The Dynamic Structure of the Estrogen Receptor

Department of Basic Sciences, The Commonwealth Medical College, Scranton, PA 18510, USA.
Journal of amino acids 07/2011; 2011:812540. DOI: 10.4061/2011/812540
Source: PubMed


The estrogen receptor (ER) mediates most of the biological effects of estrogens at the level of gene regulation by interacting through its site-specific DNA and with other coregulatory proteins. In recent years, new information regarding the dynamic structural nature of ER has emerged. The physiological effects of estrogen are manifested through ER's two isoforms, ER(α) and ER(β). These two isoforms (ER(α) and ER(β)) display distinct regions of sequence homology. The three-dimensional structures of the DNA-binding domain (DBD) and ligand-binding domain (LBD) have been solved, whereas no three-dimensional natively folded structure for the ER N-terminal domain (NTD) is available to date. However, insights about the structural and functional correlations regarding the ER NTD have recently emerged. In this paper, we discuss the knowledge about the structural characteristics of the ER in general and how the structural features of the two isoforms differ, and its subsequent role in gene regulation.

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Available from: Gianluca Toraldo, Jan 01, 2014
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    • "The full transcriptional activity of the human estrogen receptor is dependent on synergism between AF-2 and AF-1 (hormone-independent activation function) (Kumar et al., 2011). Taken together, all of the elements are highly conserved in the selected species compared to humans, which demonstrates that this estrogen receptor is highly conserved in mollusks. "
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    ABSTRACT: Mollusks have received increasing interest in ecotoxicological studies but so far the available scientific analyses of how their genes are affected by anthropogenic pollutants are scarce. The focus of this study is to identify an estrogen receptor (er) gene in the common prosobranch snail Bithynia tentaculata and to test a hypothesis that 17α-Ethinylestradiol (EE2) will modulate er gene expression after short-term exposure. We set up exposure experiments with a total of 144 snails, which were collected from a natural population in southern Sweden. Snails were exposed to either 10ng/L or 100ng/L EE2 during 24h and/or 72h. From the isolated B. tentaculata RNA we successfully identified and characterized a novel er gene and phylogenetic analyses strongly indicate that the Bithynia er gene is an ortholog to the human ERα (ESR1, NR3A1). We found a significant interaction between EE2-dose and exposure duration on the er's gene expression (Two-way ANOVA; p=0.04). We also found a significant difference in the gene expression of the er when comparing the control and 100ng/L treatment groups after 72h in female snails (One-way ANOVA; p=0.047). The results from this study should be useful for future field-related studies of estrogen receptors in natural populations of mollusks.
    Gene 02/2014; 540(1). DOI:10.1016/j.gene.2014.02.039 · 2.14 Impact Factor
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    • "Bars above the human exon sequences are indicating the location of the ligand binding domain (LBD, dark brown), F domain (F, red bar), activation factor 2α domain (AF2α, light brown bar) and activation factor 2 domain (AF2, black bars). GATA interacts with the AF2 domain [15-19]. "
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    ABSTRACT: Background The limited within-breed genetic heterogeneity and an enrichment of disease-predisposing alleles have made the dog a very suitable model for the identification of genes associated with risk for specific diseases. Canine mammary cancer is an example of such a disease. However, the underlying inherited risk factors for canine mammary tumours (CMTs) are still largely unknown. In this study, 52 single nucleotide polymorphisms (SNPs) in ten human cancer-associated genes were genotyped in two different datasets in order to identify genes/alleles associated with the development of CMTs. The first dataset consisted of English Springer Spaniel (ESS) CMT cases and controls. ESS is a dog breed known to be at increased risk of developing CMTs. In the second dataset, dogs from breeds known to have a high frequency of CMTs were compared to dogs from breeds with a lower occurrence of these tumours. Results We found significant associations to CMT for SNPs and haplotypes in the estrogen receptor 1 (ESR1) gene in the ESS material (best PBonf = 0.021). A large number of SNPs, among them several SNPs in ESR1, showed significantly different allele frequencies between the high and low risk breed groups (best PBonf = 8.8E-32, best PBPerm = 0.076). Conclusions The identification of CMT-associated SNPs in ESR1 in two independent datasets suggests that this gene might be involved in CMT development. These findings also support that CMT may serve as a good model for human breast cancer research.
    BMC Veterinary Research 04/2013; 9(1):69. DOI:10.1186/1746-6148-9-69 · 1.78 Impact Factor
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    • "The AF-1 domain is regulated by growth factor receptor signaling, including epidermal growth factor receptor (EGFR), HER2 and insulin-like growth factor receptor (IGF1-R) [7]. The DBD and LBD domains are structurally ordered with a globular profile when expressed independently [8]. The three-dimensional native-fold structure of the N terminal and hinge domains has not yet been resolved as they are intrinsically disordered regions [9]. "
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    ABSTRACT: In hormone receptor-positive breast cancers, most tumors in the early stages of development depend on the activity of the estrogen receptor and its ligand, estradiol. Anti-estrogens, such as tamoxifen, have been used as the first line of therapy for over three decades due to the fact that they elicit cell cycle arrest. Unfortunately, after an initial period, most cells become resistant to hormonal therapy. Peptidylprolyl isomerase 1 (Pin1), a protein overexpressed in many tumor types including breast, has been demonstrated to modulate ERalpha activity and is involved in resistance to hormonal therapy. Here we show a new mechanism through which CDK2 drives an ERalpha-Pin1 interaction under hormone- and growth factor-free conditions. The PI3K/AKT pathway is necessary to activate CDK2, which phosphorylates ERalphaSer294, and mediates the binding between Pin1 and ERalpha. Site-directed mutagenesis demonstrated that ERalphaSer294 is essential for Pin1-ERalpha interaction and modulates ERalpha phosphorylation on Ser118 and Ser167, dimerization and activity. These results open up new drug treatment opportunities for breast cancer patients who are resistant to anti-estrogen therapy.
    PLoS ONE 02/2013; 8(2):e55355. DOI:10.1371/journal.pone.0055355 · 3.23 Impact Factor
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