angers, Fondation de France, Fondation de l'Avenir and Conseil Régional Pays de la Loire, Conseil Régional Midi-Pyrénées, and Fondation pour la Recherche Médicale. M.A. and A.A. were supported by grants from the Ministère de la Recherche and Groupe de Réflexion sur la Recherche Cardiovasculaire, respectively. This work was supported by National Institutes of Health Grants DK015556 and HL087564 (to J.A.K. and P.W.S., respectively)., ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010)

المصدر: ISSN: 0027-8424.

مصطلحات موضوعية: fertility, vascular effects nongenomic effects, genomic actions, MESH: Analysis of Variance, MESH: Animals, MESH: Image Processing, Computer-Assisted, MESH: Immunohistochemistry, MESH: Lipoylation, MESH: Mice, Transgenic, MESH: Microarray Analysis, MESH: Ovary, MESH: Point Mutation, MESH: Receptor Cross-Talk, MESH: Uterus, MESH: Blotting, Western, MESH: Cell Membrane, MESH: Cell Movement, MESH: Cell Nucleus, MESH: Computational Biology, MESH: Endothelial Cells, MESH: Estrogen Receptor alpha, MESH: Female

الوصف: International audience ; Estrogen receptor alpha (ERα) activation functions AF-1 and AF-2 classically mediate gene transcription in response to estradiol (E2). A fraction of ERα is targeted to plasma membrane and elicits membrane-initiated steroid signaling (MISS), but the physiological roles of MISS in vivo are poorly understood. We therefore generated a mouse with a point mutation of the palmitoylation site of ERα (C451A-ERα) to obtain membrane-specific loss of function of ERα. The abrogation of membrane localization of ERα in vivo was confirmed in primary hepatocytes, and it resulted in female infertility with abnormal ovaries lacking corpora lutea and increase in luteinizing hormone levels. In contrast, E2 action in the uterus was preserved in C451A-ERα mice and endometrial epithelial proliferation was similar to wild type. However, E2 vascular actions such as rapid dilatation, acceleration of endothelial repair, and endothelial NO synthase phosphorylation were abrogated in C451A-ERα mice. A complementary mutant mouse lacking the transactivation function AF-2 of ERα (ERα-AF2(0)) provided selective loss of function of nuclear ERα actions. In ERα-AF2(0), the acceleration of endothelial repair in response to estrogen-dendrimer conjugate, which is a membrane-selective ER ligand, was unaltered, demonstrating integrity of MISS actions. In genome-wide analysis of uterine gene expression, the vast majority of E2-dependent gene regulation was abrogated in ERα-AF2(0), whereas in C451A-ERα it was nearly fully preserved, indicating that membrane-to-nuclear receptor cross-talk in vivo is modest in the uterus. Thus, this work genetically segregated membrane versus nuclear actions of a steroid hormone receptor and demonstrated their in vivo tissue-specific roles.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/24371309; inserm-01015486; https://inserm.hal.science/inserm-01015486Test; PUBMED: 24371309; PUBMEDCENTRAL: PMC3896153

الإتاحة: https://doi.org/10.1073/pnas.1322057111Test
https://inserm.hal.science/inserm-01015486Test

المؤلفون: Adlanmerini, Marine, Solinhac, Romain, Abot, Anne, Fabre, Aurelie J, Raymond-Letron, Isabelle, Guihot, Anne-Laure, Boudou, Frédéric, Sautier, Lucile, Vessières, Emilie, Kim, Sung Hoon, Lière, Philippe, Fontaine, Coralie, Krust, Andrée, Chambon, Pierre, Katzenellenbogen, John, A., Gourdy, Pierre, Shaul, Philip, W., Henrion, Daniel, Arnal, Jean-François, Lenfant, Françoise

المساهمون: Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANEXPLO, Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées Auzeville (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry, University of Illinois at Urbana-Champaign Urbana (UIUC), University of Illinois System-University of Illinois System, Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, The work at I2MC-INSERM U1048 is supported by Institut National de la Santé et de la Recherche Médicale, Université et CHU de Toulouse, Faculté de Médecine Toulouse-Rangueil, Fondation pour la Recherche Médicale, Fondation de France, Fondation de l'Avenir, Conseil Régional Midi-Pyrénées, and AVIESAN-Astra-Zeneca. The work at INSERM U1083-Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 6214 is supported by INSERM, CNRS, Centre Hospitalier Universitaire and Université d'Angers, Fondation de France, Fondation de l'Avenir and Conseil Régional Pays de la Loire, Conseil Régional Midi-Pyrénées, and Fondation pour la Recherche Médicale. M.A. and A.A. were supported by grants from the Ministère de la Recherche and Groupe de Réflexion sur la Recherche Cardiovasculaire, respectively. This work was supported by National Institutes of Health Grants DK015556 and HL087564 (to J.A.K. and P.W.S., respectively)., ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010)

المصدر: ISSN: 0027-8424.

مصطلحات موضوعية: fertility, vascular effects nongenomic effects, genomic actions, MESH: Analysis of Variance, MESH: Animals, MESH: Image Processing, Computer-Assisted, MESH: Immunohistochemistry, MESH: Lipoylation, MESH: Mice, Transgenic, MESH: Microarray Analysis, MESH: Ovary, MESH: Point Mutation, MESH: Receptor Cross-Talk, MESH: Uterus, MESH: Blotting, Western, MESH: Cell Membrane, MESH: Cell Movement, MESH: Cell Nucleus, MESH: Computational Biology, MESH: Endothelial Cells, MESH: Estrogen Receptor alpha, MESH: Female

الوصف: International audience ; Estrogen receptor alpha (ERα) activation functions AF-1 and AF-2 classically mediate gene transcription in response to estradiol (E2). A fraction of ERα is targeted to plasma membrane and elicits membrane-initiated steroid signaling (MISS), but the physiological roles of MISS in vivo are poorly understood. We therefore generated a mouse with a point mutation of the palmitoylation site of ERα (C451A-ERα) to obtain membrane-specific loss of function of ERα. The abrogation of membrane localization of ERα in vivo was confirmed in primary hepatocytes, and it resulted in female infertility with abnormal ovaries lacking corpora lutea and increase in luteinizing hormone levels. In contrast, E2 action in the uterus was preserved in C451A-ERα mice and endometrial epithelial proliferation was similar to wild type. However, E2 vascular actions such as rapid dilatation, acceleration of endothelial repair, and endothelial NO synthase phosphorylation were abrogated in C451A-ERα mice. A complementary mutant mouse lacking the transactivation function AF-2 of ERα (ERα-AF2(0)) provided selective loss of function of nuclear ERα actions. In ERα-AF2(0), the acceleration of endothelial repair in response to estrogen-dendrimer conjugate, which is a membrane-selective ER ligand, was unaltered, demonstrating integrity of MISS actions. In genome-wide analysis of uterine gene expression, the vast majority of E2-dependent gene regulation was abrogated in ERα-AF2(0), whereas in C451A-ERα it was nearly fully preserved, indicating that membrane-to-nuclear receptor cross-talk in vivo is modest in the uterus. Thus, this work genetically segregated membrane versus nuclear actions of a steroid hormone receptor and demonstrated their in vivo tissue-specific roles.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/24371309; inserm-01015486; https://inserm.hal.science/inserm-01015486Test; PUBMED: 24371309; PUBMEDCENTRAL: PMC3896153

الإتاحة: https://doi.org/10.1073/pnas.1322057111Test
https://inserm.hal.science/inserm-01015486Test

المؤلفون: Adlanmerini, Marine, Solinhac, Romain, Abot, Anne, Fabre, Aurelie J, Raymond-Letron, Isabelle, Guihot, Anne-Laure, Boudou, Frédéric, Sautier, Lucile, Vessières, Emilie, Kim, Sung Hoon, Lière, Philippe, Fontaine, Coralie, Krust, Andrée, Chambon, Pierre, Katzenellenbogen, John, A., Gourdy, Pierre, Shaul, Philip, W., Henrion, Daniel, Arnal, Jean-François, Lenfant, Françoise

المساهمون: Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANEXPLO, Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées Auzeville (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry, University of Illinois at Urbana-Champaign Urbana (UIUC), University of Illinois System-University of Illinois System, Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, The work at I2MC-INSERM U1048 is supported by Institut National de la Santé et de la Recherche Médicale, Université et CHU de Toulouse, Faculté de Médecine Toulouse-Rangueil, Fondation pour la Recherche Médicale, Fondation de France, Fondation de l'Avenir, Conseil Régional Midi-Pyrénées, and AVIESAN-Astra-Zeneca. The work at INSERM U1083-Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 6214 is supported by INSERM, CNRS, Centre Hospitalier Universitaire and Université d'Angers, Fondation de France, Fondation de l'Avenir and Conseil Régional Pays de la Loire, Conseil Régional Midi-Pyrénées, and Fondation pour la Recherche Médicale. M.A. and A.A. were supported by grants from the Ministère de la Recherche and Groupe de Réflexion sur la Recherche Cardiovasculaire, respectively. This work was supported by National Institutes of Health Grants DK015556 and HL087564 (to J.A.K. and P.W.S., respectively)., ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010)

المصدر: ISSN: 0027-8424.

مصطلحات موضوعية: fertility, vascular effects nongenomic effects, genomic actions, MESH: Analysis of Variance, MESH: Animals, MESH: Image Processing, Computer-Assisted, MESH: Immunohistochemistry, MESH: Lipoylation, MESH: Mice, Transgenic, MESH: Microarray Analysis, MESH: Ovary, MESH: Point Mutation, MESH: Receptor Cross-Talk, MESH: Uterus, MESH: Blotting, Western, MESH: Cell Membrane, MESH: Cell Movement, MESH: Cell Nucleus, MESH: Computational Biology, MESH: Endothelial Cells, MESH: Estrogen Receptor alpha, MESH: Female

الوصف: International audience ; Estrogen receptor alpha (ERα) activation functions AF-1 and AF-2 classically mediate gene transcription in response to estradiol (E2). A fraction of ERα is targeted to plasma membrane and elicits membrane-initiated steroid signaling (MISS), but the physiological roles of MISS in vivo are poorly understood. We therefore generated a mouse with a point mutation of the palmitoylation site of ERα (C451A-ERα) to obtain membrane-specific loss of function of ERα. The abrogation of membrane localization of ERα in vivo was confirmed in primary hepatocytes, and it resulted in female infertility with abnormal ovaries lacking corpora lutea and increase in luteinizing hormone levels. In contrast, E2 action in the uterus was preserved in C451A-ERα mice and endometrial epithelial proliferation was similar to wild type. However, E2 vascular actions such as rapid dilatation, acceleration of endothelial repair, and endothelial NO synthase phosphorylation were abrogated in C451A-ERα mice. A complementary mutant mouse lacking the transactivation function AF-2 of ERα (ERα-AF2(0)) provided selective loss of function of nuclear ERα actions. In ERα-AF2(0), the acceleration of endothelial repair in response to estrogen-dendrimer conjugate, which is a membrane-selective ER ligand, was unaltered, demonstrating integrity of MISS actions. In genome-wide analysis of uterine gene expression, the vast majority of E2-dependent gene regulation was abrogated in ERα-AF2(0), whereas in C451A-ERα it was nearly fully preserved, indicating that membrane-to-nuclear receptor cross-talk in vivo is modest in the uterus. Thus, this work genetically segregated membrane versus nuclear actions of a steroid hormone receptor and demonstrated their in vivo tissue-specific roles.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/24371309; inserm-01015486; https://inserm.hal.science/inserm-01015486Test; PUBMED: 24371309; PUBMEDCENTRAL: PMC3896153

الإتاحة: https://doi.org/10.1073/pnas.1322057111Test
https://inserm.hal.science/inserm-01015486Test

المؤلفون: Adlanmerini, Marine, Solinhac, Romain, Abot, Anne, Fabre, Aurelie J, Raymond-Letron, Isabelle, Guihot, Anne-Laure, Boudou, Frédéric, Sautier, Lucile, Vessières, Emilie, Kim, Sung Hoon, Lière, Philippe, Fontaine, Coralie, Krust, Andrée, Chambon, Pierre, Katzenellenbogen, John, Gourdy, Pierre, Shaul, Philip, Henrion, Daniel, Arnal, Jean-François, Lenfant, Françoise

المساهمون: Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, ANEXPLO, Génopole Toulouse Midi-Pyrénées Auzeville (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry, University of Illinois at Urbana-Champaign Urbana, University of Illinois System-University of Illinois System, Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, The work at I2MC-INSERM U1048 is supported by Institut National de la Santé et de la Recherche Médicale, Université et CHU de Toulouse, Faculté de Médecine Toulouse-Rangueil, Fondation pour la Recherche Médicale, Fondation de France, Fondation de l'Avenir, Conseil Régional Midi-Pyrénées, and AVIESAN-Astra-Zeneca. The work at INSERM U1083-Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 6214 is supported by INSERM, CNRS, Centre Hospitalier Universitaire and Université d'Angers, Fondation de France, Fondation de l'Avenir and Conseil Régional Pays de la Loire, Conseil Régional Midi-Pyrénées, and Fondation pour la Recherche Médicale. M.A. and A.A. were supported by grants from the Ministère de la Recherche and Groupe de Réflexion sur la Recherche Cardiovasculaire, respectively. This work was supported by National Institutes of Health Grants DK015556 and HL087564 (to J.A.K. and P.W.S., respectively).

المصدر: ISSN: 0027-8424.

مصطلحات موضوعية: fertility, vascular effects nongenomic effects, genomic actions, MESH: Analysis of Variance, MESH: Animals, MESH: Image Processing, Computer-Assisted, MESH: Immunohistochemistry, MESH: Lipoylation, MESH: Mice, Transgenic, MESH: Microarray Analysis, MESH: Ovary, MESH: Point Mutation, MESH: Receptor Cross-Talk, MESH: Uterus, MESH: Blotting, Western, MESH: Cell Membrane, MESH: Cell Movement, MESH: Cell Nucleus, MESH: Computational Biology, MESH: Endothelial Cells, MESH: Estrogen Receptor alpha, MESH: Female

الوصف: International audience ; Estrogen receptor alpha (ERα) activation functions AF-1 and AF-2 classically mediate gene transcription in response to estradiol (E2). A fraction of ERα is targeted to plasma membrane and elicits membrane-initiated steroid signaling (MISS), but the physiological roles of MISS in vivo are poorly understood. We therefore generated a mouse with a point mutation of the palmitoylation site of ERα (C451A-ERα) to obtain membrane-specific loss of function of ERα. The abrogation of membrane localization of ERα in vivo was confirmed in primary hepatocytes, and it resulted in female infertility with abnormal ovaries lacking corpora lutea and increase in luteinizing hormone levels. In contrast, E2 action in the uterus was preserved in C451A-ERα mice and endometrial epithelial proliferation was similar to wild type. However, E2 vascular actions such as rapid dilatation, acceleration of endothelial repair, and endothelial NO synthase phosphorylation were abrogated in C451A-ERα mice. A complementary mutant mouse lacking the transactivation function AF-2 of ERα (ERα-AF2(0)) provided selective loss of function of nuclear ERα actions. In ERα-AF2(0), the acceleration of endothelial repair in response to estrogen-dendrimer conjugate, which is a membrane-selective ER ligand, was unaltered, demonstrating integrity of MISS actions. In genome-wide analysis of uterine gene expression, the vast majority of E2-dependent gene regulation was abrogated in ERα-AF2(0), whereas in C451A-ERα it was nearly fully preserved, indicating that membrane-to-nuclear receptor cross-talk in vivo is modest in the uterus. Thus, this work genetically segregated membrane versus nuclear actions of a steroid hormone receptor and demonstrated their in vivo tissue-specific roles.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/24371309; inserm-01015486; https://www.hal.inserm.fr/inserm-01015486Test; PUBMED: 24371309

الإتاحة: https://doi.org/10.1073/pnas.1322057111Test
https://www.hal.inserm.fr/inserm-01015486Test

المؤلفون: Adlanmerini, Marine, Solinhac, Romain, Abot, Anne, Fabre, Aurelie J, Raymond-Letron, Isabelle, Guihot, Anne-Laure, Boudou, Frédéric, Sautier, Lucile, Vessières, Emilie, Kim, Sung Hoon, Lière, Philippe, Fontaine, Coralie, Krust, Andrée, Chambon, Pierre, Katzenellenbogen, John, A., Gourdy, Pierre, Shaul, Philip, W., Henrion, Daniel, Arnal, Jean-François, Lenfant, Françoise

المساهمون: Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANEXPLO, Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées Auzeville (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry, University of Illinois at Urbana-Champaign Urbana (UIUC), University of Illinois System-University of Illinois System, Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, The work at I2MC-INSERM U1048 is supported by Institut National de la Santé et de la Recherche Médicale, Université et CHU de Toulouse, Faculté de Médecine Toulouse-Rangueil, Fondation pour la Recherche Médicale, Fondation de France, Fondation de l'Avenir, Conseil Régional Midi-Pyrénées, and AVIESAN-Astra-Zeneca. The work at INSERM U1083-Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 6214 is supported by INSERM, CNRS, Centre Hospitalier Universitaire and Université d'Angers, Fondation de France, Fondation de l'Avenir and Conseil Régional Pays de la Loire, Conseil Régional Midi-Pyrénées, and Fondation pour la Recherche Médicale. M.A. and A.A. were supported by grants from the Ministère de la Recherche and Groupe de Réflexion sur la Recherche Cardiovasculaire, respectively. This work was supported by National Institutes of Health Grants DK015556 and HL087564 (to J.A.K. and P.W.S., respectively)., ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010)

المصدر: ISSN: 0027-8424.

مصطلحات موضوعية: fertility, vascular effects nongenomic effects, genomic actions, MESH: Analysis of Variance, MESH: Animals, MESH: Image Processing, Computer-Assisted, MESH: Immunohistochemistry, MESH: Lipoylation, MESH: Mice, Transgenic, MESH: Microarray Analysis, MESH: Ovary, MESH: Point Mutation, MESH: Receptor Cross-Talk, MESH: Uterus, MESH: Blotting, Western, MESH: Cell Membrane, MESH: Cell Movement, MESH: Cell Nucleus, MESH: Computational Biology, MESH: Endothelial Cells, MESH: Estrogen Receptor alpha, MESH: Female

الوصف: International audience ; Estrogen receptor alpha (ERα) activation functions AF-1 and AF-2 classically mediate gene transcription in response to estradiol (E2). A fraction of ERα is targeted to plasma membrane and elicits membrane-initiated steroid signaling (MISS), but the physiological roles of MISS in vivo are poorly understood. We therefore generated a mouse with a point mutation of the palmitoylation site of ERα (C451A-ERα) to obtain membrane-specific loss of function of ERα. The abrogation of membrane localization of ERα in vivo was confirmed in primary hepatocytes, and it resulted in female infertility with abnormal ovaries lacking corpora lutea and increase in luteinizing hormone levels. In contrast, E2 action in the uterus was preserved in C451A-ERα mice and endometrial epithelial proliferation was similar to wild type. However, E2 vascular actions such as rapid dilatation, acceleration of endothelial repair, and endothelial NO synthase phosphorylation were abrogated in C451A-ERα mice. A complementary mutant mouse lacking the transactivation function AF-2 of ERα (ERα-AF2(0)) provided selective loss of function of nuclear ERα actions. In ERα-AF2(0), the acceleration of endothelial repair in response to estrogen-dendrimer conjugate, which is a membrane-selective ER ligand, was unaltered, demonstrating integrity of MISS actions. In genome-wide analysis of uterine gene expression, the vast majority of E2-dependent gene regulation was abrogated in ERα-AF2(0), whereas in C451A-ERα it was nearly fully preserved, indicating that membrane-to-nuclear receptor cross-talk in vivo is modest in the uterus. Thus, this work genetically segregated membrane versus nuclear actions of a steroid hormone receptor and demonstrated their in vivo tissue-specific roles.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/24371309; inserm-01015486; https://inserm.hal.science/inserm-01015486Test; PUBMED: 24371309; PUBMEDCENTRAL: PMC3896153

الإتاحة: https://doi.org/10.1073/pnas.1322057111Test
https://inserm.hal.science/inserm-01015486Test