A Non-Nuclear Role of the Estrogen Receptor Alpha in the Regulation of Cell-Cell Interactions PDF Download
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Languages : en
Pages : 11
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Proliferation and metastasis of many breast cancers depend on the steroid hormone estrogen. The actions of estrogens are mediated by the estrogen receptors ERalpha and ERbeta. These hormone-regulated transcription factors translate the presence of estrogen into changes in gene expression. According to new findings, these receptors also act outside of the nucleus and are often found associated with the plasma membrane. In contrast to their roles in regulating cell proliferation, very little is known about the mechanisms by which estrogens promote metastasis. It has been suggested that estrogens aid this process by changing the expression of cell adhesion proteins, such as E-cadherin. However, results in our laboratory have opened the possibility that disruption of cell adhesions by estrogens involves the direct interaction of ER with cell adhesion proteins. The goal of this grant is to explore this possibility. If true, this mechanism would represent a novel example of a non-nuclear activity of the estrogen receptor, steer ongoing studies on the role of estrogens in the regulation of cellular adhesions into a new direction, and open new venues for the prevention, diagnosis and therapy of breast cancer.
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Category :
Languages : en
Pages : 11
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Book Description
Proliferation and metastasis of many breast cancers depend on the steroid hormone estrogen. The actions of estrogens are mediated by the estrogen receptors ERalpha and ERbeta. These hormone-regulated transcription factors translate the presence of estrogen into changes in gene expression. According to new findings, these receptors also act outside of the nucleus and are often found associated with the plasma membrane. In contrast to their roles in regulating cell proliferation, very little is known about the mechanisms by which estrogens promote metastasis. It has been suggested that estrogens aid this process by changing the expression of cell adhesion proteins, such as E-cadherin. However, results in our laboratory have opened the possibility that disruption of cell adhesions by estrogens involves the direct interaction of ER with cell adhesion proteins. The goal of this grant is to explore this possibility. If true, this mechanism would represent a novel example of a non-nuclear activity of the estrogen receptor, steer ongoing studies on the role of estrogens in the regulation of cellular adhesions into a new direction, and open new venues for the prevention, diagnosis and therapy of breast cancer.
Author: Amy L. Weinberg
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ISBN:
Category :
Languages : en
Pages : 230
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Author: Sabine Dhir
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Languages : en
Pages :
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"The early life environment has a profound effect on offspring development. Extensive research has shown multiple neural, endocrine and behavioural systems are influenced by the quality of the early environment. In the laboratory rat, mother- pup interaction is a major component of the early life environment. Variations in the frequency of pup licking/grooming (LG) over the first week of life are associated with robust and stable differences in maternal care. Female rats will exhibit high levels of maternal behaviors towards their offspring when reared by mothers who display high levels of pup LG (High LG). The same is true for female offspring reared by dams that exhibit low levels of LG (Low LG). Adoption studies show that transmission of this maternal behaviour is non-genetic. The studies of the present thesis examine how maternal care, specifically pup LG, is passed from mother to daughter and the molecular mechanism that regulates this behaviour in High and Low LG female rats. High levels of maternal LG are associated with increased levels of the steroid hormone receptor estrogen receptor alpha (ER[alpha]) in the medial preoptic area (mPOA). This brain region is a key neural structure for the regulation of maternal behaviour. Our studies show that ER[alpha] in the mPOA is critically responsible for the variation in pup LG in High and Low LG dams. Furthermore, ER[alpha] also mediates the transmission of pup LG from mother to daughter. Examination of how ER[alpha] expression is regulated in the brain revealed increased Signal Transducer and Activator of Transcription 5b (Stat5b) transcription factor and RNA Polymerase II (RNA Pol II) binding to the ER[alpha] gene promoter in High LG compared to Low LG offspring. As well, chromatin immunoprecipitation (chIP) analysis revealed increased acetylation of lysine 9 on histone 3 (H3K9ac) in High LG offspring, suggesting that the ER[alpha] promoter is a more "open" chromatin state, and more conducive to increased gene transcription compared to Low LG offspring. Furthermore, increased pup LG significantly increases promoter binding of histone 3 lysine 9 tri-methylation and the associated histone methyltransferase, G9a, in High LG offspring. While seemingly counterintuitive, assessment of the binding of G9a to ER[alpha] via co-immunoprecipitation (co-IP) and to the ER[alpha] binding site via chIP analysis determined that G9a likely acts as a co-activator of ER[alpha]. Experimental knockdown of G9a in primary dissociated cortical cultured cells show that decreasing G9a is sufficient to decrease ER[alpha] expression levels. We also explored the dual methyltransferase/co-activation properties of G9a with a specific methyltransferase inhibitor, UNC0642 and found efficient inhibition of lysine 9 methylation on histone 3, with no alterations to G9a. Analysis of potential co-factor recruitment of Glucocorticoid Receptor Interacting Protein 1 (GRIP1) and Coactivator Associated Arginine Methyltransferase 1 (CARM1) by G9a to the ER[alpha] promoter suggests that G9a functions independently of other co-activators to increase ER[alpha] transcription in High LG offspring. The results of the present thesis extend our understanding of the molecular mechanism regulating variations in maternal care in High and Low LG offspring. In High LG offspring, increased pup LG is critically dependent on ER[alpha], which is dynamically regulated by a combination of increased transcription factor binding, permissive histone modifications, and increased co-activation by G9a. Taken together, these findings suggest how the effect of maternal LG on a specific molecular target can directly mediate the transmission of individual differences in maternal care." --
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Publisher: ScholarlyEditions
ISBN: 146493181X
Category : Medical
Languages : en
Pages : 95
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Book Description
Estrogen Receptors: Advances in Research and Application: 2011 Edition is a ScholarlyBrief™ that delivers timely, authoritative, comprehensive, and specialized information about Estrogen Receptors in a concise format. The editors have built Estrogen Receptors: Advances in Research and Application: 2011 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Estrogen Receptors in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Estrogen Receptors: Advances in Research and Application: 2011 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.
Author: Kenneth S. Korach
Publisher: Springer Science & Business Media
ISBN: 9783540402503
Category : Medical
Languages : en
Pages : 240
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Book Description
From our current knowledge, it is obvious that estrogen action in volves more than reproduction and fertility. Rather, estrogens affect and influence a number of other organ systems such as the immune, cardiovascular and central nervous system as well as the gastrointes tinal tract, urinary tract and skeleton. The importance of estrogens and estrogen receptor activity is appreciated from the spectrum of significant physiological dysfunctions that occur when there is a loss The participants of the workshop VI Preface of the hormone or the receptor activity. Loss of estrogen, however (for instance during menopause), occurs with time and results in a variety of clinical conditions. We know that the developmental loss of estrogen, as seen in clinical cases of aromatase gene mutations and experimental models, has dramatic effects in both men and women alike. The evidence that these effects are mediated through the estrogen receptor(s) is based on similar but not always identical phenotypes as observed in experimental animal models of estrogen receptor mutations as well as the single clinical case of an estrogen receptor alpha mutant patient. Developing an understanding of the spectrum of estrogen in a variety of tissues related to the condition of estrogen loss is a major and highly active clinical as well as basic scientific research area. Following the discovery of a second estrogen receptor and possible receptor ligand-independent activity as well as the genomic and non genomic actions of estrogen, it is clear that the mechanisms of the effects of estrogen are multifaceted.
Author: Monika Helena Jakacka
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ISBN:
Category :
Languages : en
Pages :
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In the classical signaling pathway, the estrogen receptor (ER) binds directly to estrogen response elements (EREs) to regulate gene transcription. The ER agonist, estradiol, activates ERE-mediated transcription, whereas the antagonist, ICI 182,780, induces repression. The non-classical ER signaling pathway was examined using an AP1-regulated promoter, which is controlled by the Jun/Fos family of transcription factors. In this model system, there was a reversal of ER action relative to that seen with the ERE reporter: estradiol caused suppression and ICI 182,780 stimulated transcription of the AP1 reporter. A functional interaction between Jun and ER was detected when tested in mammalian two-hybrid assays. Mutations were introduced into the DNA binding domain of mouse ERalpha to test the hypothesis that the non-classical pathway involves ER interaction with other proteins rather than direct binding to DNA. A mutation in the proximal box of the first zinc finger (E207A/G208A) eliminated ERE binding. This mutant was inactive using the ERE reporter but retained full activity on the AP1 reporter. To clarify the functional roles of these two signaling pathways in vivo we created a Non-classical Estrogen Receptor Knock-In (NERKI) mouse model by introducing the E207A/G208A mutation by targeted mutagenesis of embryonic stem cells. Unexpectedly, heterozygous NERKI females were infertile. The mice were anovulatory, and the ovaries exhibited disorganized thecal cells and lipid deposits in stromal cells. The uteri were enlarged with evidence of cystic endometrial hyperplasia. The mammary glands were underdeveloped, with decreased branching and lobuloalveolar development. Serum levels of progesterone were reduced, but levels of gonadotropins and estrogen were normal, suggesting a primary ovarian defect. Some aspects of the NERKI phenotype such as underdevelopment of mammary glands and lack of ovulation resemble the phenotype of ERalpha knock-out mice and likely reflect the dominant-negative activity of the ERE-binding-deficient ER mutant. However, the uterine features indicate excessive estrogen action, suggesting an important physiological role for the non-classical ER pathway in this tissue. Both in vitro and in vivo studies demonstrated that the ERE-binding-independent ER signaling is a part of normal actions of estrogens.
Author: William L. McGuire
Publisher:
ISBN:
Category : Medical
Languages : en
Pages : 320
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Category :
Languages : en
Pages : 0
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The estrogen receptor (ER) regulates the expression of genes involved in the growth, proliferation and differentiation of skeletal, cardiovascular, neural and reproductive tissues. A basic scheme for the mechanism for ER action has been developed, but precise details on the interactions between ER and the cellular signaling and transcription machinery required for receptor- mediated regulation of specific target genes are still lacking. We have developed an estrogen responsive system in the fruit fly, Drosophlla melanogaster in order to explore the functional interactions between ER and other cellular proteins. Transgenic flies carrying the human ER alpha and an estrogen responsive green fluorescent protein (GFP) reporter gene were constructed. In vivo expression of the GFP reporter gene was observed when larvae were grown on a food source containing steroidal or nonsteroidal estrogens. The induction of the reporter gene by estrogens was blocked upon treatment with tamoxifen, an estrogen antagonist. However, we did not recapitulate ligand-independent activation of the receptor in vivo or in cultured Drosophila cells. An estrogen responsive Drosophila system could be used to identify and characterize the complex functional interactions between ER and the other components of the cellular transcriptional apparatus.
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Publisher: ScholarlyEditions
ISBN: 1481601652
Category : Medical
Languages : en
Pages : 135
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Book Description
Estrogen Receptors—Advances in Research and Application: 2012 Edition is a ScholarlyEditions™ eBook that delivers timely, authoritative, and comprehensive information about Estrogen Receptors. The editors have built Estrogen Receptors—Advances in Research and Application: 2012 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Estrogen Receptors in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Estrogen Receptors—Advances in Research and Application: 2012 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.
![Mechanisms of Hormonal Activation of Cdc25A and Coactivation of Estrogen Receptor [alpha] by Protein Inhibitor of Activated STAT3 (PIAS3) PDF](https://books.google.com/books/content/images/frontcover/oZP0nQAACAAJ?fife=w80-h100)
Author: Wan-Ru Lee
Publisher:
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Category :
Languages : en
Pages :
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The estrogen receptor (ER) is a ligand-activated transcription factor that regulates gene expression. The classical mechanisms of nuclear ER action include ligand-induced dimerization of ER which binds estrogen responsive elements (EREs) in promoters of target genes. In addition, non-genomic pathways of ER action have also been identified in breast cancer cells. Cdc25A is a tyrosine phosphatase that catalyzes dephosphorylation of cyclin/cyclin-dependent kinase complexes to regulate G1- to S-phase cell cycle progression. Cdc25A mRNA levels are induced by 17[beta]-estradiol (E2) in ZR-75 breast cancer cells, and deletion analysis of the Cdc25A promoter identified the -151 to -12 region as the minimal E2-responsive sequence. Subsequent mutation/deletion analysis showed that at least three different cis-elements were involved in activation of Cdc25A by E2, namely, GC-rich Sp1 binding sites, CCAAT motifs, and E2F sites. Studies with inhibitors and dominant negative expression plasmids show that E2 activates Cdc25A expression through activation of genomic ER[alpha]/Sp1 and E2F1 and cAMP-dependent activation of NF-YA. Thus, both genomic and non-genomic pathways of estrogen action are involved in induction of Cdc25A in breast cancer cells. The PIAS family was initially identified as cytokine-induced inhibitors of STATs which contain several conserved domains involved in binding to other nuclear coactivators. In this study we have investigated coactivation of ER[alpha] by PIAS3 in breast cancer cell lines transiently cotransfected with the pERE3 constructs which contain three tandem EREs linked to a luciferase reporter gene. PIAS3 coactivated ER[alpha]-mediated transactivation in cells cotransfected with pERE3 and wild-type ER[alpha]. In contrast to many other coactivators, PIAS3 also enhanced transactivation of ER[alpha] when cells were cotransfected with the TAF1 ER[alpha] mutant. In addition, PIAS3 does not interact with activation function 2 (AF2) domain of ER[alpha] in a mammalian two-hybrid assay. These data indicate that coactivation of ER[alpha] by PIAS3 was AF2-domain independent. Analysis of several PIAS3 deletion mutants showed that the region containing amino acids 274 to 416 of PIAS3 are required for coactivation suggesting that the RING finger domain and acidic region of PIAS3 are important for interactions with wild-type ER[alpha]. These results demonstrate that PIAS3 coactivated ER[alpha] and this represents a non-classical LXXLL-independent coactivation pathway.
