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Ellis R Levin - One of the best experts on this subject based on the ideXlab platform.
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plasma membrane Estrogen Receptors
Trends in Endocrinology and Metabolism, 2009Co-Authors: Ellis R LevinAbstract:It is now firmly established that Estrogen and all sex steroid Receptors exist in discrete cellular pools outside the nucleus. Estrogen Receptors (ER) have been localized to the plasma membrane where both ERα and ERβ function in a wide variety of cells and organs. ERs have also been found in discrete cytoplasmic organelles including mitochondria and the endoplasmic reticulum. In ligand-dependent fashion, each ER pool contributes to the overall, integrated effects of Estrogens producing biological outcomes. This review highlights the recent work establishing new roles and targets of membrane ER signaling. Such actions include prevention of vascular injury or cardiac hypertrophy, sexual behavior and pain perception mediated through the central nervous system, osteoblast survival, and fluid resorption in the colon.
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Nature of Functional Estrogen Receptors at the Plasma Membrane
Molecular endocrinology (Baltimore Md.), 2006Co-Authors: Ali Pedram, Mahnaz Razandi, Ellis R LevinAbstract:Although rapid signaling by Estrogen at the plasma membrane is established, it is controversial as to the nature of the receptor protein. Estrogen may bind membrane proteins comparable to classical nuclear Estrogen Receptors (ERs), but some studies identify nonclassical Receptors, such as G protein-coupled receptor (GPR)30. We took several approaches to define membrane-localized Estrogen-binding proteins. In endothelial cells (ECs) from ERα/ERβ combined-deleted mice, estradiol (E2) failed to specifically bind, and did not activate cAMP, ERK, or phosphatidyinositol 3-kinase or stimulate DNA synthesis. This is in contrast to wild-type ECs, indicating the lack of any functional Estrogen-binding proteins in ERα/ERβ combined-deleted ECs. To directly determine the identity of membrane and nuclear-localized ER, we isolated subcellular receptor pools from MCF7 cells. Putative ER proteins were trypsin digested and subjected to tandem array mass spectrometry. The output analysis identified membrane and nuclear E2-b...
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plasma membrane Estrogen Receptors exist and functions as dimers
Molecular Endocrinology, 2004Co-Authors: Mahnaz Razandi, Ali Pedram, Geoffrey L Greene, Istvan Merchenthaler, Ellis R LevinAbstract:A small pool of Estrogen Receptors (ERα and -β) localize at the plasma membrane and rapidly signal to affect cellular physiology. Although nuclear ERs function mainly as homodimers, it is unknown whether membrane-localized ER exists or functions with similar requirements. We report that the endogenous ER isoforms at the plasma membrane of breast cancer or endothelial cells exist predominantly as homodimers in the presence of 17β-estradiol (E2). Interestingly, in endothelial cells made from ERα /ERβ homozygous double-knockout mice, membrane ERα or ERβ are absent, indicating that the endogenous membrane Receptors derive from the same gene(s) as the nuclear Receptors. In ER-negative breast cancer cells or Chinese hamster ovary cells, we expressed and compared wild-type and dimer mutant mouse ERα. Only wild-type ERα supported the ability of E2 to rapidly activate ERK, cAMP, and phosphatidylinositol 3-kinase signaling. This resulted from E2 activating Gsα and Gqα at the membrane in cells expressing the wild-ty...
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proximal events in signaling by plasma membrane Estrogen Receptors
Journal of Biological Chemistry, 2003Co-Authors: Mahnaz Razandi, Ali Pedram, Steven Park, Ellis R LevinAbstract:Abstract Estradiol (E2) rapidly stimulates signal transduction from plasma membrane Estrogen Receptors (ER) that are G protein-coupled. This is reported to occur through the transactivation of the epidermal growth factor receptor (EGFR) or insulin-like growth factor-1 receptor, similar to other G protein-coupled Receptors. Here, we define the signaling events that result in EGFR and ERK activation. E2-stimulated ERK required ER in breast cancer and endothelial cells and was substantially prevented by expression of a dominant negative EGFR or by tyrphostin AG1478, a specific inhibitor for EGFR tyrosine kinase activity. Transactivation/phosphorylation of EGFR by E2 was dependent on the rapid liberation of heparin-binding EGF (HB-EGF) from cultured MCF-7 cells and was blocked by antibodies to this ligand for EGFR. Expression of dominant negative mini-genes for Gαq and Gαi blocked E2-induced, EGFR-dependent ERK activation, and Gβγ also contributed. G protein activation led to activation of matrix metalloproteinases (MMP)-2 and -9. This resulted from Src-induced MMP activation, implicated using PP2 (Src family kinase inhibitor) or the expression of a dominant negative Src protein. Antisense oligonucleotides to MMP-2 and MMP-9 or ICI 182780 (ER antagonist) each prevented E2-induced HB-EGF liberation and ERK activation. E2 also induced AKT up-regulation in MCF-7 cells and p38β MAP kinase activity in endothelial cells, blocked by an MMP inhibitor, GM6001, and tyrphostin AG1478. Targeting of only the E domain of ERα to the plasma membrane resulted in MMP activation and EGFR transactivation. Thus, specific G proteins mediate the ability of E2 to activate MMP-2 and MMP-9 via Src. This leads to HB-EGF transactivation of EGFR and signaling to multiple kinase cascades in several target cells for E2. The E domain is sufficient to enact these events, defining additional details of the important cross-talk between membrane ER and EGFR in breast cancer.
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cellular functions of plasma membrane Estrogen Receptors
Steroids, 2002Co-Authors: Ellis R LevinAbstract:Strong evidence now exists for the presence and importance of plasma membrane Estrogen Receptors (ER) in a variety of cells that are targets for steroid action. When estradiol (E2) binds cell surface proteins, the initiation of signal transduction triggers downstream signaling cascades that contribute to important functions. These functions include cell growth and survival, migration, and new blood vessel formation. In some instances these effects result from the initiation of gene transcription, upregulated through signaling from the membrane. The membrane ER probably originates from the same gene and transcript that produces the nuclear receptor. In the membrane, ER appear to localize mainly to discrete domains of the plasma membrane, known as caveolae, but the mechanisms by which this small pool of ER translocates to this site are currently unknown. At the caveolae, a cross talk with signaling molecules facilitates E2/ER cell biologic actions. This both includes direct stimulation of signaling via G protein activation, and a cross-activation of the epidermal growth factor receptor (EGFR). This review article highlights some of the important advances in understanding the cell biology of Estrogen action that emanates from the membrane.
Benita S Katzenellenbogen - One of the best experts on this subject based on the ideXlab platform.
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nuclear and extranuclear pathway inputs in the regulation of global gene expression by Estrogen Receptors
Molecular Endocrinology, 2008Co-Authors: Zeynep Madakerdogan, John A Katzenellenbogen, Benita S Katzenellenbogen, Karen J Kieser, Barry S KommAbstract:Whereas Estrogens exert their effects by binding to nuclear Estrogen Receptors (ERs) and directly altering target gene transcription, they can also initiate extranuclear signaling through activation of kinase cascades. We have investigated the impact of Estrogen-mediated extranuclear-initiated pathways on global gene expression by using Estrogen-dendrimer conjugates (EDCs), which because of their charge and size remain outside the nucleus and can only initiate extranuclear signaling. Genome-wide cDNA microarray analysis of MCF-7 breast cancer cells identified a subset of 17β-estradiol (E2)-regulated genes (∼25%) as EDC responsive. The EDC and E2-elicited increases in gene expression were due to increases in gene transcription, as observed in nuclear run-on assays and RNA polymerase II recruitment and phosphorylation. Treatment with antiEstrogen or ERα knockdown using small interfering RNA abolished EDC-mediated gene stimulation, whereas GPR30 knockdown or treatment with a GPR30-selective ligand was withou...
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distinctive actions of membrane targeted versus nuclear localized Estrogen Receptors in breast cancer cells
Molecular Endocrinology, 2005Co-Authors: Antonina Frolova, Benita S Katzenellenbogen, Jonna Frasor, Anne E CarpenterAbstract:Estrogens regulate multiple activities in breast cancer cells, including proliferation. Whereas these hormones are most commonly known to regulate gene transcription through direct interaction with Estrogen Receptors (ERs) and with specific DNA sequences of target genes, recent studies show that ER also activates a number of rapid signaling events that are initiated at the cell membrane. To study the membrane-initiated effects of Estrogen and separate them from the activities initiated by the nuclear localized ER in human breast cancer cells, we generated MDA-MB-231 breast cancer cell lines that have stably integrated either the wild-type nuclear form of ER (WT-ER) or a modified, membrane-targeted ER (MT-ER) that lacks a nuclear localization sequence and is dually acylated with a myristoylation sequence at the N terminus and a palmitoylation sequence at the C terminus. We demonstrate that MT-ER is membrane localized in the absence of estradiol (E2), showing punctate membrane and cytoplasmic speckles after...
Jutamaad Satayavivad - One of the best experts on this subject based on the ideXlab platform.
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glyphosate induces human breast cancer cells growth via Estrogen Receptors
Food and Chemical Toxicology, 2013Co-Authors: Siriporn Thongprakaisang, Apinya Thiantanawat, Nuchanart Rangkadilok, Tawit Suriyo, Jutamaad SatayavivadAbstract:Glyphosate is an active ingredient of the most widely used herbicide and it is believed to be less toxic than other pesticides. However, several recent studies showed its potential adverse health effects to humans as it may be an endocrine disruptor. This study focuses on the effects of pure glyphosate on Estrogen Receptors (ERs) mediated transcriptional activity and their expressions. Glyphosate exerted proliferative effects only in human hormone-dependent breast cancer, T47D cells, but not in hormone-independent breast cancer, MDA-MB231 cells, at 10⁻¹² to 10⁻⁶M in Estrogen withdrawal condition. The proliferative concentrations of glyphosate that induced the activation of Estrogen response element (ERE) transcription activity were 5-13 fold of control in T47D-KBluc cells and this activation was inhibited by an Estrogen antagonist, ICI 182780, indicating that the Estrogenic activity of glyphosate was mediated via ERs. Furthermore, glyphosate also altered both ERα and β expression. These results indicated that low and environmentally relevant concentrations of glyphosate possessed Estrogenic activity. Glyphosate-based herbicides are widely used for soybean cultivation, and our results also found that there was an additive Estrogenic effect between glyphosate and genistein, a phytoEstrogen in soybeans. However, these additive effects of glyphosate contamination in soybeans need further animal study.
Paul G Mermelstein - One of the best experts on this subject based on the ideXlab platform.
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membrane Estrogen Receptors activate the metabotropic glutamate Receptors mglur5 and mglur3 to bidirectionally regulate creb phosphorylation in female rat striatal neurons
Neuroscience, 2010Co-Authors: Danielle Grovestrawser, Marissa I Boulware, Paul G MermelsteinAbstract:Along with its ability to directly regulate gene expression, estradiol influences cell signaling and brain functions via rapid, membrane-initiated events. In the female rat striatum, estradiol activates membrane-localized Estrogen Receptors to influence synaptic neurotransmission, calcium channel activity, and behaviors related to motor control. Yet, the mechanism by which estradiol acts to rapidly affect striatal physiology has remained elusive. Here we find that membrane Estrogen Receptors (ERs) couple to the metabotropic glutamate Receptors mGluR5 and mGluR3, providing the framework to understand how membrane Estrogen Receptors affect striatal function. Using CREB phosphorylation as a downstream measure of ER/mGluR activation, membrane-localized Estrogen receptor α (ERα) activates mGluR5 signaling to mediate mitogen-activated protein kinase (MAPK)-dependent CREB phosphorylation. Further, ERα and Estrogen receptor β (ERβ) activate mGluR3 to attenuate L-type calcium channel-dependent CREB signaling. Interestingly, while this fundamental mechanism of ER/mGluR signaling was initially characterized in hippocampal neurons, Estrogen Receptors in striatal neurons are paired with a different set of mGluRs, resulting in the potential to functionally isolate membrane-initiated Estrogen signaling across brain regions via use of specific mGluR modulators. These results provide both a mechanism for the rapid actions of Estrogens within the female striatum, as well as demonstrate that Estrogen Receptors can interact with a more diverse set of surface membrane Receptors than previously recognized.
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Membrane Estrogen Receptors Acting Through Metabotropic Glutamate Receptors: An Emerging Mechanism of Estrogen Action in Brain
Molecular Neurobiology, 2008Co-Authors: Paul E Micevych, Paul G MermelsteinAbstract:It has been over 60years since the first studies have been published describing the effects of steroid hormones on brain function. For over 30years, Estrogen has been presumed to directly affect gene expression and protein synthesis through a specific receptor. More than 20years ago, the first Estrogen receptor was cloned and identified as a transcription factor. Yet, throughout their course of study, Estrogens have also been observed to affect nervous system function via mechanisms independent of intracellular receptor regulation of gene expression. Up until recently, the membrane Estrogen Receptors responsible for these rapid actions have remained elusive. Recent studies have demonstrated that a large number of these rapid, membrane-initiated actions of estradiol are due to surface expression of classical Estrogen Receptors. This review focuses on the importance of membrane Estrogen receptor interactions with metabotropic glutamate Receptors for understanding rapid estradiol signaling mechanisms and downstream effectors, as well as their significance in a variety of physiological processes.
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caveolin proteins are essential for distinct effects of membrane Estrogen Receptors in neurons
The Journal of Neuroscience, 2007Co-Authors: Marissa I Boulware, Holly B Kordasiewicz, Paul G MermelsteinAbstract:It has become widely accepted that along with its ability to directly regulate gene expression, estradiol also influences cell signaling and brain function via rapid membrane-initiated events. Many of these novel signaling processes are dependent on Estrogen Receptors (ERs) localized to the neuronal membrane. However, the mechanism(s) by which ERs are able to trigger cell signaling when targeted to the neuronal membrane surface has yet to be determined. In hippocampal neurons, we find that caveolin proteins are essential for the regulation of CREB (cAMP response element-binding protein) phosphorylation after estradiol activation of metabotropic glutamate receptor (mGluR) signaling. Furthermore, caveolin-1 (CAV1) and CAV3 differentially regulate the ability of estradiol to activate two discrete signaling pathways. ERα activation of mGluR1a is dependent on CAV1, whereas CAV3 is necessary for ERα and ERβ activation of mGluR2/3. These results are consistent with previous reports in non-neuronal cells, implicating the importance of caveolin proteins in rapid Estrogen signaling. In addition, the functional isolation of distinct Estrogen-sensitive signaling pathways by different caveolin proteins suggests novel mechanisms through which the membrane-initiated effects of estradiol are orchestrated.
Janake Gustafsson - One of the best experts on this subject based on the ideXlab platform.
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differential activity of bpa bpaf and bpc on zebrafish Estrogen Receptors in vitro and in vivo
Toxicology and Applied Pharmacology, 2019Co-Authors: Caroline Pinto, Janake Gustafsson, Ruixin Hao, Marina Grimaldi, Savini Thrikawala, Abdelhay Boulahtouf, Selim Aitaissa, Francois Brion, Patrick Balaguer, Maria BondessonAbstract:Abstract The high volume production compound bisphenol A (BPA) is of environmental concern largely because of its Estrogenic activity. Consequently, BPA analogues have been synthesized to be considered as replacement molecules for BPA. These analogues need to be thoroughly evaluated for their Estrogenic activity. Here, we combined mechanism zebrafish-based assays to examine Estrogenic and anti-Estrogenic activities of BPA and two of its analogues, bisphenol AF (BPAF) and bisphenol C (BPC) in vitro and in vivo. In vitro reporter cell lines were used to investigate agonistic and antagonistic effects of the three bisphenols on the three zebrafish Estrogen Receptors. The transgenic Tg(5 × ERE:GFP) and Cyp19a1b-GFP zebrafish lines were then used to analyze Estrogenic and anti-Estrogenic responses of the three bisphenols in vivo. BPA, BPAF and BPC were agonists with different potencies for the three zebrafish Estrogen Receptors in vitro. The potent zfERα-mediated activity of BPA and BPAF in vitro resulted in vivo by activation of GFP expression in zebrafish larvae in the heart (zfERα-dependent) at lower concentrations, and in the liver (zfERβ-dependent) at higher concentrations. BPC induced zfERβ-mediated luciferase expression in vitro, and the zfERβ agonism led to activation of GFP expression in the liver and the brain in vivo. In addition, BPC acted as a full antagonist on zfERα, and completely inhibited Estrogen-induced GFP expression in the heart of the zebrafish larvae. To summarize, applying a combination of zebrafish-based in vitro and in vivo methods to evaluate bisphenol analogues for Estrogenic activity will facilitate the prioritization of these chemicals for further analysis in higher vertebrates as well as the risk assessment in humans.
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Estrogen Receptors in diseases of the immune system
The Hirosaki medical journal, 2007Co-Authors: Margaret Warner, Janake GustafssonAbstract:Estrogen has distinct functions in the immune system where it acts via ERα and HERβ respectively. Surprisingly the defects in the immune system which develop in the absence of either ERα or ERβ are quite distinct from what develops in the absence of Estrogen. We have found by studying mice in which either or both Estrogen Receptors have been inactivated that the two Estrogen Receptors play distinct roles in the immune system. Loss of ERβ leads to chronic myeloid leukemia and loss of ERα leads to autoimmune disease. In mice which cannot synthesize Estrogen there is also autoimmune disease resembling Sjogrens Syndrome. We plan to study these mice further with the aim of fi nding the exact sites of action of the two Receptors in the immune system and by using specifi c ligands for ERα . or ERβ to examine how specifi c parts of the immune system can be modifi ed. These studies should lead to improved treatment of patients with diseases of the immune system.
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structural insights into corepressor recognition by antagonist bound Estrogen Receptors
Journal of Biological Chemistry, 2007Co-Authors: Nina Heldring, Janake Gustafsson, Donald P. Mcdonnell, Tanya Pawson, Eckardt Treuter, A C W PikeAbstract:Direct recruitment of transcriptional corepressors to Estrogen Receptors (ER) is thought to contribute to the tissue-specific effects of clinically important ER antagonists. Here, we present the crystal structures of two affinity-selected peptides in complex with antagonist-bound ERalpha ligand-binding domain. Both peptides adopt helical conformations, bind along the activation function 2 coregulator interaction surface, and mimic corepressor (CoRNR) sequence motif binding. Peptide binding is weak in a wild-type context but significantly enhanced by removal of ER helix 12. This region contains a previously unrecognized CoRNR motif that is able to compete with corepressors for binding to activation function 2, thereby providing a structural explanation for the poor ability of ER to directly interact with classical corepressors. Furthermore, the ability of other sequence motifs to mimic corepressor binding raises the possibility that coregulators do not necessarily require CoRNR motifs for direct recruitment to antagonist-bound ER.
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muscle glut4 regulation by Estrogen Receptors erβ and erα
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Rodrigo P A Barros, Margaret Warner, Ubiratan Fabres Machado, Janake GustafssonAbstract:Estrogen is known to influence glucose homeostasis with dominant effects in the liver, but the role of Estrogen Receptors in muscle glucose metabolism is unknown. In the present study, we investigated the expression of the two Estrogen Receptors, ERα and ERβ, and their influence on regulation of the glucose transporter, GLUT4, and its associated structural protein, caveolin-1, in mouse gastrocnemius muscle. Immunohistochemical analysis revealed that ERα and ERβ are coexpressed in the nuclei of most muscle cells, and that their levels were not affected by absence of estradiol [in aromatase-knockout (ArKO) mice]. GLUT4 expression on the muscle cell membrane was not affected by loss of ERβ but was extremely reduced in ERα-/- mice and elevated in ArKO mice. RT-PCR confirmed a parallel reduction in GLUT4 mRNA levels in ERα-/- mice. Upon treatment of ArKO mice with the ERβ agonist 2,3-bis(4-hydroxyphenyl)propionitrile, GLUT4 expression was reduced. By immunofluorescence and Western blotting, caveolin-1 expression was higher in ArKO mice and lower in ERβ-/- and ERα-/- mice than in WT littermates. GLUT4 and caveolin-1 were colocalized in WT and ArKO mice but not in ERβ-/- and ERα-/- mice. These results reveal that ERα is a positive regulator of GLUT4 expression, whereas ERβ has a suppressive role. Both ERβ and ERα are necessary for optimal caveolin-1 expression. Taken together, these results indicate that colocalization of caveolin-1 and GLUT4 is not an absolute requirement for muscle glucose metabolism but that reduction in GLUT4 could be contributing to the insulin resistance observed in ERα-/- mice.
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Estrogen Receptors alfa erα and beta erβ differentially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line hc11
Oncogene, 2005Co-Authors: Luisa A Helguero, Malin Hedengran Faulds, Janake Gustafsson, Lars Arne HaldosenAbstract:Estrogen Receptors alfa (ER α ) and beta (ER β ) differentially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line HC11