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Jean-françois Arnal - One of the best experts on this subject based on the ideXlab platform.
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membrane and nuclear Estrogen Receptor Alpha actions from tissue specificity to medical implications
Physiological Reviews, 2017Co-Authors: Francoise Lenfant, Jean-françois Arnal, Raphael Metivier, Gilles FlouriotAbstract:Estrogen Receptor Alpha (ERα) has been recognized now for several decades as playing a key role in reproduction and exerting functions in numerous nonreproductive tissues. In this review, we attemp...
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membrane and nuclear Estrogen Receptor Alpha actions from tissue specificity to medical implications
Physical Review, 2017Co-Authors: Francoise Lenfant, Jean-françois Arnal, Raphael Metivier, Gilles FlouriotAbstract:Estrogen Receptor Alpha (ERα) has been recognized now for several decades as playing a key role in reproduction and exerting functions in numerous nonreproductive tissues. In this review, we attempt to summarize the in vitro studies that are the basis of our current understanding of the mechanisms of action of ERα as a nuclear Receptor and the key roles played by its two activation functions (AFs) in its transcriptional activities. We then depict the consequences of the selective inactivation of these AFs in mouse models, focusing on the prominent roles played by ERα in the reproductive tract and in the vascular system. Evidence has accumulated over the two last decades that ERα is also associated with the plasma membrane and activates non-nuclear signaling from this site. These rapid/nongenomic/membrane-initiated steroid signals (MISS) have been characterized in a variety of cell lines, and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS and the generation of mice expressing an ERα protein impeded for membrane localization have begun to unravel the physiological role of MISS in vivo. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators based on the integration of the physiological and pathophysiological roles of MISS actions of Estrogens.
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nuclear and membrane actions of Estrogen Receptor Alpha contribution to the regulation of energy and glucose homeostasis
Advances in Experimental Medicine and Biology, 2017Co-Authors: Maeva Guillaume, Francoise Lenfant, Jean-françois Arnal, Alexandra Montagner, Coralie Fontaine, Pierre GourdyAbstract:Estrogen Receptor Alpha (ERα) has been demonstrated to play a key role in reproduction but also to exert numerous functions in nonreproductive tissues. Accordingly, ERα is now recognized as a key regulator of energy homeostasis and glucose metabolism and mediates the protective effects of Estrogens against obesity and type 2 diabetes. This chapter attempts to summarize our current understanding of the mechanisms of ERα activation and their involvement in the modulation of energy balance and glucose metabolism. We first focus on the experimental studies that constitute the basis of the understanding of ERα as a nuclear Receptor and more specifically on the key roles played by its two activation functions (AFs). We depict the consequences of the selective inactivation of these AFs in mouse models, which further underline the prominent role of nuclear ERα in the prevention of obesity and diabetes, as on the reproductive tract and the vascular system. Besides these nuclear actions, a fraction of ERα is associated with the plasma membrane and activates nonnuclear signaling from this site. Such rapid effects, called membrane-initiated steroid signals (MISS), have been characterized in a variety of cell lines and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS as well as the generation of mice expressing an ERα protein impeded for membrane localization has just begun to unravel the physiological role of MISS in vivo and their contribution to ERα-mediated metabolic protection. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators.
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0343 : Importance of the membrane Estrogen Receptor Alpha (ER) in the vascular response to shear stress in mice
Archives of Cardiovascular Diseases Supplements, 2016Co-Authors: Julie Favre, Francoise Lenfant, Jean-françois Arnal, Emilie Vessière, Anne-laure Guihot, Linda Grimaud, Laurent Loufrani, Daniel HenrionAbstract:Resistance arteries are sensitive to mechanical forces exerted on the vessel wall. While endothelial shear stress triggers flow-mediated dilation (FMD), chronic increase in shear forces drives expansive arterial remodeling. We showed previously that endothelial Estrogen Receptor Alpha (ER‹) controlled this adaptive remodeling. We aimed to evaluate ER‹contribution in acute response to flow, by using various genetic models of ER‹deficiency in male mice, reducing Estrogen hormonal influence. FMD was evaluated following step increase in flow applied to pressurized mesenteric arteries (arteriography). Arteries were isolated from wild-type (WT), (i) ER‹KO, or mice invalidated for (ii) the ligand-dependent transactivation function AF2 of ERa (AF2°) and (iii) the plasma membrane-located ER‹(mutated for the palmitoylation site C451A). In mice deficient in ER‹, FMD was attenuated (dilation 50μl/min WT: 59+/–4% vs. ER‹KO: 41+/–4% p The author hereby declares no conflict of interest
Francoise Lenfant - One of the best experts on this subject based on the ideXlab platform.
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membrane and nuclear Estrogen Receptor Alpha actions from tissue specificity to medical implications
Physiological Reviews, 2017Co-Authors: Francoise Lenfant, Jean-françois Arnal, Raphael Metivier, Gilles FlouriotAbstract:Estrogen Receptor Alpha (ERα) has been recognized now for several decades as playing a key role in reproduction and exerting functions in numerous nonreproductive tissues. In this review, we attemp...
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membrane and nuclear Estrogen Receptor Alpha actions from tissue specificity to medical implications
Physical Review, 2017Co-Authors: Francoise Lenfant, Jean-françois Arnal, Raphael Metivier, Gilles FlouriotAbstract:Estrogen Receptor Alpha (ERα) has been recognized now for several decades as playing a key role in reproduction and exerting functions in numerous nonreproductive tissues. In this review, we attempt to summarize the in vitro studies that are the basis of our current understanding of the mechanisms of action of ERα as a nuclear Receptor and the key roles played by its two activation functions (AFs) in its transcriptional activities. We then depict the consequences of the selective inactivation of these AFs in mouse models, focusing on the prominent roles played by ERα in the reproductive tract and in the vascular system. Evidence has accumulated over the two last decades that ERα is also associated with the plasma membrane and activates non-nuclear signaling from this site. These rapid/nongenomic/membrane-initiated steroid signals (MISS) have been characterized in a variety of cell lines, and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS and the generation of mice expressing an ERα protein impeded for membrane localization have begun to unravel the physiological role of MISS in vivo. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators based on the integration of the physiological and pathophysiological roles of MISS actions of Estrogens.
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nuclear and membrane actions of Estrogen Receptor Alpha contribution to the regulation of energy and glucose homeostasis
Advances in Experimental Medicine and Biology, 2017Co-Authors: Maeva Guillaume, Francoise Lenfant, Jean-françois Arnal, Alexandra Montagner, Coralie Fontaine, Pierre GourdyAbstract:Estrogen Receptor Alpha (ERα) has been demonstrated to play a key role in reproduction but also to exert numerous functions in nonreproductive tissues. Accordingly, ERα is now recognized as a key regulator of energy homeostasis and glucose metabolism and mediates the protective effects of Estrogens against obesity and type 2 diabetes. This chapter attempts to summarize our current understanding of the mechanisms of ERα activation and their involvement in the modulation of energy balance and glucose metabolism. We first focus on the experimental studies that constitute the basis of the understanding of ERα as a nuclear Receptor and more specifically on the key roles played by its two activation functions (AFs). We depict the consequences of the selective inactivation of these AFs in mouse models, which further underline the prominent role of nuclear ERα in the prevention of obesity and diabetes, as on the reproductive tract and the vascular system. Besides these nuclear actions, a fraction of ERα is associated with the plasma membrane and activates nonnuclear signaling from this site. Such rapid effects, called membrane-initiated steroid signals (MISS), have been characterized in a variety of cell lines and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS as well as the generation of mice expressing an ERα protein impeded for membrane localization has just begun to unravel the physiological role of MISS in vivo and their contribution to ERα-mediated metabolic protection. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators.
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0343 : Importance of the membrane Estrogen Receptor Alpha (ER) in the vascular response to shear stress in mice
Archives of Cardiovascular Diseases Supplements, 2016Co-Authors: Julie Favre, Francoise Lenfant, Jean-françois Arnal, Emilie Vessière, Anne-laure Guihot, Linda Grimaud, Laurent Loufrani, Daniel HenrionAbstract:Resistance arteries are sensitive to mechanical forces exerted on the vessel wall. While endothelial shear stress triggers flow-mediated dilation (FMD), chronic increase in shear forces drives expansive arterial remodeling. We showed previously that endothelial Estrogen Receptor Alpha (ER‹) controlled this adaptive remodeling. We aimed to evaluate ER‹contribution in acute response to flow, by using various genetic models of ER‹deficiency in male mice, reducing Estrogen hormonal influence. FMD was evaluated following step increase in flow applied to pressurized mesenteric arteries (arteriography). Arteries were isolated from wild-type (WT), (i) ER‹KO, or mice invalidated for (ii) the ligand-dependent transactivation function AF2 of ERa (AF2°) and (iii) the plasma membrane-located ER‹(mutated for the palmitoylation site C451A). In mice deficient in ER‹, FMD was attenuated (dilation 50μl/min WT: 59+/–4% vs. ER‹KO: 41+/–4% p The author hereby declares no conflict of interest
Sunil Wadhwa - One of the best experts on this subject based on the ideXlab platform.
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Estrogen promotes mandibular condylar fibrocartilage chondrogenesis and inhibits degeneration via Estrogen Receptor Alpha in female mice
Scientific Reports, 2018Co-Authors: Jennifer L Robinson, Paola Soria, Mark Ziggy Vrana, Jeffrey M Luchetti, J Chen, Sunil WadhwaAbstract:Temporomandibular joint degenerative disease (TMJ-DD) is a chronic form of TMJ disorder that specifically afflicts people over the age of 40 and targets women at a higher rate than men. Prevalence of TMJ-DD in this population suggests that Estrogen loss plays a role in the disease pathogenesis. Thus, the goal of the present study was to determine the role of Estrogen on chondrogenesis and homeostasis via Estrogen Receptor Alpha (ERα) during growth and maturity of the joint. Young and mature WT and ERαKO female mice were subjected to ovariectomy procedures and then given placebo or estradiol treatment. The effect of Estrogen via ERα on fibrocartilage morphology, matrix production, and protease activity was assessed. In the young mice, Estrogen via ERα promoted mandibular condylar fibrocartilage chondrogenesis partly by inhibiting the canonical Wnt signaling pathway through upregulation of sclerostin (Sost). In the mature mice, protease activity was partly inhibited with Estrogen treatment via the upregulation and activity of protease inhibitor 15 (Pi15) and Alpha-2-macroglobulin (A2m). The results from this work provide a mechanistic understanding of estradiol on TMJ growth and homeostasis and can be utilized for development of therapeutic targets to promote regeneration and inhibit degeneration of the mandibular condylar fibrocartilage.
Christopher G Maher - One of the best experts on this subject based on the ideXlab platform.
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abstract 2547 discovery and characterization of late stage breast cancer Estrogen Receptor Alpha 1 bound long non coding rnas
Cancer Research, 2017Co-Authors: Jessica Silvafisher, Abdallah M Eteleeb, Torsten O Nielsen, Charles M Perou, Jorge S Reisfilho, M J Ellis, Elaine R Mardis, Christopher G MaherAbstract:Breast cancer (BC) is the second most common newly diagnosed cancer and the second leading cause of cancer death among women in the United States. Despite the proven benefits of adjuvant endocrine therapy in women with hormone Receptor positive BC, relapses still occur even after initial treatment with endocrine therapy for 5 years, referred to as late-stage relapse. Long non-coding RNAs (lncRNAs) have been shown to be dysregulated in breast cancer. Recent studies have also shown lncRNAs to function by interfacing with corresponding RNA binding proteins to play critical regulatory roles of diverse cellular processes. Therefore, we hypothesize that lncRNAs may interact with ER to regulate genes promoting late-stage relapse. To address this, we aimed to identify lncRNAs bound to the Estrogen Receptor Alpha 1 protein (ESR1) that promote late-stage relapse breast cancer. We first used transcriptome sequencing to identify altered expression levels of lncRNAs between 72 primary tumors and 24 late-stage relapse breast cancer patients. We detected 1192 altered lncRNAs when comparing the metastatic to the primary samples (FDR Citation Format: Jessica Monique Silva-Fisher, Abdallah M. Eteleeb, Torsten Nielsen, Charles M. Perou, Jorge S. Reis-Filho, Mathew J. Ellis, Elaine R. Mardis, Christopher A. Maher. Discovery and characterization of late-stage breast cancer Estrogen Receptor Alpha 1 bound long non-coding RNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2547. doi:10.1158/1538-7445.AM2017-2547
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abstract 993 identification of Estrogen Receptor Alpha 1 bound lncrnas in aggressive breast cancer
Cancer Research, 2016Co-Authors: Jessica Silvafisher, Abdallah M Eteleeb, Torsten O Nielsen, Charles M Perou, Jorge S Reisfilho, M J Ellis, Elaine R Mardis, Christopher G MaherAbstract:Breast cancer (BC) is the second most common newly diagnosed cancer and the second leading cause of cancer death among women in the United States. Around 70% of diagnosed BCs are Estrogen Receptor positive (ER+). Despite the proven benefits of adjuvant endocrine therapy in women with hormone Receptor positive breast cancer, relapses still occur even after initial treatment with endocrine therapy for 5 years, referred to as late stage relapse. While existing studies have focused on the role of protein-coding genes, long non-coding RNAs (lncRNAs) are an emerging and under-characterized class of transcripts that have been shown to be dysregulated in breast cancer. Recently, lncRNAs have been shown to function by interfacing with corresponding RNA binding proteins to play critical regulatory roles in chromatin remodeling and diverse cellular processes by acting as decoys, guides, and scaffolds. As Estrogen Receptor expression is controlled mostly by epigenetic and post-transcriptional mechanisms, and very rarely at the genomic level, we hypothesize that lncRNAs may interact with ER to promote aggressive disease. To address this, we aimed to identify lncRNAs bound to the Estrogen Receptor Alpha 1 (ESR1) that promote late stage breast cancer. To accomplish this, we first used transcriptome sequencing to identify altered expression levels of lncRNAs between primary tumors and late-stage relapse breast cancer patients. We detected 2086 altered lncRNAs when comparing the metastatic to the primary samples with an FDR Citation Format: Jessica M. Silva-Fisher, Abdallah M. Eteleeb, Torsten O. Nielsen, Charles M. Perou, Jorge S. Reis-Filho, Mathew J. Ellis, Elaine R. Mardis, Christopher A. Maher. Identification of Estrogen Receptor Alpha 1 bound lncRNAs in aggressive breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 993.
Karen A Gould - One of the best experts on this subject based on the ideXlab platform.
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Estrogen Receptor Alpha promotes lupus in nzb nzw f1 mice in a b cell intrinsic manner
Clinical Immunology, 2017Co-Authors: Dana E Tabor, Karen A GouldAbstract:Abstract Lupus is a systemic autoimmune disease characterized by the production of autoreactive antibodies against nuclear antigens. Women are disproportionately affected by lupus, and this sex bias is thought to be due, in large part, to the ability of Estrogens to promote lupus pathogenesis. Previously, we have shown that global deletion of Estrogen Receptor Alpha (ERα) significantly attenuated loss of tolerance, immune cell activation, autoantibody production, and the development of lupus nephritis. Here we show that targeted deletion of ERα specifically in B cells retards production of pathogenic autoantibodies and the development of nephritis in lupus-prone (NZB × NZW)F1 mice. Furthermore, we observed that ERα deletion in B cells was associated with decreased B cell activation in young, pre-autoimmune (NZB × NZW)F1 females. Altogether, these data suggest that ERα acts in a B cell-intrinsic manner to control B cell activation, autoantibody production, and lupus nephritis.
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Estrogen Receptor Alpha deficiency attenuates autoimmune disease in nzb x nzw f1 mice
Genes and Immunity, 2008Co-Authors: Kimberly K Bynote, J M Hackenberg, Kenneth S Korach, D B Lubahn, Pascale H Lane, Karen A GouldAbstract:Estrogens promote lupus in humans and some mouse models of this disease. Nonetheless, little is known about the role of Estrogen Receptors in lupus pathogenesis. Here, we report that in females on the lupus-prone (NZB x NZW)F(1) background, disruption of Estrogen Receptor-Alpha (ER Alpha or Esr1) attenuated glomerulonephritis and increased survival. ER Alpha deficiency also retarded development of anti-histone/DNA antibodies, suggesting that ER Alpha promotes loss of immunologic tolerance. Furthermore, ER Alpha deficiency in (NZB x NZW)F(1) females attenuated the subsequent development of anti-double-stranded DNA (dsDNA) IgG antibodies, which are associated with glomerulonephritis in this model. We provide evidence that ER Alpha may promote lupus, at least in part, by inducing interferon-gamma, an Estrogen-regulated cytokine that impacts this disease. ER Alpha deficiency in (NZB x NZW)F(1) males increased survival and reduced anti-dsDNA antibodies, suggesting that ER Alpha also modulates lupus in males. These studies demonstrate that ER Alpha, rather than ER beta, plays a major role in regulating autoimmunity in (NZB x NZW)F(1) mice. Furthermore, our results suggest for the first time that ER Alpha promotes lupus, at least in part, by impacting the initial loss of tolerance. These data suggest that targeted therapy disrupting ER Alpha, most likely within the immune system, may be effective in the prevention and/or treatment of lupus.