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Notable papers are listed here. Papers with two red dots are highly recommended. Articles with one or zero dots are recommended but not essential.
No annotation is available in this section for this article. The content below is taken from a related TF, ESR1 (Homo sapiens).
  1. (2001) Nilsson S, Mäkelä S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JA. Mechanisms of estrogen action. Physiol. Rev., 81(4):1535-65.
    Our appreciation of the physiological functions of estrogens and the mechanisms through which estrogens bring about these functions has changed during the past decade. Just as transgenic mice were produced in which estrogen receptors had been inactivated and we thought that we were about to understand the role of estrogen receptors in physiology and pathology, it was found that there was not one but two distinct and functional estrogen receptors, now called ER alpha and ER beta. Transgenic mice in which each of the receptors or both the receptors are inactive have revealed a much broader role for estrogens in the body than was previously thought. This decade also saw the description of a male patient who had no functional ER alpha and whose continued bone growth clearly revealed an important function of estrogen in men. The importance of estrogen in both males and females was also demonstrated in the laboratory in transgenic mice in which the aromatase gene was inactivated. Finally, crystal structures of the estrogen receptors with agonists and antagonists have revealed much about how ligand binding influences receptor conformation and how this conformation influences interaction of the receptor with coactivators or corepressors and hence determines cellular response to ligands.
    Comments (post)
    Chunyan Zhao (chun...@ki.se) on April 03, 2008 wrote:
     A detailed review that includes ER stucture, ligands, splice variants, cofactors, and tissue distribution. 
  2. (2006) Ascenzi P, Bocedi A, Marino M. Structure-function relationship of estrogen receptor alpha and beta: impact on human health. Mol. Aspects Med., 27(4):299-402.
    17Beta-estradiol (E2) controls many aspects of human physiology, including development, reproduction and homeostasis, through regulation of the transcriptional activity of its cognate receptors (ERs). The crystal structures of ERs with agonists and antagonists and the use of transgenic animals have revealed much about how hormone binding influences ER conformation(s) and how this conformation(s), in turn, influences the interaction of ERs with co-activators or co-repressors and hence determines ER binding to DNA and cellular outcomes. This information has helped to shed light on the connection between E2 and the development or progression of numerous diseases. Current therapeutic strategy in the treatment of E2-related pathologies relies on the modulation of ER trancriptional activity by anti-estrogens; however, data accumulated during the last five years reveal that ER activities are not only restricted to the nucleus. ERs are very mobile proteins continuously shuttling between protein targets located within various cellular compartments (e.g., membrane, nucleus). This allows E2 to generate different and synergic signal transduction pathways (i.e., non-genomic and genomic) which provide plasticity for cell response to E2. Understanding the structural basis and the molecular mechanisms by which ER transduce E2 signals in target cells will allow to create new pharmacologic therapies aimed at the treatment of a variety of human diseases affecting the cardiovascular system, the reproductive system, the skeletal system, the nervous system, the mammary gland, and many others.
    Comments (post)
    Chunyan Zhao (chun...@ki.se) on April 03, 2008 wrote:
     A very detailed review of the molecular mechanisms by which ER transduce E2 signaling and the roles of ER in human diseases 
  3. (2005) Björnström L, Sjöberg M. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol. Endocrinol., 19(4):833-42.
    Estrogen receptors (ERs) act by regulating transcriptional processes. The classical mechanism of ER action involves estrogen binding to receptors in the nucleus, after which the receptors dimerize and bind to specific response elements known as estrogen response elements (EREs) located in the promoters of target genes. However, ERs can also regulate gene expression without directly binding to DNA. This occurs through protein-protein interactions with other DNA-binding transcription factors in the nucleus. In addition, membrane-associated ERs mediate nongenomic actions of estrogens, which can lead both to altered functions of proteins in the cytoplasm and to regulation of gene expression. The latter two mechanisms of ER action enable a broader range of genes to be regulated than the range that can be regulated by the classical mechanism of ER action alone. This review surveys our knowledge about the molecular mechanism by which ERs regulate the expression of genes that do not contain EREs, and it gives examples of the ways in which the genomic and nongenomic actions of ERs on target genes converge. Genomic and nongenomic actions of ERs that do not depend on EREs influence the physiology of many target tissues, and thus, increasing our understanding of the molecular mechanisms behind these actions is highly relevant for the development of novel drugs that target specific receptor actions.
    Comments (post)
    Chunyan Zhao (chun...@ki.se) on April 03, 2008 wrote:
     Informative figures illustrating ER Signaling Mechanisms  
  4. (2004) O'Lone R, Frith MC, Karlsson EK, Hansen U. Genomic targets of nuclear estrogen receptors. Mol. Endocrinol., 18(8):1859-75.
    Estrogen influences the physiology of many target tissues in both women and men. The long-term effects of estrogen are mediated predominantly by nuclear estrogen receptors (ERs) functioning as DNA-binding transcription factors. Tissue-specific responses to estrogen therefore result from regulation of different sets of genes. However, it remains perplexing as to what regulatory sequence contexts specify distinct genomic responses. First, this review classifies estrogen response sequences in mammalian target genes. Of note, around one third of known human target genes associate only indirectly with ER, through intermediary transcription factor(s). Then, computational approaches are presented both for refining direct ER-binding sites and for formulating hypotheses regarding the overall genomic expression pattern. Surprisingly, limited evolutionary conservation of specific estrogen-responsive sites is observed between human and mouse. Finally, consideration of the cellular functions of regulated human genes suggests links between particular biological roles and specific types of estrogen response elements, although with the important caveat that only a restricted set of target genes is available. These analyses support the view that specific, hormone-driven gene expression programs can result from the interplay of environmental and cellular cues with the distinct types of estrogen-response sequences.
    Comments (post)
    Chunyan Zhao (chun...@ki.se) on April 03, 2008 wrote:
     A detailed review of estrogen response sequences in regulatory regions of genes directly targeted by ERs 
  5. (2010) Charn TH, Liu ET, Chang EC, Lee YK, Katzenellenbogen JA, Katzenellenbogen BS. Genome-wide dynamics of chromatin binding of estrogen receptors alpha and beta: mutual restriction and competitive site selection. Mol. Endocrinol., 24(1):47-59.
    Estrogen receptors ERalpha and ERbeta, members of the nuclear receptor superfamily, exert profound effects on the gene expression and biological response programs of their target cells. Herein, we explore the dynamic interplay between these two receptors in their selection of chromatin binding sites when present separately or together in MCF-7 breast cancer cells. Treatment of cells (containing ERalpha only, ERbeta only, or ERalpha and ERbeta) with estradiol or ER subtype-selective ligands was followed by chromatin immunoprecipitation analysis with a custom-designed tiling array for ER binding sites across the genome to examine the effects of ligand-occupied and unoccupied ERalpha and ERbeta on chromatin binding. There was substantial overlap in binding sites for these estradiol-liganded nuclear receptors when present alone, but many fewer sites were shared when both ERs were present. Each ER restricted the binding site occupancy of the other, with ERalpha generally being dominant. Binding sites of both receptors were highly enriched in estrogen response element motifs, but when both ERs were present, ERalpha displaced ERbeta, shifting it into new sites less enriched in estrogen response elements. Binding regions of the two ERs also showed differences in their enrichments for other transcription factor binding motifs. Studies with ER subtype-specific ligands revealed that it was the liganded subtype that principally determined the spectrum of chromatin binding. These findings highlight the dynamic interplay between the two ERs in their selection of chromatin binding sites, with competition, restriction, and site shifting having important implications for the regulation of gene expression by these two nuclear receptors.
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  6. (2009) Welboren WJ, van Driel MA, Janssen-Megens EM, van Heeringen SJ, Sweep FC, Span PN, Stunnenberg HG. ChIP-Seq of ERalpha and RNA polymerase II defines genes differentially responding to ligands. EMBO J., 28(10):1418-28.
    We used ChIP-Seq to map ERalpha-binding sites and to profile changes in RNA polymerase II (RNAPII) occupancy in MCF-7 cells in response to estradiol (E2), tamoxifen or fulvestrant. We identify 10 205 high confidence ERalpha-binding sites in response to E2 of which 68% contain an estrogen response element (ERE) and only 7% contain a FOXA1 motif. Remarkably, 596 genes change significantly in RNAPII occupancy (59% up and 41% down) already after 1 h of E2 exposure. Although promoter proximal enrichment of RNAPII (PPEP) occurs frequently in MCF-7 cells (17%), it is only observed on a minority of E2-regulated genes (4%). Tamoxifen and fulvestrant partially reduce ERalpha DNA binding and prevent RNAPII loading on the promoter and coding body on E2-upregulated genes. Both ligands act differently on E2-downregulated genes: tamoxifen acts as an agonist thus downregulating these genes, whereas fulvestrant antagonizes E2-induced repression and often increases RNAPII occupancy. Furthermore, our data identify genes preferentially regulated by tamoxifen but not by E2 or fulvestrant. Thus (partial) antagonist loaded ERalpha acts mechanistically different on E2-activated and E2-repressed genes.
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  7. (2008) Liu Y, Gao H, Marstrand TT, Ström A, Valen E, Sandelin A, Gustafsson JA, Dahlman-Wright K. The genome landscape of ERalpha- and ERbeta-binding DNA regions. Proc. Natl. Acad. Sci. U.S.A., 105(7):2604-9.
    In this article, we have applied the ChIP-on-chip approach to pursue a large scale identification of ERalpha- and ERbeta-binding DNA regions in intact chromatin. We show that there is a high degree of overlap between the regions identified as bound by ERalpha and ERbeta, respectively, but there are also regions that are bound by ERalpha only in the presence of ERbeta, as well as regions that are selectively bound by either receptor. Analysis of bound regions shows that regions bound by ERalpha have distinct properties in terms of genome landscape, sequence features, and conservation compared with regions that are bound by ERbeta. ERbeta-bound regions are, as a group, located more closely to transcription start sites. ERalpha- and ERbeta-bound regions differ in sequence properties, with ERalpha-bound regions having an overrepresentation of TA-rich motifs including forkhead binding sites and ERbeta-bound regions having a predominance of classical estrogen response elements (EREs) and GC-rich motifs. Differences in the properties of ER bound regions might explain some of the differences in gene expression programs and physiological effects shown by the respective estrogen receptors.
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  8. (2008) Gao H, Fält S, Sandelin A, Gustafsson JA, Dahlman-Wright K. Genome-wide identification of estrogen receptor alpha-binding sites in mouse liver. Mol. Endocrinol., 22(1):10-22.
    We report the genome-wide identification of estrogen receptor alpha (ERalpha)-binding regions in mouse liver using a combination of chromatin immunoprecipitation and tiled microarrays that cover all nonrepetitive sequences in the mouse genome. This analysis identified 5568 ERalpha-binding regions. In agreement with what has previously been reported for human cell lines, many ERalpha-binding regions are located far away from transcription start sites; approximately 40% of ERalpha-binding regions are located within 10 kb of annotated transcription start sites. Almost 50% of ERalpha-binding regions overlap genes. The majority of ERalpha-binding regions lie in regions that are evolutionarily conserved between human and mouse. Motif-finding algorithms identified the estrogen response element, and variants thereof, together with binding sites for activator protein 1, basic-helix-loop-helix proteins, ETS proteins, and Forkhead proteins as the most common motifs present in identified ERalpha-binding regions. To correlate ERalpha binding to the promoter of specific genes, with changes in expression levels of the corresponding mRNAs, expression levels of selected mRNAs were assayed in livers 2, 4, and 6 h after treatment with ERalpha-selective agonist propyl pyrazole triol. Five of these eight selected genes, Shp, Stat3, Pdgds, Pck1, and Pdk4, all responded to propyl pyrazole triol after 4 h treatment. These results extend our previous studies using gene expression profiling to characterize estrogen signaling in mouse liver, by characterizing the first step in this signaling cascade, the binding of ERalpha to DNA in intact chromatin.
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  9. (2006) Carroll JS, Meyer CA, Song J, Li W, Geistlinger TR, Eeckhoute J, Brodsky AS, Keeton EK, Fertuck KC, Hall GF, Wang Q, Bekiranov S, Sementchenko V, Fox EA, Silver PA, Gingeras TR, Liu XS, Brown M. Genome-wide analysis of estrogen receptor binding sites. Nat. Genet., 38(11):1289-97.
    The estrogen receptor is the master transcriptional regulator of breast cancer phenotype and the archetype of a molecular therapeutic target. We mapped all estrogen receptor and RNA polymerase II binding sites on a genome-wide scale, identifying the authentic cis binding sites and target genes, in breast cancer cells. Combining this unique resource with gene expression data demonstrates distinct temporal mechanisms of estrogen-mediated gene regulation, particularly in the case of estrogen-suppressed genes. Furthermore, this resource has allowed the identification of cis-regulatory sites in previously unexplored regions of the genome and the cooperating transcription factors underlying estrogen signaling in breast cancer.
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  10. (2006) Carroll JS, Brown M. Estrogen receptor target gene: an evolving concept. Mol. Endocrinol., 20(8):1707-14.
    Estrogen receptor (ER) functions as a transcription factor to induce gene expression events sufficient for cell division and breast cancer progression. A significant body of work exists on the identification of ER gene targets and the cofactors that contribute to these transcription events, yet surprisingly little is known of the cis-regulatory elements involved. In this review, we investigate the advances in technology that contribute to a comprehensive understanding of ER target genes and explore recent work identifying cis-regulatory domains that augment transcription of these targets. Specifically, we find that ER association with gene targets results from an association with the pioneer factor FoxA1, responsible for recruitment of ER to the genome. Recruitment of ER to the genome does not occur at promoter proximal regions, but instead involves distal enhancer elements that function to tether the ER complex to the target gene promoters. These advances in technology permit a more detailed investigation of ER activity and may aid in the development of superior drug interventions.
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  11. (2006) Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA. International Union of Pharmacology. LXIV. Estrogen receptors. Pharmacol. Rev., 58(4):773-81.
    Abstract not available.
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  12. (2004) Walker VR, Korach KS. Estrogen receptor knockout mice as a model for endocrine research. , 45(4):455-61.
    The biological effects of estrogen in mammalian target tissues are important for multiple organ systems including the male and female reproductive tract and the neuroendocrine, skeletal, and cardiovascular systems. Numerous physiological effects of estradiol are modulated by the estrogen receptor (ER), a Class I member of the nuclear receptor superfamily. However, more recent studies have also implicated nongenomic effects of estrogen, which may involve a membrane-binding site. The two forms of the ER are the classical estrogen receptor-alpha (ERalpha) and the more recently discovered estrogen receptor-beta (ERbeta). Gene-targeting techniques were used to generate mice lacking either functional ERalpha (alphaERKO), ERbeta (betaERKO), or both ERs (alphabetaERKO) to provide a model for evaluating estrogen receptor action. These knockout models provide a unique tool to study the effects of estrogen in the context of the whole animal and to discern the role of each ER in various tissues. The reproductive phenotypes as well as some of the nonreproductive phenotypes of the different ERKO models are summarized.
    Comments (post)
    Chunyan Zhao (chun...@ki.se) on April 03, 2008 wrote:
     A detailed review of the phenotypes observed in different ER knockout models  
  13. Green S, Walter P, Kumar V, Krust A, Bornert JM, Argos P, Chambon P. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature, 320(6058):134-9.
    We have cloned and sequenced the complete complementary DNA of the oestrogen receptor (ER) present in the breast cancer cell line MCF-7. The expression of the ER cDNA in HeLa cells produces a protein that has the same relative molecular mass and binds oestradiol with the same affinity as the MCF-7 ER. There is extensive homology between the ER and the erb-A protein of the oncogenic avian erythroblastosis virus.
    Comments (post)
    Chunyan Zhao (chun...@ki.se) on April 03, 2008 wrote:
     Cloning of ESR1 
No annotation is available in this section for this article. The content below is taken from a related TF, ESR1 (Homo sapiens).
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