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Sample records for c-abl regulates estrogen

  1. c-Abl is an upstream regulator of acid sphingomyelinase in apoptosis induced by inhibition of integrins αvβ3 and αvβ5.

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    Xiuhai Ren

    Full Text Available Inhibition of integrins αvβ3/αvβ5 by the cyclic function-blocking peptide, RGDfV (Arg-Gly-Asp-Phe-Val can induce apoptosis in both normal cells and tumor cells. We show that RGDfV induced apoptosis in ECV-304 carcinoma cells, increased activity and mRNA expression of acid sphingomyelinase (ASM, and increased ceramides C(16, C(18:0, C(24:0 and C(24:1 while decreasing the corresponding sphingomyelins. siRNA to ASM decreased RGDfV-induced apoptosis as measured by TUNEL, PARP cleavage, mitochondrial depolarization, and caspase-3 and caspase-8 activities, as well as by annexinV in a 3D collagen model. These findings indicate a causal role for ASM in RGDfV-induced apoptosis in ECV-304. We have shown that c-Abl, a non-receptor tyrosine kinase, also mediates RGDfV-induced apoptosis. However, c-Abl, has not been previously linked to ASM in any system. Here we show that STI-571 (imatinib, inhibitor of c-Abl inhibited RGDfV-induced ASM activity. Furthermore, STI-571 and c-Abl-siRNA both inhibited RGDfV-induced increase in ASM mRNA, but ASM-siRNA did not affect c-Abl phosphorylation or expression, supporting that c-Abl regulates the RGDfV-induced increase in ASM expression. These studies implicate ASM as a mediator of apoptosis induced by inhibition of integrins αvβ3/αvβ5, and for the first time place c-Abl as an upstream regulator of ASM expression and activity.

  2. Breakpoint cluster region-c-abl oncogene 1, non-receptor tyrosine kinase signaling: Current patterns of the versatile regulator revisited

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    Aamir Rana

    2013-01-01

    Full Text Available Increasing sophisticated information suggests that cancer cells express constitutively active oncogenic kinases such as breakpoint cluster region- c-abl oncogene 1, non-receptor tyrosine kinase (BCR-ABL1 that promote carcinogenesis independent of extrinsic growth factors. It is a well-established fact that through the aberrant activation of BCR-ABL1 signal transduction cascade, the perception of cellular growth signals becomes disconnected from the processes promoting cell growth, and this underlies the pathophysiology of leukemia. In this particular review we discuss the oncogenes and tumor suppressors comprising the regulatory network upstream and downstream of BCR-ABL1 and dismantle how derailed BCR-ABL1 signaling provides cell a selective growth advantage. Besides, we discuss why activation of BCR-ABL1, as an outcome of distinct oncogenic events, results in miscellaneous clinical outcomes, and how the intricacy of the BCR-ABL1 signaling network might dictate therapeutic approaches. In this review, our current comprehension of BCR-ABL1 signaling will be summarized.

  3. Epigenetic regulation of estrogen-dependent memory

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    Fortress, Ashley M.; Frick, Karyn M.

    2014-01-01

    Hippocampal memory formation is highly regulated by post-translational histone modifications and DNA methylation. Accordingly, these epigenetic processes play a major role in the effects of modulatory factors, such as sex steroid hormones, on hippocampal memory. Our laboratory recently demonstrated that the ability of the potent estrogen 17β-estradiol (E2) to enhance hippocampal-dependent novel object recognition memory in ovariectomized female mice requires ERK-dependent histone H3 acetylation and DNA methylation in the dorsal hippocampus. Although these data provide valuable insight into the chromatin modifications that mediate the memory-enhancing effects of E2, epigenetic regulation of gene expression is enormously complex. Therefore, more research is needed to fully understand how E2 and other hormones employ epigenetic alterations to shape behavior. This review discusses the epigenetic alterations shown thus far to regulate hippocampal memory, briefly reviews the effects of E2 on hippocampal function, and describes in detail our work on epigenetic regulation of estrogenic memory enhancement. PMID:24878494

  4. Functional interaction between nonreceptor tyrosine kinase c-Abl and SR-Rich protein RBM39

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    Mai, Sanyue [Beijing Institute of Biotechnology, 27 Taiping Rd, Haidian District, Beijing 100850 (China); Qu, Xiuhua [General Navy Hospital of PLA, 6 Fucheng Rd, Haidian District, Beijing 100037 (China); Li, Ping; Ma, Qingjun [Beijing Institute of Biotechnology, 27 Taiping Rd, Haidian District, Beijing 100850 (China); Liu, Xuan, E-mail: liux931932@163.com [Beijing Institute of Biotechnology, 27 Taiping Rd, Haidian District, Beijing 100850 (China); Cao, Cheng, E-mail: cao_c@sohu.com [Beijing Institute of Biotechnology, 27 Taiping Rd, Haidian District, Beijing 100850 (China)

    2016-04-22

    RBM39, also known as splicing factor HCC1.4, acts as a transcriptional coactivator for the steroid nuclear receptors JUN/AP-1, ESR1/ER-α and ESR2/ER-β. RBM39 is involved in the regulation of the transcriptional responses of these steroid nuclear receptors and promotes transcriptional initiation. In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner. The results suggest that mammalian c-Abl plays an important role in steroid hormone receptor-mediated transcription by regulating RBM39. - Highlights: • c-Abl interacts with RBM39. • RBM39 is phosphorylated by c-Abl. • c-Abl regulates transcriptional coactivation activity of RBM39 on the ERα and PRβ.

  5. Melanocortin 4 receptor is not required for estrogenic regulations on energy homeostasis and reproduction

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    Brain estrogen receptor-a (ERa) is essential for estrogenic regulation of energy homeostasis and reproduction. We previously showed that ERa expressed by pro-opiomelanocortin (POMC) neurons mediates estrogen's effects on food intake, body weight, negative regulation of hypothalamic–pituitary–gonadal...

  6. Selective estrogen receptor down-regulator and selective estrogen receptor modulators differentially regulate lactotroph proliferation.

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    Sanjay Kansra

    2010-04-01

    Full Text Available We recently reported that estrogen receptor alpha (ERalpha, even in absence of estrogen (E2, plays a critical role in lactotroph homeostasis. The anti-estrogen ICI 182780 (ICI, but not tamoxifen or raloxifene, rapidly promoted the degradation of ERalpha, and inhibited cell proliferation. However, all three ER antagonists suppressed PRL release, suggesting that receptor occupation is sufficient to inhibit prl gene expression whereas receptor degradation is required to suppress lactotroph proliferation. In this study our objective was to determine whether ERalpha degradation versus occupation, differentially modulates the biological outcome of anti-estrogens.Using the rat lactotroph cell line, GH3 cells, we report that ICI induced proteosome mediated degradation of ERalpha. In contrast, an ERalpha specific antagonist, MPP, that does not promote degradation of ERalpha, did not inhibit cell proliferation. Further, ICI, but not MPP, abolished anchorage independent growth of GH3 cells. Yet, both ICI and MPP were equally effective in suppressing prl expression and release, as well as ERE-mediated transcriptional activity.Taken together, our results demonstrate that in lactotrophs, ERalpha degradation results in decreased cell proliferation, whereas ERalpha occupation by an antagonist that does not promote degradation of ERalpha is sufficient to inhibit prl expression.

  7. Estrogens regulate the hepatic effects of growth hormone, a hormonal interplay with multiple fates

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    Fernández-Pérez, Leandro; Guerra, Borja; Díaz-Chico, Juan C

    2013-01-01

    The liver responds to estrogens and growth hormone (GH) which are critical regulators of body growth, gender-related hepatic functions, and intermediate metabolism. The effects of estrogens on liver can be direct, through the direct actions of hepatic ER, or indirect, which include the crosstalk...... with endocrine, metabolic, and sex-differentiated functions of GH. Most previous studies have been focused on the influence of estrogens on pituitary GH secretion, which has a great impact on hepatic transcriptional regulation. However, there is strong evidence that estrogens can influence the GH......-regulated endocrine and metabolic functions in the human liver by acting at the level of GHR-STAT5 signaling pathway. This crosstalk is relevant because the widespread exposition of estrogen or estrogen-related compounds in human. Therefore, GH or estrogen signaling deficiency as well as the influence of estrogens...

  8. Pancreatic insulin content regulation by the estrogen receptor ER alpha.

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    Paloma Alonso-Magdalena

    Full Text Available The function of pancreatic beta-cells is the synthesis and release of insulin, the main hormone involved in blood glucose homeostasis. Estrogen receptors, ER alpha and ER beta, are important molecules involved in glucose metabolism, yet their role in pancreatic beta-cell physiology is still greatly unknown. In this report we show that both ER alpha and ER beta are present in pancreatic beta-cells. Long term exposure to physiological concentrations of 17beta-estradiol (E2 increased beta-cell insulin content, insulin gene expression and insulin release, yet pancreatic beta-cell mass was unaltered. The up-regulation of pancreatic beta-cell insulin content was imitated by environmentally relevant doses of the widespread endocrine disruptor Bisphenol-A (BPA. The use of ER alpha and ER beta agonists as well as ER alphaKO and ER betaKO mice suggests that the estrogen receptor involved is ER alpha. The up-regulation of pancreatic insulin content by ER alpha activation involves ERK1/2. These data may be important to explain the actions of E2 and environmental estrogens in endocrine pancreatic function and blood glucose homeostasis.

  9. Estrogens regulate the hepatic effects of Growth Hormone, a hormonal interplay with multiple fates

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    Leandro eFernandez-Perez

    2013-06-01

    Full Text Available The liver responds to estrogens and GH which are critical regulators of body growth, gender-related hepatic functions, and intermediate metabolism. The effects of estrogens on liver can be direct, through the direct actions of hepatic ER, or indirect, which include the crosstalk with endocrine, metabolic, and sex-differentiated functions of GH. Most previous studies have been focused on the influence of estrogens on pituitary GH secretion, which has a great impact on hepatic transcriptional regulation. However, there is strong evidence that estrogens can influence the GH-regulated endocrine and metabolic functions in the human liver by acting at the level of GHR-STAT5 signaling pathway. This cross-talk is relevant because the widespread exposition of estrogen or estrogen-related compounds in human. Therefore, GH or estrogen signaling deficiency as well as the influence of estrogens on GH biology can cause a dramatic impact in liver physiology during mammalian development and in adulthood. In this review, we will summarize the current status of the influence of estrogen on GH actions in liver. A better understanding of estrogen-GH interplay in liver will lead to improved therapy of children with growth disorders and of adults with GH deficiency.

  10. Uterine Micro-Environment and Estrogen-Dependent Regulation of Osteopontin Expression in Mouse Blastocyst

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    Qing-Zhen Xie

    2013-07-01

    Full Text Available Embryo implantation is a highly synchronized bioprocess between an activated blastocyst and a receptive uterus. In mice, successful implantation relies on the dynamic interplay of estrogen and progesterone; however, the key mediators downstream of these hormones that act on blastocyst competency and endometrium receptivity acquisition are largely unknown. In this study, we showed that the expression of osteopontin (OPN in mouse blastocysts is regulated by ovarian estrogen and uterine micro-environment. OPN mRNA is up-regulated in mouse blastocyst on day 4 of pregnancy, which is associated with ovarian estrogen secretion peak. Hormone treatment in vivo demonstrated that OPN expression in a blastocyst is regulated by estrogen through an estrogen receptor (ER. Our results of the delayed and activated implantation model showed that OPN expression is induced after estrogen injection. While estrogen treatment during embryo culture in vitro showed less effect on OPN expression, the tubal ligation model on day 3 of pregnancy confirmed that the regulation of estrogen on OPN expression in blastocyst might, through some specific cytokines, have existed in a uterine micro-environment. Collectively, our study presents that estrogen regulates OPN expression and it may play an important role during embryo implantation by activating blastocyst competence and facilitating the endometrium acceptable for active blastocyst.

  11. Progress in the molecular understanding of central regulation of body weight by estrogens

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    Saito, Kenji; Cao, Xuehong; He, Yanlin; Xu, Yong

    2015-01-01

    Objective Estrogens can act in the brain to prevent body weight gain. Tremendous research efforts have been focused on estrogen physiology in the brain in the context of body weight control; estrogen receptors and the related signals have been attractive targets for development of new obesity therapies. The objective is to review recent findings in these aspects. Methods We reviewed recent studies, primarily from those using the conventional and conditional knockout mouse strains, regarding the cellular and molecular mechanisms for the beneficial effects of estrogens on body weight balance. We also discuss emerging genetic tools that could further benefit the field of estrogen research, and newly developed estrogen-based regimen that produce body weight-lowering benefits. Results The body weight-lowering effects of estrogens are mediated by multiple forms of estrogen receptors, in different brain regions through distinct but coordinated mechanisms. Both rapid signals and “classic” nuclear receptor actions of estrogen receptors appear to contribute to estrogenic regulation on body weight. Conclusion Estrogen receptors and associated signal networks are potential targets for obesity treatment, and further investigations are warranted. PMID:25865677

  12. Role of Estrogen in Thyroid Function and Growth Regulation

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    Ana Paula Santin

    2011-01-01

    Full Text Available Thyroid diseases are more prevalent in women, particularly between puberty and menopause. It is wellknown that estrogen (E has indirect effects on the thyroid economy. Direct effects of this steroid hormone on thyroid cells have been described more recently; so, the aim of the present paper was to review the evidences of these effects on thyroid function and growth regulation, and its mechanisms. The expression and ratios of the two E receptors, α and β, that mediate the genomic effects of E on normal and abnormal thyroid tissue were also reviewed, as well as nongenomic, distinct molecular pathways. Several evidences support the hypothesis that E has a direct role in thyroid follicular cells; understanding its influence on the growth and function of the thyroid in normal and abnormal conditions can potentially provide new targets for the treatment of thyroid diseases.

  13. Estrogenic and anti-estrogenic regulation of estrogen receptor in MCF-7 breast-cancer cells: comparison of immunocytochemical data with biochemical measurements.

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    Seo, H S; Larsimont, D; Querton, G; El Khissiin, A; Laios, I; Legros, N; Leclercq, G

    1998-12-09

    Data from immunocytochemical assessment of estrogen receptor (ER) regulation in MCF-7 cells under estrogenic and anti-estrogenic stimulation were compared with those obtained by enzyme immunoassay (Abbott ER-EIA). Similar trends were observed, although ER level variations were less marked when assessed immunocytochemically. We confirmed reports of ER disappearance in the presence of estrogens (Es; E2 and DES) and pure anti-estrogens (AEs; RU 58,668 and ICI 164,384) as well as its increase with partial AEs (4-OH-TAM and RU 39,119). E2-induced ER down-regulation was partly blocked by actinomycin D (AMD), okadaic acid (OK) and cycloheximide (CHX) when assessed by these 2 methods. Down-regulation by pure AEs was not impeded by CHX, indicating that they operate differently from Es (i.e., transformation of ER to a form sensitive to constitutive degradation activity). In situ pre-labeling of the cells with [3H]TAZ indicated that all investigated ligands eliminate pre-existing ER through binding to newly synthetized receptors, since [3H]TAZ co-valently associates with ER; E2 and RU 58,668 were more effective than 4-OH-TAM in this regard. CHX blocked ER disappearance even in the presence of pure AEs, which is in contrast to the data established with cells not pre-exposed to [3H]TAZ. Nuclear location of [3H]TAZ-ER complexes may explain this discrepancy, since pure AE-ER complexes were reported to be incapable of nuclear translocation.

  14. Estrogenic Regulation of the GnRH Neuron

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    Sally eRadovick

    2012-04-01

    Full Text Available Reproductive function is regulated by the secretion of luteinizing hormone (LH and follicle-stimulating hormone (FSH from the pituitary and the steroid hormones from the gonads. The dynamic changes in the levels of the reproductive hormones regulate secondary sex characteristics, gametogenesis, cellular function and behavior. Hypothalamic GnRH neurons, with cell bodies located in the basal hypothalamus, represent the final common pathway for neuronally derived signals to the pituitary. As such, they serve as integrators of a dizzying array of signals including sensory inputs mediating information about circadian, seasonal, behavioral, pheromonal and emotional cues. Additionally, information about peripheral physiological function may also be included in the integrative signal to the GnRH neuron. These signals may communicate information about metabolic status, disease or infection. Gonadal steroid hormones arguably exert the most important effects on GnRH neuronal function. In both males and females, the gonadal steroid hormones exert negative feedback regulation on axis activity at both the level of the pituitary and the hypothalamus. These negative feedback loops regulate homeostasis of steroid hormone levels. In females, a cyclic reversal of estrogen feedback produces a positive feedback loop at both the hypothalamic and pituitary levels. Central positive feedback results in a dramatic increase in GnRH secretion (Sisk and others 2001; Clarke 1993; Moenter, Brand and Karsch 1992; Xia and others 1992. This is coupled with an increase in pituitary sensitivity to GnRH (Turzillo, DiGregorio and Nett 1995; Savoy-Moore and others 1980, which produces the massive surge in secretion of LH that triggers ovulation.

  15. Estrogenic and antiestrogenic regulation of the half-life of covalently labeled estrogen receptor in MCF-7 breast cancer cells.

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    Borrás, M; Laios, I; el Khissiin, A; Seo, H S; Lempereur, F; Legros, N; Leclercq, G

    1996-02-01

    Effect of estrogens and antiestrogens (AEs) on estrogen receptor (ER) half-life was analyzed in MCF-7 cells by assessing its progressive disappearance after covalent labeling in situ with [3H]tamoxifen aziridine ([3H]TAZ). Cells were incubated for 1 h with 20 nM [3H]TAZ either in the absence or presence of a 500-fold excess of unlabeled estradiol (E2) (non-specific binding). The entire ER population was labeled by this method as established by subsequent incubation of the cells with [125I]E2. [3H]TAZ labeled cells were maintained in culture for additional 5 h in the absence (control) or presence of increasing amounts (0.1 nM - 1 microM) of either a given estrogen (E2, estrone, diethylstilbestrol, bisphenol), a pure AE (RU 58 668, ICI 164 384) or an AE with residual estrogenic activity (RU 39 411, 4-hydroxytamoxifen, keoxifene). The progressive disappearance of nuclear and cytosolic [3H]TAZ-ER complex during 5 h incubation were assessed by their immunoprecipitation with anti-ER monoclonal antibody (H 222) followed by scintillation counting or SDS-PAGE and fluorography. Fading of labeled receptors was extremely slow (approximately 10% loss after 6 h) in absence of any hormone/antihormone indicating a long half-life of the [3H]TAZ-ER complex. Addition of estrogens as well as pure AEs led to a dramatic reduction of the half-life while AEs with residual estrogenic activity were extremely less efficient in this regard providing an explanation for the ability of latter compounds to up-regulate the receptor since they do not affect ER mRNA synthesis and stability. Receptor disappearance induced by estrogens was closely related to their binding affinity for ER. Newly synthesized ER emerged during the treatment with hormones or antihormones seems to be implicated in the phenomenon since [3H]TAZ was covalently bound and could, therefore, not be displaced by these compounds. Induction of synthesis of a short half-life peptide(s) with degradative activity was demonstrated by

  16. Estrogen receptor beta participate in the regulation of metabolizm of extracellular matrix in estrogen alpha negative breast cancer.

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    Leśniewska, Monika; Miltyk, Wojciech; Swiatecka, Jolanta; Tomaszewska, Małgorzata; Kuźmicki, Mariusz; Pałka, Jerzy; Wołczyński, Sławomir

    2009-01-01

    The biology of breast cancer is closely releted to sex steroid hormones. Estrogen receptor beta is overexpressed in around 70% breast cancer cases, referrd to as "ER positive". Estrogens bind to estrogen receptor and stimulate the transcription of genes involved in control of cell proliferation. Moreover, estrogens may induce growth factors and components of extracellular matrix and interact with them in a complex manner. Extracellular matrix and integrins play an important role in cell functions and their aberrant expressions are implicated in breast cancer development, invasion and metastasis. ER beta is certainly associated with more differentiated tumors, while evidence of role of ER beta is controversial. The highly invasive breast cancer ER beta negative cell line MDA-MB 231 can be the model of exam the role of ER beta in breast cancer. The aim of this study was to examine the role of activation of ER beta on the metabolism of the extracellular matrix and the expression of beta-1 integrin in the breast cancer cell line MDA-MB 231. The cells were exposed on the estradiol, tamoxifen, raloxifen and genisteina in dose dependent concentrations. To determine the relative rate of collagen syntesis we measured the time-dependent reduction of collagen-bound radioactivity after pulse-chase labeling with [3 H] prolina by Peterkofsky methods. The expression of beta-1 integrin was determine by Western blot analysis. The activity of MMP2 and 9 were measured using gelatin zymography with an image analysis system. Our data suggest on the role of estrogen receptor beta on the metabolism of extracellular matrix in the breast cancer line MDA - MB 231. Estradiol and SERMs regulate the expression of ECM proteins: collagen, integrins and enhance activity of metaloproteinases 2 and 9.

  17. Estrogen receptor beta participate in the regulation of metabolizm of extracellular matrix in estrogen alpha negative breast cancer.

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    Mariusz Kuźmicki

    2010-01-01

    Full Text Available The biology of breast cancer is closely releted to sex steroid hormones. Estrogen receptor beta is overexpressed in around 70% breast cancer cases, referrd to as "ER positive". Estrogens bind to estrogen receptor and stimulate the transcription of genes involved in control of cell proliferation. Moreover, estrogens may induce growth factors and components of extracellular matrix and interact with them in a complex manner. Extracellular matrix and integrins play an important role in cell functions and their aberrant expressions are implicated in breast cancer development, invasion and metastasis. ER beta is certainly associated with more differentiated tumors, while evidence of role of ER beta is controversial. The highly invasive breast cancer ER beta negative cell line MDA-MB 231 can be the model of exam the role of ER beta in breast cancer. The aim of this study was to examine the role of activation of ER beta on the metabolism of the extracellular matrix and the expression of beta-1 integrin in the breast cancer cell line MDA-MB 231. The cells were exposed on the estradiol, tamoxifen, raloxifen and genisteina in dose dependent concentrations. To determine the relative rate of collagen syntesis we measured the time-dependent reduction of collagen-bound radioactivity after pulse-chase labeling with [3 H] prolina by Peterkofsky methods. The expression of beta-1 integrin was determine by Western blot analysis. The activity of MMP2 and 9 were measured using gelatin zymography with an image analysis system. Our data suggest on the role of estrogen receptor beta on the metabolism of extracellular matrix in the breast cancer line MDA - MB 231. Estradiol and SERMs regulate the expression of ECM proteins: collagen, integrins and enhance activity of metaloproteinases 2 and 9.

  18. Estrogen Regulates Bone Turnover by Targeting RANKL Expression in Bone Lining Cells.

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    Streicher, Carmen; Heyny, Alexandra; Andrukhova, Olena; Haigl, Barbara; Slavic, Svetlana; Schüler, Christiane; Kollmann, Karoline; Kantner, Ingrid; Sexl, Veronika; Kleiter, Miriam; Hofbauer, Lorenz C; Kostenuik, Paul J; Erben, Reinhold G

    2017-07-25

    Estrogen is critical for skeletal homeostasis and regulates bone remodeling, in part, by modulating the expression of receptor activator of NF-κB ligand (RANKL), an essential cytokine for bone resorption by osteoclasts. RANKL can be produced by a variety of hematopoietic (e.g. T and B-cell) and mesenchymal (osteoblast lineage, chondrocyte) cell types. The cellular mechanisms by which estrogen acts on bone are still a matter of controversy. By using murine reconstitution models that allow for selective deletion of estrogen receptor-alpha (ERα) or selective inhibition of RANKL in hematopoietic vs. mesenchymal cells, in conjunction with in situ expression profiling in bone cells, we identified bone lining cells as important gatekeepers of estrogen-controlled bone resorption. Our data indicate that the increase in bone resorption observed in states of estrogen deficiency in mice is mainly caused by lack of ERα-mediated suppression of RANKL expression in bone lining cells.

  19. Role of estrogen receptors in the regulation of reactive gliosis

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    Luis Miguel Garcia-Segura

    2015-02-01

    Full Text Available Although estradiol may directly act on neurons to promote neuroprotection in vitro, the participation of other cell types is also necessary to maintain global tissue homeostasis in vivo (Arevalo et al., 2010; Johann and Beyer, 2013; Acaz-Fonseca et al., 2014. Thus, estradiol acts on glial and endothelial cells to maintain the function of the neurovascular unit, regulates gliosis and the inflammatory response of astrocytes and microglia to control neuroinflammation and acts on neurons, astrocytes and oligodendrocytes to maintain the function and propagating properties of neuronal circuits (Garcia-Ovejero et al., 2005; Tapia-Gonzalez et al., 2008; Barrerto et al., 2009; Cerciat et al., 2010; López Rodríguez et al., 2011; Barreto et al., 2014. Glial cells express estrogen receptors (ERs, including ERalpha, ERbeta and G protein-coupled estrogen receptor-1 (GPER (Garcia-Ovjero et al., 2005; Dhandapani and Brann, 2007 and brain injury induces both the synthesis of estradiol in both reactive astrocytes and the expression of ERs in these cells (Garcia-Ovejero et al., 2002. This suggests that astrocytes may play an important role in the neuroprotective actions of estradiol. Indeed, recent studies, using conditional KO mice for ERalpha and ERbeta, have shown that in an experimental model of multiple sclerosis the protective action of estradiol is mediated by ERalpha expressed in astrocytes, but not by ERalpha expressed in neurons or ERbeta expressed in astrocytes or neurons (Spence et al., 2013. ERs in glial cells activate several neuroprotective mechanisms in response to estradiol, including the release of factors that have trophic effects on neurons and other cell types and the control of neuroinflammation, edema and extracellular glutamate levels. Classical ERs associated with the plasma membrane of astrocytes are involved in the estradiol-induced release of transforming growth factor (TGF-beta, through the activation of the PI3K/Akt signaling

  20. G protein-coupled estrogen receptor regulates embryonic heart rate in zebrafish.

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    Romano, Shannon N; Edwards, Hailey E; Souder, Jaclyn Paige; Ryan, Kevin J; Cui, Xiangqin; Gorelick, Daniel A

    2017-10-24

    Estrogens act by binding to estrogen receptors alpha and beta (ERα, ERβ), ligand-dependent transcription factors that play crucial roles in sex differentiation, tumor growth and cardiovascular physiology. Estrogens also activate the G protein-coupled estrogen receptor (GPER), however the function of GPER in vivo is less well understood. Here we find that GPER is required for normal heart rate in zebrafish embryos. Acute exposure to estrogens increased heart rate in wildtype and in ERα and ERβ mutant embryos but not in GPER mutants. GPER mutant embryos exhibited reduced basal heart rate, while heart rate was normal in ERα and ERβ mutants. We detected gper transcript in discrete regions of the brain and pituitary but not in the heart, suggesting that GPER acts centrally to regulate heart rate. In the pituitary, we observed gper expression in cells that regulate levels of thyroid hormone triiodothyronine (T3), a hormone known to increase heart rate. Compared to wild type, GPER mutants had reduced levels of T3 and estrogens, suggesting pituitary abnormalities. Exposure to exogenous T3, but not estradiol, rescued the reduced heart rate phenotype in gper mutant embryos, demonstrating that T3 acts downstream of GPER to regulate heart rate. Using genetic and mass spectrometry approaches, we find that GPER regulates maternal estrogen levels, which are required for normal embryonic heart rate. Our results demonstrate that estradiol plays a previously unappreciated role in the acute modulation of heart rate during zebrafish embryonic development and suggest that GPER regulates embryonic heart rate by altering maternal estrogen levels and embryonic T3 levels.

  1. Estrogens regulate neuroinflammatory genes via estrogen receptors α and β in the frontal cortex of middle-aged female rats

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    Mahó Sándor

    2011-07-01

    Full Text Available Abstract Background Estrogens exert anti-inflammatory and neuroprotective effects in the brain mainly via estrogen receptors α (ERα and β (ERβ. These receptors are members of the nuclear receptor superfamily of ligand-dependent transcription factors. This study was aimed at the elucidation of the effects of ERα and ERβ agonists on the expression of neuroinflammatory genes in the frontal cortex of aging female rats. Methods To identify estrogen-responsive immunity/inflammation genes, we treated middle-aged, ovariectomized rats with 17β-estradiol (E2, ERα agonist 16α-lactone-estradiol (16α-LE2 and ERβ agonist diarylpropionitrile (DPN, or vehicle by Alzet minipump delivery for 29 days. Then we compared the transcriptomes of the frontal cortex of estrogen-deprived versus ER agonist-treated animals using Affymetrix Rat230 2.0 expression arrays and TaqMan-based quantitative real-time PCR. Microarray and PCR data were evaluated by using Bioconductor packages and the RealTime StatMiner software, respectively. Results Microarray analysis revealed the transcriptional regulation of 21 immunity/inflammation genes by 16α-LE2. The subsequent comparative real-time PCR study analyzed the isotype specific effects of ER agonists on neuroinflammatory genes of primarily glial origin. E2 regulated the expression of sixteen genes, including down-regulation of complement C3 and C4b, Ccl2, Tgfb1, macrophage expressed gene Mpeg1, RT1-Aw2, Cx3cr1, Fcgr2b, Cd11b, Tlr4 and Tlr9, and up-regulation of defensin Np4 and RatNP-3b, IgG-2a, Il6 and ER gene Esr1. Similar to E2, both 16α-LE2 and DPN evoked up-regulation of defensins, IgG-2a and Il6, and down-regulation of C3 and its receptor Cd11b, Ccl2, RT1-Aw2 and Fcgr2b. Conclusions These findings provide evidence that E2, 16α-LE2 and DPN modulate the expression of neuroinflammatory genes in the frontal cortex of middle-aged female rats via both ERα and ERβ. We propose that ERβ is a promising target to suppress

  2. Hypothalamic regulation of metabolism : Role of thyroid hormone and estrogen

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    Zhang, Z.

    2017-01-01

    Thyroid hormone and estrogen both play an essential role in energy metabolism. The current thesis investigated the possible central effects of these hormones in the control of energy metabolism by administrating triiodothyronine (T3), estradiol (E2) and thyrotropin-releasing hormone (TRH) in

  3. The regulation of MS-KIF18A expression and cross talk with estrogen receptor.

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    Margalit Zusev

    2009-07-01

    Full Text Available This study provides a novel view on the interactions between the MS-KIF18A, a kinesin protein, and estrogen receptor alpha (ERalpha which were studied in vivo and in vitro. Additionally, the regulation of MS-KIF18A expression by estrogen was investigated at the gene and protein levels. An association between recombinant proteins; ERalpha and MS-KIF18A was demonstrated in vitro in a pull down assay. Such interactions were proven also for endogenous proteins in MBA-15 cells were detected prominently in the cytoplasm and are up-regulated by estrogen. Additionally, an association between these proteins and the transcription factor NF-kappaB was identified. MS-KIF18A mRNA expression was measured in vivo in relation to age and estrogen level in mice and rats models. A decrease in MS-KIF18A mRNA level was measured in old and in OVX-estrogen depleted rats as compared to young animals. The low MS-KIF18A mRNA expression in OVX rats was restored by estrogen treatment. We studied the regulation of MS-KIF18A transcription by estrogen using the luciferase reporter gene and chromatin immuno-precipitation (ChIP assays. The luciferase reporter gene assay demonstrated an increase in MS-KIF18A promoter activity in response to 10(-8 M estrogen and 10(-7M ICI-182,780. Complimentary, the ChIP assay quantified the binding of ERalpha and pcJun to the MS-KIF18A promoter that was enhanced in cells treated by estrogen and ICI-182,780. In addition, cells treated by estrogen expressed higher levels of MS-KIF18A mRNA and protein and the protein turnover in MBA-15 cells was accelerated. Presented data demonstrated that ERalpha is a defined cargo of MS-KIF18A and added novel insight on the role of estrogen in regulation of MS-KIF18A expression both in vivo and in vitro.

  4. Estrogens, selective estrogen receptor modulators, and a selective estrogen receptor down-regulator inhibit endothelial production of tissue factor pathway inhibitor 1

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    Ree Anne

    2006-10-01

    Full Text Available Abstract Background Hormone therapy, oral contraceptives, and tamoxifen increase the risk of thrombotic disease. These compounds also reduce plasma content of tissue factor pathway inhibitor-1 (TFPI, which is the physiological inhibitor of the tissue factor pathway of coagulation. The current aim was to study if estrogens and estrogen receptor (ER modulators may inhibit TFPI production in cultured endothelial cells and, if so, identify possible mechanisms involved. Methods Human endothelial cell cultures were treated with 17β-estradiol (E2, 17α-ethinylestradiol (EE2, tamoxifen, raloxifene, or fulvestrant. Protein levels of TFPI in cell media and cell lysates were measured by an enzyme-linked immunosorbent assay, and TFPI mRNA levels were assessed by quantitative PCR. Expression of ERα was analysed by immunostaining. Results All compounds (each in a concentration of 10 nM reduced TFPI in cell medium, by 34% (E2, 21% (EE2, 16% (tamoxifen, and 28% (raloxifene, respectively, with identical inhibitory effects on cellular TFPI levels. Expression of TFPI mRNA was principally unchanged. Treatment with fulvestrant, which was also associated with down-regulation of secreted TFPI (9% with 10 nM and 26% with 1000 nM, abolished the TFPI-inhibiting effect of raloxifene, but not of the other compounds. Notably, the combination of 1000 nM fulvestrant and 10 nM raloxifene increased TFPI secretion, and, conversely, 10 nM of either tamoxifen or raloxifene seemed to partly (tamoxifen or fully (raloxifene counteract the inhibitory effect of 1000 nM fulvestrant. The cells did not express the regular nuclear 66 kDa ERα, but instead a 45 kDa ERα, which was not regulated by estrogens or ER modulators. Conclusion E2, EE2, tamoxifen, raloxifene, and fulvestrant inhibited endothelial production of TFPI by a mechanism apparently independent of TFPI transcription.

  5. Hypothalamic regulation of metabolism: Role of thyroid hormone and estrogen

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    Zhang, Z.

    2017-01-01

    Thyroid hormone and estrogen both play an essential role in energy metabolism. The current thesis investigated the possible central effects of these hormones in the control of energy metabolism by administrating triiodothyronine (T3), estradiol (E2) and thyrotropin-releasing hormone (TRH) in distinct hypothalamic nuclei. We evaluated various aspects of metabolic alterations including glucose and lipid metabolism, food intake, body weight, body temperature, locomotor activity, energy expenditu...

  6. Endogenous Estrogen-Mediated Heme Oxygenase Regulation in Experimental Menopause

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    Anikó Pósa

    2015-01-01

    Full Text Available Estrogen deficiency is one of the main causes of age-associated diseases in the cardiovascular system. Female Wistar rats were divided into four experimental groups: pharmacologically ovariectomized, surgically ovariectomized, and 24-month-old intact aging animals were compared with a control group. The activity and expression of heme oxygenases (HO in the cardiac left ventricle, the concentrations of cardiac interleukin-6 (IL-6 and tumor necrosis factor-α (TNF-α, the myeloperoxidase (MPO activity in the cardiac left ventricle, and the effects of heme oxygenase blockade (by 24-hour and 1-hour pretreatment with tin-protoporphyrin IX, SnPP on the epinephrine and phentolamine-induced electrocardiogram ST segment changes in vivo were investigated. The cardiac HO activity and the expression of HO-1 and HO-2 were significantly decreased in the aged rats and after ovariectomy. Estrogen depletion was accompanied by significant increases in the expression of IL-6 and TNF-α. The aged and ovariectomized animals exhibited a significantly elevated MPO activity and a significant ST segment depression. After pretreatment with SnPP augmented ST segment changes were determined. These findings demonstrate that the sensitivity to cardiac ischemia in estrogen depletion models is associated with suppression of the activity and expression of the HO system and increases in the secretion of proinflammatory cytokines and biomarkers.

  7. Endogenous Estrogen-Mediated Heme Oxygenase Regulation in Experimental Menopause

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    Pósa, Anikó; Veszelka, Médea; Berkó, Anikó Magyariné; Baráth, Zoltán; Ménesi, Rudolf; Pávó, Imre; László, Ferenc; Varga, Csaba

    2015-01-01

    Estrogen deficiency is one of the main causes of age-associated diseases in the cardiovascular system. Female Wistar rats were divided into four experimental groups: pharmacologically ovariectomized, surgically ovariectomized, and 24-month-old intact aging animals were compared with a control group. The activity and expression of heme oxygenases (HO) in the cardiac left ventricle, the concentrations of cardiac interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), the myeloperoxidase (MPO) activity in the cardiac left ventricle, and the effects of heme oxygenase blockade (by 24-hour and 1-hour pretreatment with tin-protoporphyrin IX, SnPP) on the epinephrine and phentolamine-induced electrocardiogram ST segment changes in vivo were investigated. The cardiac HO activity and the expression of HO-1 and HO-2 were significantly decreased in the aged rats and after ovariectomy. Estrogen depletion was accompanied by significant increases in the expression of IL-6 and TNF-α. The aged and ovariectomized animals exhibited a significantly elevated MPO activity and a significant ST segment depression. After pretreatment with SnPP augmented ST segment changes were determined. These findings demonstrate that the sensitivity to cardiac ischemia in estrogen depletion models is associated with suppression of the activity and expression of the HO system and increases in the secretion of proinflammatory cytokines and biomarkers. PMID:26064421

  8. Estrogen levels, emotion regulation, and emotional symptoms of women with premenstrual dysphoric disorder: The moderating effect of estrogen receptor 1α polymorphism.

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    Yen, Ju-Yu; Wang, Peng-Wei; Su, Chen-Hsiang; Liu, Tai-Ling; Long, Cheng-Yu; Ko, Chih-Hung

    2017-11-14

    This study evaluated the association between estrogen levels, emotion regulation, depression, anxiety, and stress of women with premenstrual dysphoric disorder (PMDD). We also evaluated the moderating effect of estrogen receptor (ESR) α-Xbal polymorphism on the aforementioned association. A total of 100 women were diagnosed with PMDD based on psychiatric interviews and a prospective investigation of 3 menstrual cycles. A total of 96 normal individuals were recruited as controls. Their estrogen levels, depression, anxiety, stress, and ESR α-Xbal polymorphism in both premenstrual and follicular phases were assessed, and these data were included in the final analysis. The PMDD group had high depression, anxiety, and stress and low emotional adjusting and tolerating in the premenstrual phase. Emotional adjustment was negatively associated with depression, anxiety and stress. No association was observed between PMDD and estrogen level. However, premenstrual estrogen level was negatively correlated with anxiety and stress in women with PMDD. The association was only significant in G carriers of ESR α-Xbal, as was the difference in premenstrual emotion regulation between the PMDD and control groups. The results demonstrate the association between estrogen and anxiety in PMDD, supporting the claim that women with PMDD differ in their responses to normal estrogen levels. Furthermore, this association and dysfunctional emotional regulation in PMDD existed only among the G carriers of ESR α-Xbal polymorphism. Future studies should investigate the effect of estrogen on brain functions involving emotional regulation in women with PMDD, stratified by ESR α-Xbal polymorphism. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Microarray Analysis on Gene Regulation by Estrogen, Progesterone and Tamoxifen in Human Endometrial Stromal Cells

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    Chun-E Ren

    2015-03-01

    Full Text Available Epithelial stromal cells represent a major cellular component of human uterine endometrium that is subject to tight hormonal regulation. Through cell-cell contacts and/or paracrine mechanisms, stromal cells play a significant role in the malignant transformation of epithelial cells. We isolated stromal cells from normal human endometrium and investigated the morphological and transcriptional changes induced by estrogen, progesterone and tamoxifen. We demonstrated that stromal cells express appreciable levels of estrogen and progesterone receptors and undergo different morphological changes upon hormonal stimulation. Microarray analysis indicated that both estrogen and progesterone induced dramatic alterations in a variety of genes associated with cell structure, transcription, cell cycle, and signaling. However, divergent patterns of changes, and in some genes opposite effects, were observed for the two hormones. A large number of genes are identified as novel targets for hormonal regulation. These hormone-responsive genes may be involved in normal uterine function and the development of endometrial malignancies.

  10. Post-Transcriptional Regulation of Chemokine Receptor CXCR4 by Estrogen in HER2 Overexpressing, Estrogen Receptor-Positive Breast Cancer Cells

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    Sengupta, Surojeet; Schiff, Rachel; Katzenellenbogen, Benita S.

    2008-01-01

    Expression of the chemokine receptor CXCR4, a G protein-coupled receptor, and HER2, a receptor tyrosine kinase, strongly correlates with the aggressive and metastatic potential of breast cancer cells. We studied estrogen regulation of CXCR4 in estrogen receptor (ER)-positive MCF-7 breast cancer cells overexpressing HER2 (MCF7-HER2). Although estrogen evoked no change in CXCR4 mRNA levels, CXCR4 protein was significantly up-regulated after estrogen treatment of these cells, whereas estrogen had no effect on CXCR4 protein level in parental MCF7 cells that are low in HER2. Use of the CXCR4 specific inhibitor, AMD 3100, indicated that this increase in CXCR4 protein was partially responsible for the increase in estrogen-induced migration of these cells. The estrogen-induced increase in CXCR4 protein in MCF-7-HER2 cells was abrogated by the antiestrogen ICI 182780 and by gefitinib (Iressa; a phosphotyrosine kinase inhibitor), indicating an ER-mediated effect and confirming involvement of receptor tyrosine kinases, respectively. Using specific pathway inhibitors, we show that the estrogen-induced increase in CXCR4 involves PI3K/AKT, MAPK and mTOR pathways. PI3K/AKT and MAPK pathways are known to result in the phosphorylation and functional inactivation of tuberin (TSC2) of tuberous sclerosis complex thereby negating its inhibitory effects on mTOR, which in turn stimulates the translational machinery. Small interfering RNA (siRNA) mediated knockdown of tuberin elevated the level of CXCR4 protein in MCF7-HER2 cells and also nullified further estrogen up-regulation of CXCR4. This study suggests a pivotal role of PI3K, MAPK and mTOR pathways, via tuberin, in post-transcriptional control of CXCR4, initiated through estrogen-stimulated crosstalk between ER and HER2. Thus, post-transcriptional regulation of CXCR4 by estrogens acting through ER via kinase pathways may play a critical role in determining the metastatic potential of breast cancer cells. PMID:18807177

  11. Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System.

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    Lawana, Vivek; Singh, Neeraj; Sarkar, Souvarish; Charli, Adhithiya; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Anumantha G; Kanthasamy, Arthi

    2017-12-01

    A growing body of evidence suggests that excessive microglial activation and pesticide exposure may be linked to the etiology of PD; however, the mechanisms involved remain elusive. Emerging evidence indicates that intracellular inflammasome complex namely NLRP3 complex is involved in the recognition and execution of host inflammatory response. Thus, in the present study, we investigated the hypothesis that NLRP3 inflammasome activation is linked to rotenone (ROT)-induced microglial activation which is dependent upon a priming stimulus by a pathogen-associated molecular pattern (PAMP) or damage associated molecular pattern (DAMP), respectively. Herein using both BV2 cells and primary microglial cells, we show that LPS priming and subsequent ROT stimulation enhanced NLRP3 inflammasome activation, c-Abl and PKCδ activation, mitochondrial dysfunction, NF-κB activation, and autophagic markers, while TFEB levels were decreased dramatically. Mechanistic studies revealed c-Abl acts as a proximal signal that exacerbated the activation of the afore mentioned markers. Intriguingly, siRNA-mediated depletion or pharmacological inhibition of c-Abl via dasatinib abrogated LPS and ROT-induced microglial activation response via attenuation of NLRP3 inflammasome activation, mitochondrial oxidative stress, and ALS dysfunction. Moreover, mitoTEMPO, a mitochondrial antioxidant, attenuated NLRP3 inflammasome activation effects via blockade of c-Abl and PKCδ activation. In LPS treated mice, dasatinib attenuated NLRP3 inflammasome activation, c-Abl and PKCδ activation; and sickness behavior. Together our findings identify an exaggerated ROS/c-Abl/NLRP3 signaling axis in the heightened microglial activation response evidenced in LPS-primed ROT-stimulated microglial cells and suggest that targeting c-Abl-regulated NLRP3 inflammasome signaling offers a novel therapeutic strategy for PD treatment. Graphical Abstract ᅟ.

  12. Estrogen receptor-a in medial amygdala neurons regulates body weight

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    Estrogen receptor–a (ERa) activity in the brain prevents obesity in both males and females. However, the ERa-expressing neural populations that regulate body weight remain to be fully elucidated. Here we showed that single-minded–1 (SIM1) neurons in the medial amygdala (MeA) express abundant levels ...

  13. c-Abl inhibition mitigates diet-induced obesity through improving insulin sensitivity of subcutaneous fat in mice.

    Science.gov (United States)

    Wu, Rong; Sun, Jian-Guang; Wang, Ji-Qiu; Li, Binhua; Liu, Qingsong; Ning, Guang; Jin, Wanzhu; Yuan, Zengqiang

    2017-05-01

    High-energy diets are among the main causes of the global epidemic of metabolic disorders, including obesity and type 2 diabetes. The mechanisms of high-energy-diet-induced metabolic disorders are complex and largely unknown. The non-receptor tyrosine kinase c-Abl plays an important role in adipogenesis in vitro but its role in vivo in the regulation of metabolism is still elusive. Hence, we sought to address the role of c-Abl in diet-induced obesity and obesity-associated insulin resistance. The expression of c-Abl in different fat tissues from obese humans or mice fed a high-fat diet (HFD) were first analysed by western blotting and quantitative PCR. We employed conditional deletion of the c-Abl gene (also known as Abl1) in adipose tissue using Fabp4-Cre and 6-week-old mice were fed with either a chow diet (CD) or an HFD. Age-matched wild-type mice were treated with the c-Abl inhibitor nilotinib or with vehicle and exposed to either CD or HFD, followed by analysis of body mass, fat mass, glucose and insulin tolerance. Histological staining, ELISA and biochemical analysis were used to clarify details of changes in physiology and molecular signalling. c-Abl was highly expressed in subcutaneous fat from obese humans and HFD-induced obese mice. Conditional knockout of c-Abl in adipose tissue improved insulin sensitivity and mitigated HFD-induced body mass gain, hyperglycaemia and hyperinsulinaemia. Consistently, treatment with nilotinib significantly reduced fat mass and improved insulin sensitivity in HFD-fed mice. Further biochemical analyses suggested that c-Abl inhibition improved whole-body insulin sensitivity by reducing HFD-triggered insulin resistance and increasing adiponectin in subcutaneous fat. Our findings define a new biological role for c-Abl in the regulation of diet-induced obesity through improving insulin sensitivity of subcutaneous fat. This suggests it may become a novel therapeutic target in the treatment of metabolic disorders.

  14. MiR-22/Sp-1 Links Estrogens With the Up-Regulation of Cystathionine γ-Lyase in Myocardium, Which Contributes to Estrogenic Cardioprotection Against Oxidative Stress.

    Science.gov (United States)

    Wang, Long; Tang, Zhi-Ping; Zhao, Wei; Cong, Bing-Hai; Lu, Jian-Qiang; Tang, Xiao-Lu; Li, Xiao-Han; Zhu, Xiao-Yan; Ni, Xin

    2015-06-01

    Hydrogen sulfide, generated in the myocardium predominantly via cystathionine-γ-lyase (CSE), is cardioprotective. Our previous study has shown that estrogens enhance CSE expression in myocardium of female rats. The present study aims to explore the mechanisms by which estrogens regulate CSE expression, in particular to clarify the role of estrogen receptor subtypes and the transcriptional factor responsible for the estrogenic effects. We found that either the CSE inhibitor or the CSE small interfering RNA attenuated the protective effect of 17β-estradiol (E2) against H2O2- and hypoxia/reoxygenation-induced injury in primary cultured neonatal cardiomyocytes. E2 stimulates CSE expression via estrogen receptor (ER)-α both in cultured cardiomyocytes in vitro and in the myocardium of female mice in vivo. A specificity protein-1 (Sp-1) consensus site was identified in the rat CSE promoter and was found to mediate the E2-induced CSE expression. E2 increases ERα and Sp-1 and inhibits microRNA (miR)-22 expression in myocardium of ovariectomized rats. In primary cardiomyocytes, E2 stimulates Sp-1 expression through the ERα-mediated down-regulation of miR-22. It was confirmed that both ERα and Sp-1 were targeted by miR-22. In the myocardium of ovariectomized rats, the level of miR-22 inversely correlated to CSE, ERα, Sp-1, and antioxidant biomarkers and positively correlated to oxidative biomarkers. In summary, this study demonstrates that estrogens stimulate Sp-1 through the ERα-mediated down-regulation of miR-22 in cardiomyocytes, leading to the up-regulation of CSE, which in turn results in an increase of antioxidative defense. Interaction of ERα, miR-22, and Sp-1 may play a critical role in the control of oxidative stress status in the myocardium of female rats.

  15. Estrogen receptor α functions in the regulation of motivation and spatial cognition in young male rats.

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    Katrin Meyer

    Full Text Available Estrogenic functions in regulating behavioral states such as motivation, mood, anxiety, and cognition are relatively well documented in female humans and animals. In males, however, although the entire enzymatic machinery for producing estradiol and the corresponding receptors are present, estrogenic functions have been largely neglected. Therefore, and as a follow-up study to previous research, we sub-chronically applied a specific estrogen receptor α (ERα antagonist in young male rats before and during a spatial learning task (holeboard. The male rats showed a dose-dependent increase in motivational, but not cognitive, behavior. The expression of hippocampal steroid receptor genes, such as glucocorticoid (GR, mineralocorticoid (MR, androgen (AR, and the estrogen receptor ERα but not ERβ was dose-dependently reduced. The expression of the aromatase but not the brain-derived neurotrophic factor (BDNF encoding gene was also suppressed. Reduced gene expression and increased behavioral performance converged at an antagonist concentration of 7.4 µmol. The hippocampal and blood serum hormone levels (corticosterone, testosterone, and 17β-estradiol did not differ between the experimental groups and controls. We conclude that steroid receptors (and BDNF act in a concerted, network-like manner to affect behavior and mutual gene expression. Therefore, the isolated view on single receptor types is probably insufficient to explain steroid effects on behavior. The steroid network may keep motivation in homeostasis by supporting and constraining the behavioral expression of motivation.

  16. Discovery and Characterization of a Cell-Permeable, Small-Molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Jingsong; Campobasso, Nino; Biju, Mangatt P.; Fisher, Kelly; Pan, Xiao-Qing; Cottom, Josh; Galbraith, Sarah; Ho, Thau; Zhang, Hong; Hong, Xuan; Ward, Paris; Hofmann, Glenn; Siegfried, Brett; Zappacosta, Francesca; Washio, Yoshiaki; Cao, Ping; Qu, Junya; Bertrand, Sophie; Wang, Da-Yuan; Head, Martha S.; Li, Hu; Moores, Sheri; Lai, Zhihong; Johanson, Kyung; Burton, George; Erickson-Miller, Connie; Simpson, Graham; Tummino, Peter; Copeland, Robert A.; Oliff, Allen (GSKPA)

    2014-10-02

    c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the {alpha}I helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the {alpha}I helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.

  17. Molecular characterization and estrogen regulation of hypothalamic KISS1 gene in the pig.

    Science.gov (United States)

    Tomikawa, Junko; Homma, Tamami; Tajima, Shigeyuki; Shibata, Takako; Inamoto, Yoko; Takase, Kenji; Inoue, Naoko; Ohkura, Satoshi; Uenoyama, Yoshihisa; Maeda, Kei-ichiro; Tsukamura, Hiroko

    2010-02-01

    Kisspeptin-GPR54 signaling plays an essential role in normal reproduction in mammals via stimulation of gonadotropin secretion. Here, we cloned the porcine KISS1 cDNA from the hypothalamic tissue and investigated the effect of estrogen on the distribution and numbers of KISS1 mRNA-expressing cells in the porcine hypothalamus. The full length of the cDNA was 857 bp encoding the kisspeptin of 54 amino acids, with the C-terminal active motif designated kisspeptin-10 being identical to that of mouse, rat, cattle, and sheep. In situ hybridization analysis revealed that KISS1-positive cell populations were mainly distributed in the hypothalamic periventricular nucleus (PeN) and arcuate nucleus (ARC). KISS1 expression in the PeN of ovariectomized (OVX) pigs was significantly upregulated by estradiol benzoate (EB) treatment. On the other hand, KISS1-expressing cells were abundantly distributed throughout the ARC in both OVX and OVX with EB animals. The number of KISS1-expressing neurons was significantly lowered by EB treatment only in the most caudal part of the ARC, but other ARC populations were not affected. The present study thus suggests that the PeN kisspeptin neurons could be responsible for the estrogen positive feedback regulation to induce gonadotropin-releasing hormone/luteinizing hormone (GnRH/LH) surge in the pig. In addition, the caudal ARC kisspeptin neurons could be involved in the estrogen negative feedback regulation of GnRH/LH release. This is the first report of identification of porcine KISS1 gene and of estrogen regulation of KISS1 expression in the porcine brain, which may be helpful for better understanding of the role of kisspeptin in reproduction of the pig.

  18. Molecular conservation of estrogen-response associated with cell cycle regulation, hormonal carcinogenesis and cancer in zebrafish and human cancer cell lines

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    Govindarajan Kunde R

    2011-05-01

    Full Text Available Abstract Background The zebrafish is recognized as a versatile cancer and drug screening model. However, it is not known whether the estrogen-responsive genes and signaling pathways that are involved in estrogen-dependent carcinogenesis and human cancer are operating in zebrafish. In order to determine the potential of zebrafish model for estrogen-related cancer research, we investigated the molecular conservation of estrogen responses operating in both zebrafish and human cancer cell lines. Methods Microarray experiment was performed on zebrafish exposed to estrogen (17β-estradiol; a classified carcinogen and an anti-estrogen (ICI 182,780. Zebrafish estrogen-responsive genes sensitive to both estrogen and anti-estrogen were identified and validated using real-time PCR. Human homolog mapping and knowledge-based data mining were performed on zebrafish estrogen responsive genes followed by estrogen receptor binding site analysis and comparative transcriptome analysis with estrogen-responsive human cancer cell lines (MCF7, T47D and Ishikawa. Results Our transcriptome analysis captured multiple estrogen-responsive genes and signaling pathways that increased cell proliferation, promoted DNA damage and genome instability, and decreased tumor suppressing effects, suggesting a common mechanism for estrogen-induced carcinogenesis. Comparative analysis revealed a core set of conserved estrogen-responsive genes that demonstrate enrichment of estrogen receptor binding sites and cell cycle signaling pathways. Knowledge-based and network analysis led us to propose that the mechanism involving estrogen-activated estrogen receptor mediated down-regulation of human homolog HES1 followed by up-regulation cell cycle-related genes (human homologs E2F4, CDK2, CCNA, CCNB, CCNE, is highly conserved, and this mechanism may involve novel crosstalk with basal AHR. We also identified mitotic roles of polo-like kinase as a conserved signaling pathway with multiple entry

  19. Molecular conservation of estrogen-response associated with cell cycle regulation, hormonal carcinogenesis and cancer in zebrafish and human cancer cell lines.

    Science.gov (United States)

    Lam, Siew Hong; Lee, Serene G P; Lin, Chin Y; Thomsen, Jane S; Fu, Pan Y; Murthy, Karuturi R K; Li, Haixia; Govindarajan, Kunde R; Nick, Lin C H; Bourque, Guillaume; Gong, Zhiyuan; Lufkin, Thomas; Liu, Edison T; Mathavan, Sinnakaruppan

    2011-05-16

    The zebrafish is recognized as a versatile cancer and drug screening model. However, it is not known whether the estrogen-responsive genes and signaling pathways that are involved in estrogen-dependent carcinogenesis and human cancer are operating in zebrafish. In order to determine the potential of zebrafish model for estrogen-related cancer research, we investigated the molecular conservation of estrogen responses operating in both zebrafish and human cancer cell lines. Microarray experiment was performed on zebrafish exposed to estrogen (17β-estradiol; a classified carcinogen) and an anti-estrogen (ICI 182,780). Zebrafish estrogen-responsive genes sensitive to both estrogen and anti-estrogen were identified and validated using real-time PCR. Human homolog mapping and knowledge-based data mining were performed on zebrafish estrogen responsive genes followed by estrogen receptor binding site analysis and comparative transcriptome analysis with estrogen-responsive human cancer cell lines (MCF7, T47D and Ishikawa). Our transcriptome analysis captured multiple estrogen-responsive genes and signaling pathways that increased cell proliferation, promoted DNA damage and genome instability, and decreased tumor suppressing effects, suggesting a common mechanism for estrogen-induced carcinogenesis. Comparative analysis revealed a core set of conserved estrogen-responsive genes that demonstrate enrichment of estrogen receptor binding sites and cell cycle signaling pathways. Knowledge-based and network analysis led us to propose that the mechanism involving estrogen-activated estrogen receptor mediated down-regulation of human homolog HES1 followed by up-regulation cell cycle-related genes (human homologs E2F4, CDK2, CCNA, CCNB, CCNE), is highly conserved, and this mechanism may involve novel crosstalk with basal AHR. We also identified mitotic roles of polo-like kinase as a conserved signaling pathway with multiple entry points for estrogen regulation. The findings

  20. BMP4 Cross-talks With Estrogen/ERα Signaling to Regulate Adiposity and Glucose Metabolism in Females

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    Shu-wen Qian

    2016-09-01

    Full Text Available Similar to estrogens, bone morphogenetic protein 4 (BMP4 promotes the accumulation of more metabolically active subcutaneous fat and reduction of visceral fat. However, whether there is a cross-talk between BMP4 and estrogen signaling remained unknown. Herein, we found that BMP4 deficiency in white adipose tissue (WAT increased the estrogen receptor α (ERα level and its signaling, which prevented adult female mice from developing high fat diet (HFD-induced obesity and insulin resistance; estrogens depletion up regulated BMP4 expression to overcome overt adiposity and impaired insulin sensitivity with aging, and failure of BMP4 regulation due to genetic knockout led to more fat gain in aged female mice. This mutual regulation between BMP4 and estrogen/ERα signaling may also happen in adipose tissue of women, since the BMP4 level significantly increased after menopause, and was inversely correlated with body mass index (BMI. These findings suggest a counterbalance between BMP4 and estrogen/ERα signaling in the regulation of adiposity and relative metabolism in females.

  1. Estrogen receptor alpha is cell cycle-regulated and regulates the cell cycle in a ligand-dependent fashion.

    Science.gov (United States)

    JavanMoghadam, Sonia; Weihua, Zhang; Hunt, Kelly K; Keyomarsi, Khandan

    2016-06-17

    Estrogen receptor alpha (ERα) has been implicated in several cell cycle regulatory events and is an important predictive marker of disease outcome in breast cancer patients. Here, we aimed to elucidate the mechanism through which ERα influences proliferation in breast cancer cells. Our results show that ERα protein is cell cycle-regulated in human breast cancer cells and that the presence of 17-β-estradiol (E2) in the culture medium shortened the cell cycle significantly (by 4.5 hours, P fashion. These results provide the rationale for an effective treatment strategy that includes a cell cycle inhibitor in combination with a drug that lowers estrogen levels, such as an aromatase inhibitor, and an antiestrogen that does not result in the degradation of ERα, such as tamoxifen.

  2. Inhibition of c-Abl kinase activity renders cancer cells highly sensitive to mitoxantrone.

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    Kemal Alpay

    Full Text Available Although c-Abl has increasingly emerged as a key player in the DNA damage response, its role in this context is far from clear. We studied the effect of inhibition of c-Abl kinase activity by imatinib with chemotherapy drugs and found a striking difference in cell survival after combined mitoxantrone (MX and imatinib treatment compared to a panel of other chemotherapy drugs. The combinatory treatment induced apoptosis in HeLa cells and other cancer cell lines but not in primary fibroblasts. The difference in MX and doxorubicin was related to significant augmentation of DNA damage. Transcriptionally active p53 accumulated in cells in which human papillomavirus E6 normally degrades p53. The combination treatment resulted in caspase activation and apoptosis, but this effect did not depend on either p53 or p73 activity. Despite increased p53 activity, the cells arrested in G2 phase became defective in this checkpoint, allowing cell cycle progression. The effect after MX treatment depended partially on c-Abl: Short interfering RNA knockdown of c-Abl rendered HeLa cells less sensitive to MX. The effect of imatinib was decreased by c-Abl siRNA suggesting a role for catalytically inactive c-Abl in the death cascade. These findings indicate that MX has a unique cytotoxic effect when the kinase activity of c-Abl is inhibited. The treatment results in increased DNA damage and c-Abl-dependent apoptosis, which may offer new possibilities for potentiation of cancer chemotherapy.

  3. Estrogen receptor–α in medial amygdala neurons regulates body weight

    Science.gov (United States)

    Xu, Pingwen; Cao, Xuehong; He, Yanlin; Zhu, Liangru; Yang, Yongjie; Saito, Kenji; Wang, Chunmei; Yan, Xiaofeng; Hinton, Antentor Othrell; Zou, Fang; Ding, Hongfang; Xia, Yan; Yan, Chunling; Shu, Gang; Wu, San-Pin; Yang, Bin; Feng, Yuxin; Clegg, Deborah J.; DeMarchi, Richard; Khan, Sohaib A.; Tsai, Sophia Y.; DeMayo, Francesco J.; Wu, Qi; Tong, Qingchun; Xu, Yong

    2015-01-01

    Estrogen receptor–α (ERα) activity in the brain prevents obesity in both males and females. However, the ERα-expressing neural populations that regulate body weight remain to be fully elucidated. Here we showed that single-minded–1 (SIM1) neurons in the medial amygdala (MeA) express abundant levels of ERα. Specific deletion of the gene encoding ERα (Esr1) from SIM1 neurons, which are mostly within the MeA, caused hypoactivity and obesity in both male and female mice fed with regular chow, increased susceptibility to diet-induced obesity (DIO) in males but not in females, and blunted the body weight–lowering effects of a glucagon-like peptide-1–estrogen (GLP-1–estrogen) conjugate. Furthermore, selective adeno-associated virus-mediated deletion of Esr1 in the MeA of adult male mice produced a rapid body weight gain that was associated with remarkable reductions in physical activity but did not alter food intake. Conversely, overexpression of ERα in the MeA markedly reduced the severity of DIO in male mice. Finally, an ERα agonist depolarized MeA SIM1 neurons and increased their firing rate, and designer receptors exclusively activated by designer drug–mediated (DREADD-mediated) activation of these neurons increased physical activity in mice. Collectively, our results support a model where ERα signals activate MeA neurons to stimulate physical activity, which in turn prevents body weight gain. PMID:26098212

  4. Thyroid Hormone and Estrogen Regulate Exercise-Induced Growth Hormone Release

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    Ignacio, Daniele Leão; da S. Silvestre, Diego H.; Cavalcanti-de-Albuquerque, João Paulo Albuquerque; Louzada, Ruy Andrade

    2015-01-01

    Growth hormone (GH) regulates whole body metabolism, and physical exercise is the most potent stimulus to induce its secretion in humans. The mechanisms underlying GH secretion after exercise remain to be defined. The aim of this study was to elucidate the role of estrogen and pituitary type 1 deiodinase (D1) activation on exercise-induced GH secretion. Ten days after bilateral ovariectomy, animals were submitted to 20 min of treadmill exercise at 75% of maximum aerobic capacity and tissues were harvested immediately or 30 min after exercise. Non-exercised animals were used as controls. A significant increase in D1 activity occurred immediately after exercise (~60%) in sham-operated animals and GH was higher (~6-fold) 30 min after exercise. Estrogen deficient rats exhibited basal levels of GH and D1 activity comparable to those found in control rats. However, after exercise both D1 activity and serum GH levels were blunted compared to sedentary rats. To understand the potential cause-effect of D1 activation in exercise-induced GH release, we pharmacologically blocked D1 activity by propylthiouracil (PTU) injection into intact rats and submitted them to the acute exercise session. D1 inhibition blocked exercise-induced GH secretion, although basal levels were unaltered. In conclusion, estrogen deficiency impairs the induction of thyroid hormone activating enzyme D1 in the pituitary, and GH release by acute exercise. Also, acute D1 activation is essential for exercise-induced GH response. PMID:25874614

  5. Synthesis and evaluation of raloxifene derivatives as a selective estrogen receptor down-regulator.

    Science.gov (United States)

    Shoda, Takuji; Kato, Masashi; Fujisato, Takuma; Misawa, Takashi; Demizu, Yosuke; Inoue, Hideshi; Naito, Mikihiko; Kurihara, Masaaki

    2016-07-01

    Estrogen receptors (ERs) play a major role in the growth of human breast cancer cells. A selective estrogen receptor down-regulator (SERD) that acts as not only an inhibitor of ligand binding, but also induces the down-regulation of ER, would be useful for the treatment for ER-positive breast cancer. We previously reported that tamoxifen derivatives, which have a long alkyl chain, had the ability to down-regulate ERα. With the aim of expanding range of the currently available SERDs, we designed and synthesized raloxifene derivatives, which had various lengths of the long alkyl chains, and evaluated their SERD activities. All compounds were able to bind ERα, and RC10, which has a decyl group on the amine moiety of raloxifene, was shown to be the most potent compound. Our findings suggest that the ligand core was replaceable, and that the alkyl length was important for controlling SERD activity. Moreover, RC10 showed antagonistic activity and its potency was superior to that of 4,4'-(heptane-4,4-diyl)bis(2-methylphenol) (18), a competitive antagonist of ER without SERD activity. These results provide information that will be useful for the development of promising SERDs candidates. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Estrogen receptor (ER) beta regulates ERalpha expression in stromal cells derived from ovarian endometriosis.

    Science.gov (United States)

    Trukhacheva, Elena; Lin, Zhihong; Reierstad, Scott; Cheng, You-Hong; Milad, Magdy; Bulun, Serdar E

    2009-02-01

    Estradiol and its nuclear receptors, estrogen receptor (ER) alpha and ERbeta, play critical roles in endometrium and endometriosis. Levels of ERbeta, due to pathological hypomethylation of its promoter, are significantly higher in endometriotic vs. endometrial tissue and stromal cells, whereas ERalpha levels are lower in endometriosis. Estradiol regulates ERalpha gene expression via its alternatively used promoters A, B, and C. The aim of the study was to determine whether high levels of ERbeta in endometriotic stromal cells from ovarian endometriomas regulate ERalpha gene expression. ERbeta knockdown significantly increased ERalpha mRNA and protein levels in endometriotic stromal cells. Conversely, ERbeta overexpression in endometrial stromal cells decreased ERalpha mRNA and protein levels. ERbeta knockdown significantly decreased proliferation of endometriotic stromal cells. Chromatin immunoprecipitation assays demonstrated that estradiol enhanced ERbeta binding to nonclassical activator protein 1 and specificity protein 1 motifs in the ERalpha gene promoters A and C and a classic estrogen response element in promoter B in endometriotic stromal cells. High levels of ERbeta suppress ERalpha expression and response to estradiol in endometrial and endometriotic stromal cells via binding to classic and nonclassic DNA motifs in alternatively used ERalpha promoters. ERbeta also regulates cell cycle progression and might contribute to proliferation of endometriotic stromal cells. We speculate that a significantly increased ratio of ERbeta:ERalpha in endometriotic tissues may also suppress progesterone receptor expression and contribute to progesterone resistance. Thus, ERbeta may serve as a significant therapeutic target for endometriosis.

  7. Global analysis of estrogen receptor beta binding to breast cancer cell genome reveals an extensive interplay with estrogen receptor alpha for target gene regulation.

    Science.gov (United States)

    Grober, Oli M V; Mutarelli, Margherita; Giurato, Giorgio; Ravo, Maria; Cicatiello, Luigi; De Filippo, Maria Rosaria; Ferraro, Lorenzo; Nassa, Giovanni; Papa, Maria Francesca; Paris, Ornella; Tarallo, Roberta; Luo, Shujun; Schroth, Gary P; Benes, Vladimir; Weisz, Alessandro

    2011-01-14

    Estrogen receptors alpha (ERα) and beta (ERβ) are transcription factors (TFs) that mediate estrogen signaling and define the hormone-responsive phenotype of breast cancer (BC). The two receptors can be found co-expressed and play specific, often opposite, roles, with ERβ being able to modulate the effects of ERα on gene transcription and cell proliferation. ERβ is frequently lost in BC, where its presence generally correlates with a better prognosis of the disease. The identification of the genomic targets of ERβ in hormone-responsive BC cells is thus a critical step to elucidate the roles of this receptor in estrogen signaling and tumor cell biology. Expression of full-length ERβ in hormone-responsive, ERα-positive MCF-7 cells resulted in a marked reduction in cell proliferation in response to estrogen and marked effects on the cell transcriptome. By ChIP-Seq we identified 9702 ERβ and 6024 ERα binding sites in estrogen-stimulated cells, comprising sites occupied by either ERβ, ERα or both ER subtypes. A search for TF binding matrices revealed that the majority of the binding sites identified comprise one or more Estrogen Response Element and the remaining show binding matrixes for other TFs known to mediate ER interaction with chromatin by tethering, including AP2, E2F and SP1. Of 921 genes differentially regulated by estrogen in ERβ+ vs ERβ- cells, 424 showed one or more ERβ site within 10 kb. These putative primary ERβ target genes control cell proliferation, death, differentiation, motility and adhesion, signal transduction and transcription, key cellular processes that might explain the biological and clinical phenotype of tumors expressing this ER subtype. ERβ binding in close proximity of several miRNA genes and in the mitochondrial genome, suggests the possible involvement of this receptor in small non-coding RNA biogenesis and mitochondrial genome functions. Results indicate that the vast majority of the genomic targets of ERβ can bind

  8. Global analysis of estrogen receptor beta binding to breast cancer cell genome reveals an extensive interplay with estrogen receptor alpha for target gene regulation

    Directory of Open Access Journals (Sweden)

    Papa Maria

    2011-01-01

    Full Text Available Abstract Background Estrogen receptors alpha (ERα and beta (ERβ are transcription factors (TFs that mediate estrogen signaling and define the hormone-responsive phenotype of breast cancer (BC. The two receptors can be found co-expressed and play specific, often opposite, roles, with ERβ being able to modulate the effects of ERα on gene transcription and cell proliferation. ERβ is frequently lost in BC, where its presence generally correlates with a better prognosis of the disease. The identification of the genomic targets of ERβ in hormone-responsive BC cells is thus a critical step to elucidate the roles of this receptor in estrogen signaling and tumor cell biology. Results Expression of full-length ERβ in hormone-responsive, ERα-positive MCF-7 cells resulted in a marked reduction in cell proliferation in response to estrogen and marked effects on the cell transcriptome. By ChIP-Seq we identified 9702 ERβ and 6024 ERα binding sites in estrogen-stimulated cells, comprising sites occupied by either ERβ, ERα or both ER subtypes. A search for TF binding matrices revealed that the majority of the binding sites identified comprise one or more Estrogen Response Element and the remaining show binding matrixes for other TFs known to mediate ER interaction with chromatin by tethering, including AP2, E2F and SP1. Of 921 genes differentially regulated by estrogen in ERβ+ vs ERβ- cells, 424 showed one or more ERβ site within 10 kb. These putative primary ERβ target genes control cell proliferation, death, differentiation, motility and adhesion, signal transduction and transcription, key cellular processes that might explain the biological and clinical phenotype of tumors expressing this ER subtype. ERβ binding in close proximity of several miRNA genes and in the mitochondrial genome, suggests the possible involvement of this receptor in small non-coding RNA biogenesis and mitochondrial genome functions. Conclusions Results indicate that the

  9. Post-translational regulation of endothelial nitric oxide synthase (eNOS) by estrogens in the rat vagina.

    Science.gov (United States)

    Musicki, Biljana; Liu, Tongyun; Strong, Travis D; Lagoda, Gwen A; Bivalacqua, Trinity J; Burnett, Arthur L

    2010-05-01

    Estrogens control vaginal blood flow during female sexual arousal mostly through nitric oxide (NO). Although vascular effects of estrogens are attributed to an increase in endothelial NO production, the mechanisms of endothelial NO synthase (eNOS) regulation by estrogens in the vagina are largely unknown. Our hypothesis was that estrogens regulate eNOS post-translationally in the vagina, providing a mechanism to affect NO bioavailability without changes in eNOS protein expression. We measured eNOS phosphorylation and eNOS interaction with caveolin-1 and heat shock protein 90 (HSP90) in the distal and proximal vagina of female rats at diestrus, 7 days after ovariectomy and 2 days after replacement of ovariectomized rats with estradiol-17beta (15 microg). Molecular mechanisms of eNOS regulation by estrogen in the rat vagina. We localized phospho-eNOS (Ser-1177) immunohistochemically to the endothelium lining blood vessels and vaginal sinusoids. Estrogen withdrawal decreased phosphorylation of eNOS on its positive regulatory site (Ser-1177) and increased eNOS binding to its negative regulator caveolin-1 (without affecting eNOS/HSP90 interaction), and they were both normalized by estradiol replacement. Protein expressions of phosphorylated Akt (protein kinase B) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) were not affected by estrogen status, suggesting that the effect of estrogens on eNOS (Ser-1177) phosphorylation was not mediated by activated AKT or ERK1/2. eNOS phosphorylation on its negative regulatory site (Ser-114) was increased in the vagina by estrogen withdrawal and normalized by estradiol replacement, implying that the maintenance of low phosphorylation of eNOS on this site by estradiol may limit eNOS interaction with caveolin-1 and preserve the enzyme's activity. Total eNOS, inducible NOS, caveolin-1, and HSP90 protein expressions were not affected by ovariectomy or estradiol replacement in the distal or proximal vagina. These results

  10. Tamoxifen and Fulvestrant Hybrids Showed Potency as Selective Estrogen Receptor Down-Regulators.

    Science.gov (United States)

    Shoda, Takuji; Kato, Masashi; Fujisato, Takuma; Demizu, Yosuke; Inoue, Hideshi; Naito, Mikihiko; Kurihara, Masaaki

    2017-01-01

    Estrogen receptors (ERs) are an important target for the management of breast cancers. Selective estrogen receptor down-regulators (SERDs) block ER activity, as well as reduce ERα protein levels in cells, and therefore are promising therapeutic agents for the treatment of breast cancers. In order to develop potent SERDs, we prepared tamoxifen and fulvestrant hybrids and evaluated their binding activity and down-regulation of ERα. We designed and synthesized tamoxifen derivatives, which had a 4,4,5,5,5- pentafluoropentyl group on the terminal alkyl chain. The oxidation state of the sulfur atom and alkyl length between the sulfur and nitrogen atoms were varied. Western blotting was performed to determine the ability to down-regulate ERα. Binding affinities of synthesized compounds were evaluated by a fluorescence polarization-based competitive binding assay. We successfully prepared nine compounds. Treatment with 11, 14, and 17 effectively reduced ERα protein levels in MCF-7 cells in a concentration-dependent manner. This reduction was inhibited by a proteasome inhibitor. The ability of 14 to down-regulate the ERα protein level was equal to fulvestrant. All compounds showed a largely equal affinity for ERα. As indicated by Western blots, the ERα degradation activity was observed only in the series of butyl linker derivatives, namely, 11, 14, and 17. These findings suggest that the specific length of the alkyl chain is an important factor in controlling the down-regulation of ER. These results provide useful information for designing promising SERD candidates. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Estrogen induced {beta}-1,4-galactosyltransferase 1 expression regulates proliferation of human breast cancer MCF-7 cells

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Hee-Jung [Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan (Korea, Republic of); Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan-city, Gyeongsangnam-do (Korea, Republic of); Chung, Tae-Wook; Kim, Cheorl-Ho [Department of Molecular and Cellular Glycobiology, College of Natural Science, Sungkyunkwan University, Suwon, Kyungki-do (Korea, Republic of); Jeong, Han-Sol; Joo, Myungsoo [Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan-city, Gyeongsangnam-do (Korea, Republic of); Youn, BuHyun, E-mail: bhyoun72@pusan.ac.kr [Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan (Korea, Republic of); Ha, Ki-Tae, E-mail: hagis@pusan.ac.kr [Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan-city, Gyeongsangnam-do (Korea, Republic of)

    2012-10-05

    Highlights: Black-Right-Pointing-Pointer We examined the regulation and biological functions of B4GALT1 expression induced by estrogen. Black-Right-Pointing-Pointer Estrogen-induced B4GALT1 expression through the direct binding of ER-{alpha} to ERE in MCF-7 cells. Black-Right-Pointing-Pointer B4GALT1 expression activates the proliferation of MCF-7 cells via its receptor function. Black-Right-Pointing-Pointer Thus, we suggest B4GALT1 as a molecular target for inhibiting breast cancer proliferation. -- Abstract: Beta 1,4-galactosyltransferase 1 (B4GALT1) synthesizes galactose {beta}-1,4-N-acetylglucosamine (Gal{beta}1-4GlcNAc) groups on N-linked sugar chains of glycoproteins, which play important roles in many biological events, including the proliferation and migration of cancer cells. A previous microarray study reported that this gene is expressed by estrogen treatment in breast cancer. In this study, we examined the regulatory mechanisms and biological functions of estrogen-induced B4GALT1 expression. Our data showed that estrogen-induced expression of B4GALT1 is localized in intracellular compartments and in the plasma membrane. In addition, B4GALT1 has an enzyme activity involved in the production of the Gal{beta}1-4GlcNAc structure. The result from a promoter assay and chromatin immunoprecipitation revealed that 3 different estrogen response elements (EREs) in the B4GALT1 promoter are critical for responsiveness to estrogen. In addition, the estrogen antagonists ICI 182,780 and ER-{alpha}-ERE binding blocker TPBM inhibit the expression of estrogen-induced B4GALT1. However, the inhibition of signal molecules relating to the extra-nuclear pathway, including the G-protein coupled receptors, Ras, and mitogen-activated protein kinases, had no inhibitory effects on B4GALT1 expression. The knock-down of the B4GALT1 gene and the inhibition of membrane B4GALT1 function resulted in the significant inhibition of estrogen-induced proliferation of MCF-7 cells. Considering

  12. Evaluation of potential implication of membrane estrogen binding sites on ERE-dependent transcriptional activity and intracellular estrogen receptor-alpha regulation in MCF-7 breast cancer cells.

    Science.gov (United States)

    Seo, Hye Sook; Leclercq, Guy

    2002-01-01

    The potential involvement of membrane estrogen binding sites in the induction of ERE-dependent transcriptional activity as well as in the regulation of intracellular estrogen receptor alpha (ER-alpha) level under estradiol (E2) stimulation was investigated. Our approach relied upon the use of two DCC-treated E2-BSA (bovine serum albumin) solutions (E2-6-BSA and E2-17-BSA). The absence of detectable free E2 in these solutions was established. Both E2-BSA conjugates led to a transient dose-dependent stimulation of the expression of ERE-luciferase (LUC) reporter gene in MVLN cells (MCF-7 cells stably transfected with a pVit-tk-LUC reporter plasmid), a property not recorded with free E2, which maintained enhanced transcriptional activity during the whole experiment. A very low concentration of E2 (10 pM) synergistically acted with E2-BSA conjugates. Hence, ERE-dependent transcriptional activity induced by these conjugates appeared to result from their known interactions with membrane estrogen binding sites. Anti-estrogens (AEs: 4-OH-TAM and RU 58,668), which antagonize genomic ER responses, abrogated the luciferase activity induced by E2-BSA conjugates, confirming a potential relationship between membrane-related signals and intracellular ER. Moreover, induction of luciferase was recorded when the cells were exposed to IBMX (3-isobutyl-1-methylxanthine) and cyclic nucleotides (cAMP/cGMP), suggesting the implication of the latter in the signal transduction pathway leading to the expression of the reporter gene. Growth factors (IGF-I, EGF and TGF-alpha) also slightly stimulated luciferase and synergistically acted with 10 pM E2, or 1 microM E2-BSA conjugates, in agreement with the concept of a cross-talk between steroids and peptides acting on the cell membrane. Remarkably, E2-BSA conjugates, IBMX and all investigated growth factors failed to down-regulate intracellular ER in MCF-7 cells, indicating the need for a direct intracellular interaction of the ligand with the

  13. Selective Estrogen Receptor Modulators Regulate Dendritic Spine Plasticity in the Hippocampus of Male Rats

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    Ignacio González-Burgos

    2012-01-01

    Full Text Available Some selective estrogen receptor modulators, such as raloxifene and tamoxifen, are neuroprotective and reduce brain inflammation in several experimental models of neurodegeneration. In addition, raloxifene and tamoxifen counteract cognitive deficits caused by gonadal hormone deprivation in male rats. In this study, we have explored whether raloxifene and tamoxifen may regulate the number and geometry of dendritic spines in CA1 pyramidal neurons of the rat hippocampus. Young adult male rats were injected with raloxifene (1 mg/kg, tamoxifen (1 mg/kg, or vehicle and killed 24 h after the injection. Animals treated with raloxifene or tamoxifen showed an increased numerical density of dendritic spines in CA1 pyramidal neurons compared to animals treated with vehicle. Raloxifene and tamoxifen had also specific effects in the morphology of spines. These findings suggest that raloxifene and tamoxifen may influence the processing of information by hippocampal pyramidal neurons by affecting the number and shape of dendritic spines.

  14. c-Abl inhibitors enable insights into the pathophysiology and neuroprotection in Parkinson’s disease

    OpenAIRE

    Dan Lindholm; Dan Duc Pham; Annunziata Cascone; Ove Eriksson; Krister Wennerberg; Mart Saarma

    2016-01-01

    Parkinson’s disease (PD) is a progressive neurodegenerative disorder causing movement disabilities and several non-motor symptoms in afflicted patients. Recent studies in animal models of PD and analyses of brain specimen from PD patients revealed an increase in the level and activity of the non-receptor tyrosine kinase Abelson (c-Abl) in dopaminergic neurons with phosphorylation of protein substrates, such as α-synuclein and the E3 ubiquitin ligase, Parkin. Most significantly inhibition of c...

  15. Estrogen regulation of microcephaly genes and evolution of brain sexual dimorphism in primates.

    Science.gov (United States)

    Shi, Lei; Lin, Qiang; Su, Bing

    2015-06-30

    Sexual dimorphism in brain size is common among primates, including humans, apes and some Old World monkeys. In these species, the brain size of males is generally larger than that of females. Curiously, this dimorphism has persisted over the course of primate evolution and human origin, but there is no explanation for the underlying genetic controls that have maintained this disparity in brain size. In the present study, we tested the effect of the female hormone (estradiol) on seven genes known to be related to brain size in both humans and nonhuman primates, and we identified half estrogen responsive elements (half EREs) in the promoter regions of four genes (MCPH1, ASPM, CDK5RAP2 and WDR62). Likewise, at sequence level, it appears that these half EREs are generally conserved across primates. Later testing via a reporter gene assay and cell-based endogenous expression measurement revealed that estradiol could significantly suppress the expression of the four affected genes involved in brain size. More intriguingly, when the half EREs were deleted from the promoters, the suppression effect disappeared, suggesting that the half EREs mediate the regulation of estradiol on the brain size genes. We next replicated these experiments using promoter sequences from chimpanzees and rhesus macaques, and observed a similar suppressive effect of estradiol on gene expression, suggesting that this mechanism is conserved among primate species that exhibit brain size dimorphism. Brain size dimorphism among certain primates, including humans, is likely regulated by estrogen through its sex-dependent suppression of brain size genes during development.

  16. Regulation of P450 oxidoreductase by gonadotropins in rat ovary and its effect on estrogen production

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    Uesaka Miki

    2008-12-01

    Full Text Available Abstract Background P450 oxidoreductase (POR catalyzes electron transfer to microsomal P450 enzymes. Its deficiency causes Antley-Bixler syndrome (ABS, and about half the patients with ABS have ambiguous genitalia and/or impaired steroidogenesis. POR mRNA expression is up-regulated when mesenchymal stem cells (MSCs differentiate into steroidogenic cells, suggesting that the regulation of POR gene expression is important for steroidogenesis. In this context we examined the regulation of POR expression in ovarian granulosa cells by gonadotropins, and its possible role in steroidogenesis. Methods Changes in gene expression in MSCs during differentiation into steroidogenic cells were examined by DNA microarray analysis. Changes in mRNA and protein expression of POR in the rat ovary or in granulosa cells induced by gonadotropin treatment were examined by reverse transcription-polymerase chain reaction and western blotting. Effects of transient expression of wild-type or mutant (R457H or V492E POR proteins on the production of estrone in COS-7 cells were examined in vitro. Effects of POR knockdown were also examined in estrogen producing cell-line, KGN cells. Results POR mRNA was induced in MSCs following transduction with the SF-1 retrovirus, and was further increased by cAMP treatment. Expression of POR mRNA, as well as Cyp19 mRNA, in the rat ovary were induced by equine chorionic gonadotropin and human chorionic gonadotropin. POR mRNA and protein were also induced by follicle stimulating hormone in primary cultured rat granulosa cells, and the induction pattern was similar to that for aromatase. Transient expression of POR in COS-7 cells, which expressed a constant amount of aromatase protein, greatly increased the rate of conversion of androstenedione to estrone, in a dose-dependent manner. The expression of mutant POR proteins (R457H or V492E, such as those found in ABS patients, had much less effect on aromatase activity than expression of wild

  17. c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells

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    Diana M. Dunn

    2015-08-01

    Full Text Available The ability of Heat Shock Protein 90 (Hsp90 to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific “client” proteins. The intracellular signaling mechanisms directly regulating Aha1 association with Hsp90 remain unknown. Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1, promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity, enhances Hsp90 interaction with kinase clients, and compromises the chaperoning of non-kinase clients such as glucocorticoid receptor and CFTR. Suggesting a regulatory paradigm, we also find that Y223 phosphorylation leads to ubiquitination and degradation of hAha1 in the proteasome. Finally, pharmacologic inhibition of c-Abl prevents hAha1 interaction with Hsp90, thereby hypersensitizing cancer cells to Hsp90 inhibitors both in vitro and ex vivo.

  18. UTX promotes hormonally responsive breast carcinogenesis through feed-forward transcription regulation with estrogen receptor.

    Science.gov (United States)

    Xie, G; Liu, X; Zhang, Y; Li, W; Liu, S; Chen, Z; Xu, B; Yang, J; He, L; Zhang, Z; Jin, T; Yi, X; Sun, L; Shang, Y; Liang, J

    2017-09-28

    UTX is implicated in embryonic development and lineage specification. However, how this X-linked histone demethylase contributes to the occurrence and progression of breast cancer remains to be clarified. Here we report that UTX is physically associated with estrogen receptor (ER) and functions in ER-regulated transcription. We showed that UTX coordinates with JHDM1D and CBP to direct H3K27 methylation-acetylation transition and to create a permissive chromatin state on ER targets. Genome-wide analysis of the transcriptional targets of UTX by ChIP-seq identified a set of genes such as chemokine receptor CXCR4 that are intimately involved in breast cancer tumorigenesis and metastasis. We demonstrated that UTX promotes the proliferation and migration of ER(+) breast cancer cells. Interestingly, UTX itself is transactivated by ER, forming a feed-forward loop in the regulation of hormone response. Indeed, UTX is upregulated during ER(+) breast cancer progression, and the expression level of UTX is positively correlated with that of CXCR4 and negatively correlated with the overall survival of ER(+) breast cancer patients. Our study identified a feed-forward loop between UTX and ER in the regulation of hormonally responsive breast carcinogenesis, supporting the pursuit of UTX as an emerging therapeutic target for the intervention of certain ER(+) breast cancer with specific epigenetic vulnerability.

  19. Crucial role of estrogen for the mammalian female in regulating semen coagulation and liquefaction in vivo.

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    Shuai Li

    2017-04-01

    Full Text Available Semen liquefaction changes semen from a gel-like to watery consistency and is required for sperm to gain mobility and swim to the fertilization site in the Fallopian tubes. Kallikrein-related peptidases 3 (KLK3 and other kallikrein-related peptidases from male prostate glands are responsible for semen liquefaction by cleaving gel-forming proteins (semenogelin and collagen. In a physiological context, the liquefaction process occurs within the female reproductive tract. How seminal proteins interact with the female reproductive environment is still largely unexplored. We previously reported that conditional genetic ablation of Esr1 (estrogen receptor α in the epithelial cells of the female reproductive tract (Wnt7aCre/+;Esr1f/f causes female infertility, partly due to a drastic reduction in the number of motile sperm entering the oviduct. In this study, we found that post-ejaculated semen from fertile wild-type males was solidified and the sperm were entrapped in Wnt7aCre/+;Esr1f/f uteri, compared to the watery semen (liquefied found in Esr1f/f controls. In addition, semenogelin and collagen were not degraded in Wnt7aCre/+;Esr1f/f uteri. Amongst multiple gene families aberrantly expressed in the absence of epithelial ESR1, we have identified that a lack of Klks in the uterus is a potential cause for the liquefaction defect. Pharmacological inhibition of KLKs in the uterus replicated the phenotype observed in Wnt7aCre/+;Esr1f/f uteri, suggesting that loss of uterine and seminal KLK function causes this liquefaction defect. In human cervical cell culture, expression of several KLKs and their inhibitors (SPINKs was regulated by estrogen in an ESR1-dependent manner. Our study demonstrates that estrogen/ESR1 signaling in the female reproductive tract plays an indispensable role in normal semen liquefaction, providing fundamental evidence that exposure of post-ejaculated semen to the suboptimal microenvironment in the female reproductive tract leads

  20. Bidirectional regulation of bakuchiol, an estrogenic-like compound, on catecholamine secretion

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    Mao, Haoping; Wang, Hong; Ma, Shangwei; Xu, Yantong; Zhang, Han; Wang, Yuefei [Tianjin State Key Laboratory of Modern Chinese Medicine, Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae (China); Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin (China); Niu, Zichang [First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin (China); Fan, Guanwei; Zhu, Yan [Tianjin State Key Laboratory of Modern Chinese Medicine, Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae (China); Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin (China); Gao, Xiu Mei, E-mail: gaoxiumei@tjutcm.edu.cn [Tianjin State Key Laboratory of Modern Chinese Medicine, Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae (China); Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin (China)

    2014-01-01

    Excess or deficiency of catecholamine (CA) secretion was related with several diseases. Recently, estrogen and phytoestrogens were reported to regulate the activity of CA system. Bakuchiol is a phytoestrogen isolated from the seeds of Psoralea corylifolia L. (Leguminosae) which has been used in Traditional Chinese medicine as a tonic or aphrodisiac. In the present study, bovine adrenal medullary cells were employed to investigate the effects and mechanisms of bakuchiol on the regulation of CA secretion. Further, its anti-depressant like and anti-stress effects were evaluated by using behavioral despair and chronic immobilization stress models. Our results indicated that bakuchiol showed bidirectional regulation on CA secretion. It stimulated basal CA secretion in a concentration dependent manner (p < 0.01), while it reduced 300 μM acetylcholine (ACh) (p < 0.01), 100 μM veratridine (Ver) (p < 0.01) and 56 mM K{sup +} (p < 0.05) induced CA secretion, respectively. We also found that the stimulation of basal CA secretion by bakuchiol may act through estrogen-like effect and the JNK pathway in an extra-cellular calcium independent manner. Further, bakuchiol elevated tyrosine hydroxylase Ser40 and Ser31 phosphorylation (p < 0.01) through the PKA and ERK1/2 pathways, respectively. Bakuchiol inhibited ACh, Ver and 56 mM K{sup +} induced CA secretion was related with reduction of intracellular calcium rise. In vivo experiments, we found that bakuchiol significantly reduced immobilization time in behavioral despair mouse (p < 0.05 or 0.01), and plasma epinephrine (E) and norepinephrine (NE) levels in chronic immobilization stress (p < 0.05). Overall, these results present a bidirectional regulation of bakuchiol on CA secretion which indicated that bakuchiol may exert anti-stress and the potential anti-depressant-like effects. - Highlights: • Bakuchiol stimulated basal catecholamine secretion. • Bakuchiol inhibited various secretagogues induced catecholamine secretion

  1. The Selective Estrogen Receptor Modulator Raloxifene Regulates Arginine-Vasopressin Gene Expression in Human Female Neuroblastoma Cells Through G Protein-Coupled Estrogen Receptor and ERK Signaling.

    Science.gov (United States)

    Grassi, Daniela; Ghorbanpoor, Samar; Acaz-Fonseca, Estefania; Ruiz-Palmero, Isabel; Garcia-Segura, Luis M

    2015-10-01

    The selective estrogen receptor modulator raloxifene reduces blood pressure in hypertensive postmenopausal women. In the present study we have explored whether raloxifene regulates gene expression of arginine vasopressin (AVP), which is involved in the pathogenesis of hypertension. The effect of raloxifene was assessed in human female SH-SY5Y neuroblastoma cells, which have been recently identified as a suitable cellular model to study the estrogenic regulation of AVP. Raloxifene, within a concentration ranging from 10(-10) M to 10(-6) M, decreased the mRNA levels of AVP in SH-SY5Y cells with maximal effect at 10(-7) M. This effect of raloxifene was imitated by an agonist (±)-1-[(3aR*,4S*,9bS*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone of G protein-coupled estrogen receptor-1 (GPER) and blocked by an antagonist (3aS*,4R*,9bR*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta[c]quinoline of GPER and by GPER silencing. Raloxifene induced a time-dependent increase in the level of phosphorylated ERK1 and ERK2, by a mechanism blocked by the GPER antagonist. The treatment of SH-SY5Y cells with either a MAPK/ERK kinase 1/2-specific inhibitor (1,4-diamino-2, 3-dicyano-1,4-bis(2-aminophenylthio)butadine) or a protein kinase C inhibitor (sotrastaurin) blocked the effects of raloxifene on the phosphorylation of ERK1/2 and the regulation of AVP mRNA levels. These results reveal a mechanism mediating the regulation of AVP expression by raloxifene, involving the activation of GPER, which in turn activates protein kinase C, MAPK/ERK kinase, and ERK. The regulation of AVP by raloxifene and GPER may have implications for the treatment of blood hypertension(.).

  2. Selective Estrogen Receptor Modulators regulate reactive microglia after penetrating brain injury

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    George E. Barreto

    2014-06-01

    Full Text Available Following brain injury, microglia assume a reactive-like state and secrete pro-inflammatory molecules that can potentiate damage. A therapeutic strategy that may limit microgliosis is of potential interest. In this context, selective estrogen receptor modulators, such as raloxifene and tamoxifen, are known to reduce microglia activation induced by neuroinflammatory stimuli in young animals. In the present study, we have assessed whether raloxifene and tamoxifen are able to affect microglia activation after brain injury in young and aged animals in time points relevant to clinics, which is hours after brain trauma. Volume fraction of MHC-II+ microglia was estimated according to the point-counting method of Weibel within a distance of 350 μm from the lateral border of the wound, and cellular morphology was measured by fractal analysis. Two groups of animals were studied: 1 young rats, ovariectomized at 2 months of age; and 2 aged rats, ovariectomized at 18 months of age. Fifteen days after ovariectomy animals received a stab wound brain injury and the treatment with estrogenic compounds. Our findings indicate that raloxifene and tamoxifen reduced microglia activation in both young and aged animals. Although the volume fraction of reactive microglia was found lower in aged animals, this was accompanied by important changes in cell morphology, where aged microglia assume a bushier and hyperplasic aspect when compared to young microglia. These data suggest that early regulation of microglia activation provides a mechanism by which SERMs may exert a neuroprotective effect in the setting of a brain trauma.

  3. Estrogen-dependent sushi domain containing 3 regulates cytoskeleton organization and migration in breast cancer cells.

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    Moy, I; Todorović, V; Dubash, A D; Coon, J S; Parker, J B; Buranapramest, M; Huang, C C; Zhao, H; Green, K J; Bulun, S E

    2015-01-15

    Aromatase inhibitors (AIs) are the standard endocrine therapy for postmenopausal breast cancer; however, currently used biomarkers, such as, estrogen receptor-alpha/progesterone receptor (ERα/PR), predict only slightly more than half of the potential responders to AI treatment. To identify novel markers of AI responsiveness, a genome-wide microarray analysis was performed using primary breast tumor samples from 50 postmenopausal women who later developed metastatic breast cancer. Sushi domain containing 3 (SUSD3) is a significantly differentially expressed gene, with 3.38-fold higher mRNA levels in AI-responsive breast tumors vs non-responders (Pbreast tumors and treatment with estradiol increased SUSD3 expression in ERα-positive breast cancer cells. Treatment with an antiestrogen or ERα knockdown abolished basal and estradiol-dependent SUSD3 expression. Recruitment of ERα upstream of the transcription start site of SUSD3 was demonstrated by chromatin immunoprecipitation-PCR. Flow cytometric analysis of SUSD3-knockdown cells revealed blunted estradiol effects on progression into S and M phases. SUSD3 was localized to the plasma membrane of breast cancer cells. SUSD3 knockdown decreased the appearance of actin-rich protrusions, stress fibers and large basal focal adhesions, while increasing the presence of cortical actin concomitant with a decrease in Rho and focal adhesion kinase activity. SUSD3-deficient cells demonstrated diminished cell spreading, cell-cell adhesion and motility. In conclusion, SUSD3 is a novel promoter of estrogen-dependent cell proliferation and regulator of cell-cell and cell-substrate interactions and migration in breast cancer. It may serve as a novel predictor of response to endocrine therapy and potential therapeutic target.

  4. TGF-β1 regulation of estrogen production in mature rat Leydig cells.

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    Man-Li Liu

    Full Text Available BACKGROUND: Besides androgens, estrogens produced in Leydig cells are also crucial for mammalian germ cell differentiation. Transforming growth factor-β1 (TGF-β1 is now known to have multiple effects on regulation of Leydig cell function. The objective of the present study is to determine whether TGF-β1 regulates estradiol (E2 synthesis in adult rat Leydig cells and then to assess the impact of TGF-β1 on Cx43-based gap junctional intercellular communication (GJIC between Leydig cells. METHODOLOGY/PRINCIPAL FINDINGS: Primary cultured Leydig cells were incubated in the presence of recombinant TGF-β1 and the production of E2 as well as testosterone (T were measured by RIA. The activity of P450arom was addressed by the tritiated water release assay and the expression of Cyp19 gene was evaluated by Western blotting and real time RT-PCR. The expression of Cx43 and GJIC were investigated with immunofluorescence and fluorescence recovery after photo-bleaching (FRAP, respectively. Results from this study show that TGF-β1 down-regulates the level of E2 secretion and the activity of P450arom in a dose-dependent manner in adult Leydig cells. In addition, the expression of Cx43 and GJIC was closely related to the regulation of E2 and TGF-β1, and E2 treatment in turn restored the inhibition of TGF-β1 on GJIC. CONCLUSIONS: Our results indicate, for the first time in adult rat Leydig cells, that TGF-β1 suppresses P450arom activity, as well as the expression of the Cyp19 gene, and that depression of E2 secretion leads to down-regulation of Cx43-based GJIC between Leydig cells.

  5. Bisphenol A regulates the estrogen receptor alpha signaling in developing hippocampus of male rats through estrogen receptor.

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    Xu, Xiao-Bin; He, Ye; Song, Chen; Ke, Xin; Fan, Shi-Jun; Peng, Wei-Jie; Tan, Ruei; Kawata, Mitsuhiro; Matsuda, Ken-Ichi; Pan, Bing-Xing; Kato, Nobumasa

    2014-12-01

    Bisphenol A (BPA), one of the most common environmental endocrine disruptors, has been recognized to have wide adverse effects on the brain development and behavior. These adversities are related to its ability to bind estrogen receptor (ER) with subsequent alteration of its expression in the target areas. However, very little is known about whether BPA exposure also affects ER phosphorylation and its translocation to nucleus during postnatal development, two critical steps for its function. Here, we found that during development from postnatal day 7 (P7) to P21, the alpha subtype of ER (ERα) in the hippocampus of male rats experienced remarkable alterations in terms of its expression, phosphorylation and translocation to nucleus. Exposure to low level of BPA had bidirectional, development-dependent effects on the expression of ERα mRNA and protein, but decreased ERα phosphorylation and impaired its translocation to nucleus throughout the period investigated. Treatment with low dose of ICI 182,780 (ICI), an ER antagonist to block the binding of ER with BPA, reversed the altered ERα following BPA exposure, highlighting critical involvement of ER. Moreover, ICI treatment rescued the hippocampus-dependent behavioral deficits in the adult rats experiencing early-life BPA exposure. Overall, our results indicate that BPA interferes with the ERα signaling in the developing hippocampus in an ER-dependent manner, which may underlie its adverse behavioral and cognitive outcomes in adult animals. © 2014 Wiley Periodicals, Inc.

  6. Loading-related regulation of gene expression in bone in the contexts of estrogen deficiency, lack of estrogen receptor alpha and disuse.

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    Zaman, Gul; Saxon, Leanne K; Sunters, Andrew; Hilton, Helen; Underhill, Peter; Williams, Debbie; Price, Joanna S; Lanyon, Lance E

    2010-03-01

    Loading-related changes in gene expression in resident cells in the tibia of female mice in the contexts of normality (WT), estrogen deficiency (WT-OVX), absence of estrogen receptor alpha (ERalpha(-/-)) and disuse due to sciatic neurectomy (WT-SN) were established by microarray. Total RNA was extracted from loaded and contra-lateral non-loaded tibiae at selected time points after a single, short period of dynamic loading sufficient to engender an osteogenic response. There were marked changes in the expression of many genes according to context as well as in response to loading within those contexts. In WT mice at 3, 8, 12 and 24 h after loading the expression of 642, 341, 171 and 24 genes, respectively, were differentially regulated compared with contra-lateral bones which were not loaded. Only a few of the genes differentially regulated by loading in the tibiae of WT mice have recognized roles in bone metabolism or have been linked previously to osteogenesis (Opn, Sost, Esr1, Tgfb1, Lrp1, Ostn, Timp, Mmp, Ctgf, Postn and Irs1, BMP and DLX5). The canonical pathways showing the greatest loading-related regulation were those involving pyruvate metabolism, mitochondrial dysfunction, calcium-induced apoptosis, glycolysis/gluconeogenesis, aryl hydrocarbon receptor and oxidative phosphorylation. In the tibiae from WT-OVX, ERalpha(-/-) and WT-SN mice, 440, 439 and 987 genes respectively were differentially regulated by context alone compared to WT. The early response to loading in tibiae of WT-OVX mice involved differential regulation compared to their contra-lateral non-loaded pair of fewer genes than in WT, more down-regulation than up-regulation and a later response. This was shared by WT-SN. In tibiae of ERalpha(-/-) mice, the number of genes differentially regulated by loading was markedly reduced at all time points. These data indicate that in resident bone cells, both basal and loading-related gene expression is substantially modified by context. Many of the

  7. Estrogen Receptor Alpha (ESR1-Dependent Regulation of the Mouse Oviductal Transcriptome.

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    Katheryn L Cerny

    Full Text Available Estrogen receptor-α (ESR1 is an important transcriptional regulator in the mammalian oviduct, however ESR1-dependent regulation of the transcriptome of this organ is not well defined, especially at the genomic level. The objective of this study was therefore to investigate estradiol- and ESR1-dependent regulation of the transcriptome of the oviduct using transgenic mice, both with (ESR1KO and without (wild-type, WT a global deletion of ESR1. Oviducts were collected from ESR1KO and WT littermates at 23 days of age, or ESR1KO and WT mice were treated with 5 IU PMSG to stimulate follicular development and the production of ovarian estradiol, and the oviducts collected 48 h later. RNA extracted from whole oviducts was hybridized to Affymetrix Genechip Mouse Genome 430-2.0 arrays (n = 3 arrays per genotype and treatment or reverse transcribed to cDNA for analysis of the expression of selected mRNAs by real-time PCR. Following microarray analysis, a statistical two-way ANOVA and pairwise comparison (LSD test revealed 2428 differentially expressed transcripts (DEG's, P < 0.01. Genotype affected the expression of 2215 genes, treatment (PMSG affected the expression of 465 genes, and genotype x treatment affected the expression of 438 genes. With the goal of determining estradiol/ESR1-regulated function, gene ontology (GO and bioinformatic pathway analyses were performed on DEG's in the oviducts of PMSG-treated ESR1KO versus PMSG-treated WT mice. Significantly enriched GO molecular function categories included binding and catalytic activity. Significantly enriched GO cellular component categories indicated the extracellular region. Significantly enriched GO biological process categories involved a single organism, modulation of a measurable attribute and developmental processes. Bioinformatic analysis revealed ESR1-regulation of the immune response within the oviduct as the primary canonical pathway. In summary, a transcriptomal profile of estradiol- and

  8. 17β-Estradiol regulates the gene expression of voltage-gated sodium channels: role of estrogen receptor α and estrogen receptor β.

    Science.gov (United States)

    Hu, Fang; Wang, Qiang; Wang, Peizhi; Wang, Wenjuan; Qian, Wenyi; Xiao, Hang; Wang, Lin

    2012-04-01

    Estradiol (E2) plays a key role in pain modulation, and the biological effects of E2 are transduced by binding estrogen receptors (ERs). Voltage-gated sodium (Nav) channels are responsible for the generation and propagation of action potentials in the membranes of most neurons and excitable cells. Adult dorsal root ganglion (DRG) neurons can express the ERs (ERα and ERβ), and Nav channels (TTX-S: Nav1.1, Nav1.6, and Nav1.7; and TTX-R: Nav1.8, and Nav1.9). Although E2 modulates Nav channel currents, little is known about the molecular mechanisms involved. In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. By means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice, whereas Nav1.6 mRNA decreased in αERKO, but not in βERKO mice. The mRNA expressions of Nav subtypes were increased in E2-treated WT ovariectomized animals. We also found that E2-regulation of Nav1.1 and Nav1.9 mRNA expressions is dependent on ERα, ERβ, and another ER, whereas E2-regulation of Nav1.8 appears to be in an ERβ-dependent manner.

  9. Estrogen-related receptor γ is a novel catabolic regulator of osteoarthritis pathogenesis.

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    Son, Young-Ok; Chun, Jang-Soo

    2018-01-25

    Osteoarthritis (OA) is the most common form of arthritis and is a leading cause of disability with a large socioeconomic cost. OA is a whole-joint disease characterized by cartilage destruction, synovial inflammation, osteophyte formation, and subchondral bone sclerosis. To date, however, no effective disease-modifying therapies for OA have been developed. The estrogen-related receptors (ERRs), a family of orphan nuclear receptor transcription factors, are composed of ERRα, ERRβ, and ERRγ, which play diverse biological functions such as cellular energy metabolism. However, the role of ERRs in OA pathogenesis has not been studied yet. Among the ERR family members, ERRγ is markedly upregulated in human and various models of mouse OA cartilage. Adenovirus-mediated overexpression of ERRγ in the mouse knee joint tissue caused OA pathogenesis. Additionally, cartilage-specific ERRγ transgenic (Tg) mice exhibited enhanced experimental OA. Consistently, ERRγ in articular chondrocytes directly caused expression of matrix metalloproteinase (MMP) 3 and MMP13, which play a crucial role in cartilage destruction. In contrast, genetic ablation of Esrrg or shRNA-mediated Esrrg silencing in the joint tissues abrogated experimental OA in mice. These results collectively indicated that ERRγ is a novel catabolic regulator of OA pathogenesis and can be used as a therapeutic target for OA.

  10. Regulation of DNA Damage Response by Estrogen Receptor β-Mediated Inhibition of Breast Cancer Associated Gene 2

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    Yuan-Hao Lee

    2015-04-01

    Full Text Available Accumulating evidence suggests that ubiquitin E3 ligases are involved in cancer development as their mutations correlate with genomic instability and genetic susceptibility to cancer. Despite significant findings of cancer-driving mutations in the BRCA1 gene, estrogen receptor (ER-positive breast cancers progress upon treatment with DNA damaging-cytotoxic therapies. In order to understand the underlying mechanism by which ER-positive breast cancer cells develop resistance to DNA damaging agents, we employed an estrogen receptor agonist, Erb-041, to increase the activity of ERβ and negatively regulate the expression and function of the estrogen receptor α (ERα in MCF-7 breast cancer cells. Upon Erb-041-mediated ERα down-regulation, the transcription of an ERα downstream effector, BCA2 (Breast Cancer Associated gene 2, correspondingly decreased. The ubiquitination of chromatin-bound BCA2 was induced by ultraviolet C (UVC irradiation but suppressed by Erb-041 pretreatment, resulting in a blunted DNA damage response. Upon BCA2 silencing, DNA double-stranded breaks increased with Rad51 up-regulation and ataxia telangiectasia mutated (ATM activation. Mechanistically, UV-induced BCA2 ubiquitination and chromatin binding were found to promote DNA damage response and repair via the interaction of BCA2 with ATM, γH2AX and Rad51. Taken together, this study suggests that Erb-041 potentiates BCA2 dissociation from chromatin and co-localization with Rad51, resulting in inhibition of homologous recombination repair.

  11. MicroRNA-152 mediates DNMT1-regulated DNA methylation in the estrogen receptor α gene.

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    Yung-Song Wang

    Full Text Available BACKGROUND: Estrogen receptor α (ERα has been shown to protect against atherosclerosis. Methylation of the ERα gene can reduce ERα expression leading to a higher risk for cardiovascular disease. Recently, microRNAs have been found to regulate DNA methyltransferases (DNMTs and thus control methylation status in several genes. We first searched for microRNAs involved in DNMT-associated DNA methylation in the ERα gene. We also tested whether statin and a traditional Chinese medicine (San-Huang-Xie-Xin-Tang, SHXXT could exert a therapeutic effect on microRNA, DNMT and ERα methylation. METHODOLOGY/PRINCIPAL FINDINGS: The ERα expression was decreased and ERα methylation was increased in LPS-treated human aortic smooth muscle cells (HASMCs and the aorta from rats under a high-fat diet. MicroRNA-152 was found to be down regulated in the LPS-treated HASMCs. We validated that microRNA-152 can knock down DNMT1 in HASMCs leading to hypermethylation of the ERα gene. Statin had no effect on microRNA-152, DNMT1 or ERα expression. On the contrary, SHXXT could restore microRNA-152, decrease DNMT1 and increase ERα expression in both cellular and animal studies. CONCLUSIONS/SIGNIFICANCE: The present study showed that microRNA-152 decreases under the pro-atherosclerotic conditions. The reduced microRNA-152 can lose an inhibitory effect on DNA methyltransferase, which leads to hypermethylation of the ERα gene and a decrease of ERα level. Although statin can not reverse these cascade proatherosclerotic changes, the SHXXT shows a promising effect to inhibit this unwanted signaling pathway.

  12. PGC-1{beta} regulates mouse carnitine-acylcarnitine translocase through estrogen-related receptor {alpha}

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    Gacias, Mar; Perez-Marti, Albert; Pujol-Vidal, Magdalena; Marrero, Pedro F. [Department of Biochemistry and Molecular Biology, School of Pharmacy and the Institute of Biomedicine of the University of Barcelona (IBUB) (Spain); Haro, Diego, E-mail: dharo@ub.edu [Department of Biochemistry and Molecular Biology, School of Pharmacy and the Institute of Biomedicine of the University of Barcelona (IBUB) (Spain); Relat, Joana [Department of Biochemistry and Molecular Biology, School of Pharmacy and the Institute of Biomedicine of the University of Barcelona (IBUB) (Spain)

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer The Cact gene is induced in mouse skeletal muscle after 24 h of fasting. Black-Right-Pointing-Pointer The Cact gene contains a functional consensus sequence for ERR. Black-Right-Pointing-Pointer This sequence binds ERR{alpha} both in vivo and in vitro. Black-Right-Pointing-Pointer This ERRE is required for the activation of Cact expression by the PGC-1/ERR axis. Black-Right-Pointing-Pointer Our results add Cact as a genuine gene target of these transcriptional regulators. -- Abstract: Carnitine/acylcarnitine translocase (CACT) is a mitochondrial-membrane carrier proteins that mediates the transport of acylcarnitines into the mitochondrial matrix for their oxidation by the mitochondrial fatty acid-oxidation pathway. CACT deficiency causes a variety of pathological conditions, such as hypoketotic hypoglycemia, cardiac arrest, hepatomegaly, hepatic dysfunction and muscle weakness, and it can be fatal in newborns and infants. Here we report that expression of the Cact gene is induced in mouse skeletal muscle after 24 h of fasting. To gain insight into the control of Cact gene expression, we examine the transcriptional regulation of the mouse Cact gene. We show that the 5 Prime -flanking region of this gene is transcriptionally active and contains a consensus sequence for the estrogen-related receptor (ERR), a member of the nuclear receptor family of transcription factors. This sequence binds ERR{alpha}in vivo and in vitro and is required for the activation of Cact expression by the peroxisome proliferator-activated receptor gamma coactivator (PGC)-1/ERR axis. We also demonstrate that XTC790, the inverse agonist of ERR{alpha}, specifically blocks Cact activation by PGC-1{beta} in C2C12 cells.

  13. Membrane Estrogen Receptor Alpha Targeting and its Association with SHC in Regulating Breast Cancer Cell Proliferation

    Science.gov (United States)

    2004-06-01

    1130-1131. 22. Mesbah , M, Nemere, 1, Papagerakis, P., Nefussi, J. R., Orestes-Cardoso, S., 5. Watson, C. S., Campbell, C. H . & Gametchu, B. (1999) F.p...Rodabough, R. J., Gilligan, M. A., Cyr, M. G., Thomson, C. A., Khandekar, J., Petrovitch, H ., and McTiernan, A. Influence of estrogen plus... H ., Gustafsson, J. A., Nilsson, S., and Ohlsson, C. Estren is a selective estrogen receptor modulator with transcriptional activity. Mol Pharmacol

  14. The Cell Surface Estrogen Receptor, G Protein- Coupled Receptor 30 (GPR30, is Markedly Down Regulated During Breast Tumorigenesis

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    Indira Poola

    2008-01-01

    Full Text Available Background: GPR30 is a cell surface estrogen receptor that has been shown to mediate a number of non-genomic rapid effects of estrogen and appear to balance the signaling of estrogen and growth factors. In addition, progestins appear to use GPR30 for their actions. Therefore, GPR30 could play a critical role in hormonal regulation of breast epithelial cell integrity. Deregulation of the events mediated by GPR30 could contribute to tumorigenesis.Methods: To understand the role of GPR30 in the deregulation of estrogen signaling processes during breast carcinogenesis, we have undertaken this study to investigate its expression at mRNA levels in tumor tissues and their matched normal tissues. We compared its expression at mRNA levels by RT quantitative real-time PCR relative to GAPDH in ERα”—positive (n = 54 and ERα”—negative (n = 45 breast cancer tissues to their matched normal tissues.Results: We report here, for the first time, that GPR30 mRNA levels were significantly down-regulated in cancer tissues in comparison with their matched normal tissues (p 0.0001 by two sided paired t-test. The GPR30 expression levels were significantly lower in tumor tissues from patients (n = 29 who had lymph node metastasis in comparison with tumors from patients (n = 53 who were negative for lymph node metastasis (two sample t-test, p 0.02, but no association was found with ERα, PR and other tumor characteristics.Conclusions: Down-regulation of GPR30 could contribute to breast tumorigenesis and lymph node metastasis.

  15. Interaction of proliferation cell nuclear antigen (PCNA with c-Abl in cell proliferation and response to DNA damages in breast cancer.

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    Huajun Zhao

    Full Text Available Cell proliferation in primary and metastatic tumors is a fundamental characteristic of advanced breast cancer. Further understanding of the mechanism underlying enhanced cell growth will be important in identifying novel prognostic markers and therapeutic targets. Here we demonstrated that tyrosine phosphorylation of the proliferating cell nuclear antigen (PCNA is a critical event in growth regulation of breast cancer cells. We found that phosphorylation of PCNA at tyrosine 211 (Y211 enhanced its association with the non-receptor tyrosine kinase c-Abl. We further demonstrated that c-Abl facilitates chromatin association of PCNA and is required for nuclear foci formation of PCNA in cells stressed by DNA damage as well as in unperturbed cells. Targeting Y211 phosphorylation of PCNA with a cell-permeable peptide inhibited the phosphorylation and reduced the PCNA-Abl interaction. These results show that PCNA signal transduction has an important impact on the growth regulation of breast cancer cells.

  16. Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases.

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    Preciados, Mark; Yoo, Changwon; Roy, Deodutta

    2016-12-13

    these genes are involved with brain diseases, such as Alzheimer's Disease (AD), Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorder, and Brain Neoplasms. For example, the search of enriched pathways showed that top ten E2 interacting genes in AD-APOE, APP, ATP5A1, CALM1, CASP3, GSK3B, IL1B, MAPT, PSEN2 and TNF-underlie the enrichment of the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD pathway. With AD, the six E2-responsive genes are NRF1 target genes: APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1. These genes are also responsive to the following EEDs: ethinyl estradiol (APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1), BPA (APBB2, EIF2S1, ENO1, MAPT, and PAXIP1), dibutyl phthalate (DPYSL2, EIF2S1, and ENO1), diethylhexyl phthalate (DPYSL2 and MAPT). To validate findings from Comparative Toxicogenomics Database (CTD) curated data, we used Bayesian network (BN) analysis on microarray data of AD patients. We observed that both gender and NRF1 were associated with AD. The female NRF1 gene network is completely different from male human AD patients. AD-associated NRF1 target genes-APLP1, APP, GRIN1, GRIN2B, MAPT, PSEN2, PEN2, and IDE-are also regulated by E2. NRF1 regulates targets genes with diverse functions, including cell growth, apoptosis/autophagy, mitochondrial biogenesis, genomic instability, neurogenesis, neuroplasticity, synaptogenesis, and senescence. By activating or repressing the genes involved in cell proliferation, growth suppression, DNA damage/repair, apoptosis/autophagy, angiogenesis, estrogen signaling, neurogenesis, synaptogenesis, and senescence, and inducing a wide range of DNA damage, genomic instability and DNA methylation and transcriptional repression, NRF1 may act as a major regulator of EEDs-induced brain health deficits. In summary, estrogenic endocrine disrupting chemicals-modified genes in brain health deficits are part of both estrogen and NRF1 signaling pathways. Our findings suggest that in

  17. Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases

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    Mark Preciados

    2016-12-01

    NRF1. Some of these genes are involved with brain diseases, such as Alzheimer’s Disease (AD, Parkinson’s Disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorder, and Brain Neoplasms. For example, the search of enriched pathways showed that top ten E2 interacting genes in AD—APOE, APP, ATP5A1, CALM1, CASP3, GSK3B, IL1B, MAPT, PSEN2 and TNF—underlie the enrichment of the Kyoto Encyclopedia of Genes and Genomes (KEGG AD pathway. With AD, the six E2-responsive genes are NRF1 target genes: APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1. These genes are also responsive to the following EEDs: ethinyl estradiol (APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1, BPA (APBB2, EIF2S1, ENO1, MAPT, and PAXIP1, dibutyl phthalate (DPYSL2, EIF2S1, and ENO1, diethylhexyl phthalate (DPYSL2 and MAPT. To validate findings from Comparative Toxicogenomics Database (CTD curated data, we used Bayesian network (BN analysis on microarray data of AD patients. We observed that both gender and NRF1 were associated with AD. The female NRF1 gene network is completely different from male human AD patients. AD-associated NRF1 target genes—APLP1, APP, GRIN1, GRIN2B, MAPT, PSEN2, PEN2, and IDE—are also regulated by E2. NRF1 regulates targets genes with diverse functions, including cell growth, apoptosis/autophagy, mitochondrial biogenesis, genomic instability, neurogenesis, neuroplasticity, synaptogenesis, and senescence. By activating or repressing the genes involved in cell proliferation, growth suppression, DNA damage/repair, apoptosis/autophagy, angiogenesis, estrogen signaling, neurogenesis, synaptogenesis, and senescence, and inducing a wide range of DNA damage, genomic instability and DNA methylation and transcriptional repression, NRF1 may act as a major regulator of EEDs-induced brain health deficits. In summary, estrogenic endocrine disrupting chemicals-modified genes in brain health deficits are part of both estrogen and NRF1 signaling pathways. Our

  18. Suppression of cell proliferation and regulation of estrogen receptor alpha signaling pathway by arsenic trioxide on human breast cancer MCF-7 cells.

    Science.gov (United States)

    Chow, Stephanie K Y; Chan, Judy Y W; Fung, Kwok Pui

    2004-08-01

    In recent years, breast cancers have aroused much concern. Together with a growing incidence all over the world, the development of drug resistance to tamoxifen, the most commonly prescribed chemotherapeutic drug for breast cancer patients, has highlighted the importance of developing a new chemotherapeutic drug in combating breast cancer. With the aim of treating breast cancers, the anti-tumor effects of arsenic trioxide in MCF-7 cells have been studied. MCF-7 cells are estrogen responsive cells which mimic breast cancers at the early stage. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and direct cell counting were used to measure cell proliferation. The mechanisms of action were elucidated through the measurement of estrogen receptor (ER) binding, mRNA and protein levels of ERalpha and its activity. We have demonstrated that arsenic trioxide was capable of reducing cell survival in MCF-7 cells via the suppression of the estrogen-induced growth stimulatory effects in MCF-7 cells. Arsenic trioxide was shown to suppress the action of estrogen through the regulation of the ERalpha signaling pathway. Arsenic trioxide could down-regulate ERalpha mRNA and protein levels without competing with estrogen for ERalpha binding. Arsenic trioxide also inhibited the transcription activity mediated by the ERalpha signaling pathway and ultimately it down-regulated c-myc protein expression and inhibited cell entry to S phase under estrogen's stimulation. In conclusion, arsenic trioxide could inhibit the growth of MCF-7 cells by reducing the growth stimulatory effect of estrogen. As estrogen is a primary risk factor in promoting the growth of breast tumor cells, the anti-estrogenicity exhibited by arsenic trioxide sheds light on the therapy of breast cancer.

  19. Post-transcriptional regulation of human breast cancer cell proteome by unliganded estrogen receptor β via microRNAs.

    Science.gov (United States)

    Nassa, Giovanni; Tarallo, Roberta; Giurato, Giorgio; De Filippo, Maria Rosaria; Ravo, Maria; Rizzo, Francesca; Stellato, Claudia; Ambrosino, Concetta; Baumann, Marc; Lietzèn, Niina; Nyman, Tuula A; Weisz, Alessandro

    2014-04-01

    Estrogen receptor β (ERβ) is a member of the nuclear receptor family of homeostatic regulators that is frequently lost in breast cancer (BC), where its presence correlates with a better prognosis and a less aggressive clinical outcome of the disease. In contrast to ERα, its closest homolog, ERβ shows significant estrogen-independent activities, including the ability to inhibit cell cycle progression and regulate gene transcription in the absence of the ligand. Investigating the nature and extent of this constitutive activity of ERβ in BC MCF-7 and ZR-75.1 cells by means of microRNA (miRNA) sequencing, we identified 30 miRNAs differentially expressed in ERβ+ versus ERβ- cells in the absence of ligand, including up-regulated oncosuppressor miRs such miR-30a. In addition, a significant fraction of >1,600 unique proteins identified in MCF-7 cells by iTRAQ quantitative proteomics were either increased or decreased by ERβ, revealing regulation of multiple cell pathways by ligand-free receptors. Transcriptome analysis showed that for a large number of proteins regulated by ERβ, the corresponding mRNAs are unaffected, including a large number of putative targets of ERβ-regulated miRNAs, indicating a central role of miRNAs in mediating BC cell proteome regulation by ERβ. Expression of a mimic of miR-30a-5p, a direct target and downstream effector of ERβ in BC, led to the identification of several target transcripts of this miRNA, including 11 encoding proteins whose intracellular concentration was significantly affected by unliganded receptor. These results demonstrate a significant effect of ligand-free ERβ on BC cell functions via modulation of the cell proteome and suggest that miRNA regulation might represent a key event in the control of the biological and clinical phenotype of hormone-responsive BC by this nuclear receptor.

  20. Post-transcriptional Regulation of Human Breast Cancer Cell Proteome by Unliganded Estrogen Receptor β via microRNAs*

    Science.gov (United States)

    Nassa, Giovanni; Tarallo, Roberta; Giurato, Giorgio; De Filippo, Maria Rosaria; Ravo, Maria; Rizzo, Francesca; Stellato, Claudia; Ambrosino, Concetta; Baumann, Marc; Lietzèn, Niina; Nyman, Tuula A.; Weisz, Alessandro

    2014-01-01

    Estrogen receptor β (ERβ) is a member of the nuclear receptor family of homeostatic regulators that is frequently lost in breast cancer (BC), where its presence correlates with a better prognosis and a less aggressive clinical outcome of the disease. In contrast to ERα, its closest homolog, ERβ shows significant estrogen-independent activities, including the ability to inhibit cell cycle progression and regulate gene transcription in the absence of the ligand. Investigating the nature and extent of this constitutive activity of ERβ in BC MCF-7 and ZR-75.1 cells by means of microRNA (miRNA) sequencing, we identified 30 miRNAs differentially expressed in ERβ+ versus ERβ− cells in the absence of ligand, including up-regulated oncosuppressor miRs such miR-30a. In addition, a significant fraction of >1,600 unique proteins identified in MCF-7 cells by iTRAQ quantitative proteomics were either increased or decreased by ERβ, revealing regulation of multiple cell pathways by ligand-free receptors. Transcriptome analysis showed that for a large number of proteins regulated by ERβ, the corresponding mRNAs are unaffected, including a large number of putative targets of ERβ-regulated miRNAs, indicating a central role of miRNAs in mediating BC cell proteome regulation by ERβ. Expression of a mimic of miR-30a-5p, a direct target and downstream effector of ERβ in BC, led to the identification of several target transcripts of this miRNA, including 11 encoding proteins whose intracellular concentration was significantly affected by unliganded receptor. These results demonstrate a significant effect of ligand-free ERβ on BC cell functions via modulation of the cell proteome and suggest that miRNA regulation might represent a key event in the control of the biological and clinical phenotype of hormone-responsive BC by this nuclear receptor. PMID:24525454

  1. Epigenetic Basis for the Regulation of Estrogen Receptor Alpha Activity in Breast Cancer Cells

    Science.gov (United States)

    2009-04-01

    Ibrahim, J. A. Mejia, D. Booser, R. L. Theriault, A. U. Buzdar, P. J. Dempsey, R. Rouzier, N. Sneige, J. S. Ross, T. Vidaurre, H. L. Gomez , G. N...that FOXA1 defines a domain of the estrogen response. PNAS 102 11651–11656. Lapointe J, Li C, Higgins JP, van de Rijn M, Bair E, Montgomery K, Ferrari M

  2. Elevated peritoneal expression and estrogen regulation of nociceptive ion channels in endometriosis.

    Science.gov (United States)

    Greaves, Erin; Grieve, Kelsey; Horne, Andrew W; Saunders, Philippa T K

    2014-09-01

    Ovarian suppression is a common treatment for endometriosis-associated pelvic pain. Its exact mechanism of action is poorly understood, although it is assumed to reflect reduced production/action of estrogens. The objective of the study was to measure the expression of mRNAs encoded by nociceptive genes in the peritoneum of women with chronic pelvic pain (CPP) with or without endometriosis and to investigate whether estrogens alter nociceptive gene expression in human sensory neurons. The study was performed using human tissue analysis and cell culture. The study was conducted at a university research institute. Peritoneal biopsies were obtained from women with CPP and endometriosis (n = 12), CPP and no endometriosis (n = 10), and no pain or endometriosis (n = 5). Endometriosis lesions were obtained from women with endometriosis (n = 18). mRNAs encoding ion channels (P2RX3, SCN9A, SCN11A, TRPA1, TRPV1) and the neurotransmitter TAC1 were measured in human tissue samples and in human embryonic stem cell-derived sensory neurons treated with estrogens. TRPV1, TRPA1, and SCN11A mRNAs were significantly higher in the peritoneum from women with endometriosis (P < .001, P < .01). TRPV1, SCN9A, and TAC1 were elevated in endometriosis lesions (P < .05). P2RX3 mRNA was increased in the peritoneum of women with CPP, with and without endometriosis (P < .05). Incubation of sensory neurons with 17β-estradiol increased TRPV1 mRNA (P < .01). The estrogen receptor-β-selective agonist 2,3-bis(4-hydroxy-phenyl)-propionitrile increased concentrations of TRPV1, P2RX3, SCN9A, and TAC1 mRNAs. Estrogen-dependent expression of TRPV1 in sensory neurons may explain why ovarian suppression can reduce endometriosis-associated pain. Strategies directly targeting ion channels may offer an alternative option for the management of CPP.

  3. Regulation of Growth and Metastases in an Estrogen Independent Breast Cancer Cell by Vitamin D Compounds

    Science.gov (United States)

    2001-08-01

    jellyfish Aequorea Victoria (previously described in original grant proposal). Orthotopic implantation of SUMp159PTGFP was carried out to allow for the...the presence of a TATA box at -29 bp. the selective estrogen response modifier (SERM) tamoxifen and is not Putative transcription factor binding sites...TATA box E1C2. The cycling conditions for the secondary PCR reaction were as in addition to consensus sequences corresponding to AP-1, follows: 5 cycles

  4. Cell cycle and anti-estrogen effects synergize to regulate cell proliferation and ER target gene expression.

    Directory of Open Access Journals (Sweden)

    Mathieu Dalvai

    Full Text Available Antiestrogens are designed to antagonize hormone induced proliferation and ERalpha target gene expression in mammary tumor cells. Commonly used drugs such as OH-Tamoxifen and ICI 182780 (Fulvestrant block cell cycle progression in G0/G1. Inversely, the effect of cell cycle stage on ER regulated gene expression has not been tested directly. We show that in ERalpha-positive breast cancer cells (MCF-7 the estrogen receptor gene and downstream target genes are cell cycle regulated with expression levels varying as much as three-fold between phases of the cell cycle. Steroid free culture conditions commonly used to assess the effect of hormones or antiestrogens on gene expression also block MCF-7 cells in G1-phase when several ERalpha target genes are overexpressed. Thus, cell cycle effects have to be taken into account when analyzing the impact of hormonal treatments on gene transcription. We found that antiestrogens repress transcription of several ERalpha target genes specifically in S phase. This observation corroborates the more rapid and strong impact of antiestrogen treatments on cell proliferation in thymidine, hydroxyurea or aphidicolin arrested cells and correlates with an increase of apoptosis compared to similar treatments in lovastatin or nocodazol treated cells. Hence, cell cycle effects synergize with the action of antiestrogens. An interesting therapeutic perspective could be to enhance the action of anti-estrogens by associating hormone-therapy with specific cell cycle drugs.

  5. Estrogen Replacement Regulates Vaginal Innervations in Ovariectomized Adult Virgin Rats: A Histological Study

    Directory of Open Access Journals (Sweden)

    Ting Li

    2017-01-01

    Full Text Available Background. Our previous Gräfenberg spot findings confirmed that the distal-third areas of the anterior vaginal wall bore a significantly greater number of nerves and sexual hormone may have certain degree of influence on these significant differences. However, the role of estrogen in vaginal innervations remains controversial. Methods. To investigate whether hormonal-neural interactions occur in the vagina, sixty rats were randomly divided into six groups: Sham-operated, ovariectomy, and 4 treatment groups. After 2 weeks of treatment, vaginal biopsies were prepared with hematoxylin and eosin and PGP9.5 using immunohistochemistry. Results. The density of small nerve fibers was significantly higher in the distal-half areas of intact vaginal walls than the proximal-half areas (P=0.001. In contrast, the overall PGP 9.5-ir fiber innervation density was significantly decreased in the OVX rats subjected to surgical menopause. Sustained estrogen administration for 2 weeks resulted in nerve fiber proliferation, with values reaching normal levels in the low-dose estradiol valerate group. Conclusion. Our findings indicate that systemic hormonal therapy with low-dose estradiol valerate is effective and safe for treating deficient vaginal innervation caused by low level of estrogen activity in menopausal women and may aid studies to identify an optimal estradiol dose to provide relief from vaginal discomfort.

  6. Drug and cell type-specific regulation of genes with different classes of estrogen receptor beta-selective agonists.

    Directory of Open Access Journals (Sweden)

    Sreenivasan Paruthiyil

    2009-07-01

    Full Text Available Estrogens produce biological effects by interacting with two estrogen receptors, ERalpha and ERbeta. Drugs that selectively target ERalpha or ERbeta might be safer for conditions that have been traditionally treated with non-selective estrogens. Several synthetic and natural ERbeta-selective compounds have been identified. One class of ERbeta-selective agonists is represented by ERB-041 (WAY-202041 which binds to ERbeta much greater than ERalpha. A second class of ERbeta-selective agonists derived from plants include MF101, nyasol and liquiritigenin that bind similarly to both ERs, but only activate transcription with ERbeta. Diarylpropionitrile represents a third class of ERbeta-selective compounds because its selectivity is due to a combination of greater binding to ERbeta and transcriptional activity. However, it is unclear if these three classes of ERbeta-selective compounds produce similar biological activities. The goals of these studies were to determine the relative ERbeta selectivity and pattern of gene expression of these three classes of ERbeta-selective compounds compared to estradiol (E(2, which is a non-selective ER agonist. U2OS cells stably transfected with ERalpha or ERbeta were treated with E(2 or the ERbeta-selective compounds for 6 h. Microarray data demonstrated that ERB-041, MF101 and liquiritigenin were the most ERbeta-selective agonists compared to estradiol, followed by nyasol and then diarylpropionitrile. FRET analysis showed that all compounds induced a similar conformation of ERbeta, which is consistent with the finding that most genes regulated by the ERbeta-selective compounds were similar to each other and E(2. However, there were some classes of genes differentially regulated by the ERbeta agonists and E(2. Two ERbeta-selective compounds, MF101 and liquiritigenin had cell type-specific effects as they regulated different genes in HeLa, Caco-2 and Ishikawa cell lines expressing ERbeta. Our gene profiling studies

  7. Drug and cell type-specific regulation of genes with different classes of estrogen receptor beta-selective agonists.

    Science.gov (United States)

    Paruthiyil, Sreenivasan; Cvoro, Aleksandra; Zhao, Xiaoyue; Wu, Zhijin; Sui, Yunxia; Staub, Richard E; Baggett, Scott; Herber, Candice B; Griffin, Chandi; Tagliaferri, Mary; Harris, Heather A; Cohen, Isaac; Bjeldanes, Leonard F; Speed, Terence P; Schaufele, Fred; Leitman, Dale C

    2009-07-17

    Estrogens produce biological effects by interacting with two estrogen receptors, ERalpha and ERbeta. Drugs that selectively target ERalpha or ERbeta might be safer for conditions that have been traditionally treated with non-selective estrogens. Several synthetic and natural ERbeta-selective compounds have been identified. One class of ERbeta-selective agonists is represented by ERB-041 (WAY-202041) which binds to ERbeta much greater than ERalpha. A second class of ERbeta-selective agonists derived from plants include MF101, nyasol and liquiritigenin that bind similarly to both ERs, but only activate transcription with ERbeta. Diarylpropionitrile represents a third class of ERbeta-selective compounds because its selectivity is due to a combination of greater binding to ERbeta and transcriptional activity. However, it is unclear if these three classes of ERbeta-selective compounds produce similar biological activities. The goals of these studies were to determine the relative ERbeta selectivity and pattern of gene expression of these three classes of ERbeta-selective compounds compared to estradiol (E(2)), which is a non-selective ER agonist. U2OS cells stably transfected with ERalpha or ERbeta were treated with E(2) or the ERbeta-selective compounds for 6 h. Microarray data demonstrated that ERB-041, MF101 and liquiritigenin were the most ERbeta-selective agonists compared to estradiol, followed by nyasol and then diarylpropionitrile. FRET analysis showed that all compounds induced a similar conformation of ERbeta, which is consistent with the finding that most genes regulated by the ERbeta-selective compounds were similar to each other and E(2). However, there were some classes of genes differentially regulated by the ERbeta agonists and E(2). Two ERbeta-selective compounds, MF101 and liquiritigenin had cell type-specific effects as they regulated different genes in HeLa, Caco-2 and Ishikawa cell lines expressing ERbeta. Our gene profiling studies demonstrate that

  8. Nuclear and Membrane Actions of Estrogen Receptor Alpha: Contribution to the Regulation of Energy and Glucose Homeostasis.

    Science.gov (United States)

    Guillaume, Maeva; Montagner, Alexandra; Fontaine, Coralie; Lenfant, Françoise; Arnal, Jean-François; Gourdy, Pierre

    2017-01-01

    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.

  9. PAC down-regulates estrogen receptor alpha and suppresses epithelial-to-mesenchymal transition in breast cancer cells.

    Science.gov (United States)

    Al-Howail, Huda A; Hakami, Hana A; Al-Otaibi, Basem; Al-Mazrou, Amer; Daghestani, Maha H; Al-Jammaz, Ibrahim; Al-Khalaf, Huda H; Aboussekhra, Abdelilah

    2016-07-27

    Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Therefore, novel molecules and therapeutic options are urgently needed for this category of patients. Recently, we have identified PAC as a curcumin analogue with potent anti-cancer features. HPLC was used to evaluate the stability of PAC and curcumin in PBS and also in circulating blood. Cytotoxicity/apoptosis was assessed in different breast cancer cell lines using propidium iodide/annexinV associated with flow cytometry. Furthermore, immunoblotting analysis determined the effects of PAC on different oncogenic proteins and pathways. Additionally, the real time xCELLigence RTCA technology was applied to investigate the effect of PAC on the cellular proliferation, migration and invasion capacities. PAC is more stable than curcumin in PBS and in circulating blood. Furthermore, we have shown differential sensitivity of estrogen receptor-alfa positive (ERα(+)) and estrogen receptor alfa negative (ERα(-)) breast cancer cells to PAC, which down-regulated ERα in both cell types. This led to complete disappearance of ERα in ERα(-) cells, which express very low level of this receptor. Interestingly, specific down-regulation of ERα in receptor positive cells increased the apoptotic response of these cells to PAC, confirming that ERα inhibits PAC-dependent induction of apoptosis, which could be mediated through ERα down-regulation. Additionally, PAC inhibited the proliferation and suppressed the epithelial-to-mesenchymal transition process in breast cancer cells, with higher efficiency on the TNBC subtype. This effect was also observed in vivo on tumor xenografts. Additionally, PAC suppressed the expression/secretion of 2 important cytokines IL-6 and MCP-1, and consequently inhibited the paracrine procarcinogenic effects of breast cancer cells on breast stromal fibroblasts

  10. Molecular characterization of c-Abl/c-Src kinase inhibitors targeted against murine tumour progenitor cells that express stem cell markers.

    Directory of Open Access Journals (Sweden)

    Thomas Kruewel

    Full Text Available BACKGROUND: The non-receptor tyrosine kinases c-Abl and c-Src are overexpressed in various solid human tumours. Inhibition of their hyperactivity represents a molecular rationale in the combat of cancerous diseases. Here we examined the effects of a new family of pyrazolo [3,4-d] pyrimidines on a panel of 11 different murine lung tumour progenitor cell lines, that express stem cell markers, as well as on the human lung adenocarcinoma cell line A549, the human hepatoma cell line HepG2 and the human colon cancer cell line CaCo2 to obtain insight into the mode of action of these experimental drugs. METHODOLOGY/PRINCIPAL FINDINGS: Treatment with the dual kinase inhibitors blocked c-Abl and c-Src kinase activity efficiently in the nanomolar range, induced apoptosis, reduced cell viability and caused cell cycle arrest predominantly at G0/G1 phase while western blot analysis confirmed repressed protein expression of c-Abl and c-Src as well as the interacting partners p38 mitogen activated protein kinase, heterogenous ribonucleoprotein K, cyclin dependent kinase 1 and further proteins that are crucial for tumour progression. Importantly, a significant repression of the epidermal growth factor receptor was observed while whole genome gene expression analysis evidenced regulation of many cell cycle regulated genes as well integrin and focal adhesion kinase (FAK signalling to impact cytoskeleton dynamics, migration, invasion and metastasis. CONCLUSIONS/SIGNIFICANCE: Our experiments and recently published in vivo engraftment studies with various tumour cell lines revealed the dual kinase inhibitors to be efficient in their antitumour activity.

  11. Differential regulation of GPR54 transcription by specificity protein-1 and partial estrogen response element in mouse pituitary cells.

    Science.gov (United States)

    DeFino, Mia C; Wacker, Jennifer L; Lyssand, John S; Wang, Edith H; Hague, Chris

    2010-03-19

    Precise spatial and temporal expression of the recently identified G-protein coupled receptor GPR54 is critical for proper reproductive function and metastasis suppression. However, regulatory factors that control GPR54 expression remain unknown. Thus, the identification of these cis-acting DNA elements can provide insight into the role of GPR54 in reproduction and cancer. Using luciferase reporter, electrophoretic mobility shift, and chromatin immunoprecipitation assays, we demonstrate that three SP1 sites and a partial estrogen response element modulate mouse GPR54 (mGPR54) promoter activity. Supporting experiments show transcription factor SP1 binds directly to the mGPR54 promoter region and activates gene expression. In conclusion, these novel findings now identify factors that regulate activity of the mGPR54 promoter, and these factors are highly conserved across multiple mammalian species. Published by Elsevier Inc.

  12. DLK1 is a novel regulator of bone mass that mediates estrogen deficiency-induced bone loss in mice

    DEFF Research Database (Denmark)

    Abdallah, Basem M; Ditzel, Nicholas; Mahmood, Amer

    2011-01-01

    . In a number of in vitro culture systems, Dlk1 stimulated osteoclastogenesis indirectly through osteoblast-dependent increased production of proinflammatory bone-resorbing cytokines (eg, Il7, Tnfa, and Ccl3). We found that ovariectomy (ovx)-induced bone loss was associated with increased production of Dlk1...... in the bone marrow by activated T cells. Interestingly, Dlk1(-/-) mice were significantly protected from ovx-induced bone loss compared with wild-type mice. Thus we identified Dlk1 as a novel regulator of bone mass that functions to inhibit bone formation and to stimulate bone resorption. Increasing DLK1...... production by T cells under estrogen deficiency suggests its possible use as a therapeutic target for preventing postmenopausal bone loss....

  13. Lycium chinense Improves Post-Menopausal Obesity via Regulation of PPAR-γ and Estrogen Receptor-α/β Expressions.

    Science.gov (United States)

    Kim, Mi Hye; Kim, Eun-Jung; Choi, You Yeon; Hong, Jongki; Yang, Woong Mo

    2017-01-01

    The fruit of Lycium chinense Miller (Solanaceae) is used as a functional food and a medicinal herb for treating many specific health concerns. Weight gain induced by estrogen deficiency is a problem for post-menopausal women around the globe. The present study investigates the effects of aqueous extract of L. chinense (LC) on post-menopausal obesity. Female C57BL/6 mice were ovariectomized and fed on high-fat diet (HFD) for 12 weeks to induce post-menopausal obesity. LC extract (1[Formula: see text]mg/kg and 10[Formula: see text]mg/kg) was orally administrated for 6 weeks with continuous HFD feeding. Ovarian adipose tissues and uterus were weighed. Serum triglyceride, cholesterol, LDL-cholesterol and fasting glucose levels were analyzed. The expressions of adipocyte-specific factors and estrogen receptors (ERs) were investigated. Additionally, lipid accumulation was confirmed in differentiated 3T3-L1 adipocytes. Increased body weight due to post-menopausal obesity was ameliorated about 14.7% and 17.76% by treatment of 1[Formula: see text]mg/kg and 10[Formula: see text]mg/kg LC, respectively. LC treatment reduced both of serum lipid and fasting blood glucose levels. Adipocyte hypertrophy and fatty liver were ameliorated in LC-treated groups. In LC-treated adipocyte cells, lipid accumulation was significantly inhibited. The expression of perilipin in adipose tissues was decreased by LC. In addition, expression of PPAR-[Formula: see text] protein was down-regulated in adipose tissues and differentiated adipocytes, while GLUT4 expression was increased in adipose tissues by LC treatment. Moreover, LC treatment up-regulated the expressions of ER-[Formula: see text]/[Formula: see text] accompanied with increased uterine weight. These results showed the ameliorative effects of LC on overweight after menopause. Post-menopausal obesity may be improved by LC treatment.

  14. Estrogen Injection

    Science.gov (United States)

    ... estradiol cypionate and estradiol valerate forms of estrogen injection are used to treat hot flushes (hot flashes; ... consider a different treatment. These forms of estrogen injection are also sometimes used to treat the symptoms ...

  15. Estrogen Test

    Science.gov (United States)

    ... eGFR) Estrogen/Progesterone Receptor Status Estrogens Ethanol Extractable Nuclear Antigen Antibodies (ENA) Panel Factor V Leiden Mutation ... and Acute Coronary Syndrome Heart Disease Hemochromatosis Hemoglobin Abnormalities Hepatitis HIV Infection and AIDS Huntington Disease Hypertension ...

  16. Effects on DHEA levels by estrogen in rat astrocytes and CNS co-cultures via the regulation of CYP7B1-mediated metabolism

    DEFF Research Database (Denmark)

    Fex Svenningsen, Åsa; Wicher, Grzegorz; Lundqvist, Johan

    2011-01-01

    The neurosteroid dehydroepiandrosterone (DHEA) is formed locally in the CNS and has been implicated in several processes essential for CNS function, including control of neuronal survival. An important metabolic pathway for DHEA in the CNS involves the steroid hydroxylase CYP7B1. In previous...... studies, CYP7B1 was identified as a target for estrogen regulation in cells of kidney and liver. In the current study, we examined effects of estrogens on CYP7B1-mediated metabolism of DHEA in primary cultures of rat astrocytes and co-cultures of rat CNS cells. Astrocytes, which interact with neurons...... in several ways, are important for brain neurosteroidogenesis. We found that estradiol significantly suppressed CYP7B1-mediated DHEA hydroxylation in primary mixed CNS cultures from fetal and newborn rats. Also, CYP7B1-mediated DHEA hydroxylation and CYP7B1 mRNA were markedly suppressed by estrogen...

  17. Neuroprotective efficacy of a new brain-penetrating C-Abl inhibitor in a murine Parkinson's disease model.

    Directory of Open Access Journals (Sweden)

    Syed Z Imam

    Full Text Available Experimental evidence suggests that oxidative and nitrative mechanisms account for much of the dopaminergic neuronal injury in Parkinson's disease (PD. The ubiquitously expressed non-receptor tyrosine kinase c-Abl is activated by oxidative stress and thus, may play a role in redox-mediated neurodegeneration. Recently, we reported that c-Abl is activated in PD and that a c-Abl inhibitor mitigated neuronal damage in a PD animal model, suggesting a novel neuroprotective therapeutic approach. In the studies presented here, we evaluated the efficacy of a potent and clinically relevant second-generation irreversible Abl kinase inhibitor, INNO-406, as a therapeutic agent for PD. Our studies reveal that INNO-406 is capable of preventing the progression of dopaminergic neuronal damage in a toxin-induced C57 mouse model of PD. Using bovine brain microvessel endothelium as an in vitro blood-brain barrier (BBB model, we detected rapid and significant transfer of INNO-406. Additionally, pharmacokinetic analyses demonstrated significant nanomolar concentrations of INNO-406 in brain in the presence or absence of MPTP administration, however, INNO-406 did not alter the brain levels of MPP+ in MPTP-treated mice. Finally, we showed that 10 mg/kg of INNO-406 given to C57 mice for one week before MPTP treatment (4×20 mg/kg i.p., every 2 h and then for one week after MPTP treatment decreased the loss of dopamine in the striatum by 45% and the loss of TH+ neurons in substantia nigra pars compacts by 40%. This treatment regimen also abrogated activation of c-Abl, tyrosine phosphorylation of the Abl substrate and E3-ubiquitin ligase parkin, and accumulation of the toxic parkin substrate AIMP2. We propose that compounds of the INNO-406 class of Abl inhibitors will be useful new neuroprotective drugs for the treatment of PD-like pathology in preclinical systems that should be easily translated to the clinic.

  18. IL-8 Is Involved in Estrogen-Related Receptor α-Regulated Proliferation and Migration of Colorectal Cancer Cells.

    Science.gov (United States)

    Ding, Sijuan; Tang, Zhaohui; Jiang, Yongjun; Huang, Honglin; Luo, Pengfei; Qing, Bohua; Zhang, Siyuan; Tang, Ruoting

    2017-10-09

    Studies revealed that estrogenic signals were involved in the development of colorectal cancer (CRC), while the roles of estrogen related receptor (ERR) on the progression of CRC have not been well illustrated. Its roles on the development of CRC were investigated. The expression of ERRα/β/γ in CRC cells were measured. The effects of ERRα on cell proliferation, migration and expression of cytokines were investigated accordingly. Our data revealed that the expression of ERRα, while not ERRβ or ERRγ, was significantly increased in CRC cells and clinical CRC tissues. Both the inverse agonist of ERRα (XCT-790) and si-ERRα can inhibit the proliferation of CRC cells. XCT-790 treatment can also suppress the wound healing and in vitro migration of CRC cells. Cytokine assays showed that XCT-790 can significantly decrease the expression of interleukin-8 (IL-8), while not IL-4, IL-6, IL-8, IL-9, IL-10, IL-18, IFN-γ, or TGF-β, in CRC cells. Over expression of ERRα increased the expression of IL-8. Luciferase assay showed XCT-790 decreased the promoter activity of IL-8. XCT-790 can increase the decay of IL-8 mRNA in SW480 cells. The recombinant IL-8 (rIL-8) can rescue XCT-790 induced suppression of proliferation and migration of CRC cells. XCT-790 can decrease the phosphorylation of ERK1/2 and STAT3, two downstream signal molecules of IL-8, in CRC cells. While rIL-8 can markedly attenuate XCT-790 induced dephosphorylation of ERK1/2 and STAT3. Our data showed that ERRα can trigger the proliferation and migration of CRC cells via up regulation of IL-8. Therefor targeted inhibition of ERRα/IL-8 might be a potential approach for CRC treatment and drug development.

  19. Role of the proteasome in the regulation of estrogen receptor alpha turnover and function in MCF-7 breast carcinoma cells.

    Science.gov (United States)

    Laïos, Ioanna; Journé, Fabrice; Nonclercq, Denis; Vidal, Doris Salazar; Toillon, Robert-Alain; Laurent, Guy; Leclercq, Guy

    2005-03-01

    Estrogen receptor alpha (ER) turnover in MCF-7 cells was assessed by pulse chase analysis and measurement of ER steady-state level. In untreated cells, degradation of (35)S-labeled ER was characterized by a slow phase followed by a more rapid decline. Without ligand, ER elimination was totally compensated by synthesis which maintained receptor homeostasis. Estradiol (E(2)) and the pure antiestrogen RU 58,668 abolished the slow phase of ER breakdown and enhanced the degradation of neosynthesized ER, producing a low ER steady-state level. By contrast, the partial antiestrogen OH-Tam was ineffective in this respect and caused ER accumulation. Regardless of the conditions, ER breakdown was abolished by proteasome inhibition (MG-132). ER ligands decreased cell capacity to bind [(3)H]E(2), even in the presence of MG-132, indicating that the regulation of ER level and E(2) binding capacity occurs through distinct mechanisms. MG-132 partially blocked the basal transcription of an ERE-dependent reporter gene and modified the ability of E(2) to induce the expression of the latter: the hormone was unable to restore the transactivation activity measured without MG-132. RU 58,668 and OH-Tam failed to enhance the inhibitory action of MG-132, suggesting that a loss of basal ER-mediated transactivation mainly affects the stimulatory effect of estrogens. Overall, our findings reveal that ER steady state level, ligand binding capacity and transactivation potency fit in a complex regulatory scheme involving distinct mechanisms, which may be dissociated from each other under various treatments.

  20. Vertebrate estrogen regulates the development of female characteristics in silkworm, Bombyx mori.

    Science.gov (United States)

    Shen, Guanwang; Lin, Ying; Yang, Congwen; Xing, Runmiao; Zhang, Haiyan; Chen, Enxiang; Han, Chaoshan; Liu, Hongling; Zhang, Weiwei; Xia, Qingyou

    2015-01-01

    The vertebrate estrogens include 17-β-estradiol (E2), which has an analog in silkworm ovaries. In this study, the Bombyx mori vitellogenin gene (BmVg) was used as a biomarker to analyze the function of the E2 in silkworm. In most oviparous animals, Vg has female-specific expression. However, BmVg expression was also detected in B. mori males. Stage specific fluctuation of BmVg expression was similar in males and females, but expression levels in males were lower than in females. E2 treatment by injection or feeding of male larvae in the final instar stage induced and stimulated male BmVg transcription and protein synthesis. When silkworm ovary primordia were transplanted into males, BmVg was induced in male fat bodies. Transplanted ovaries primordia were also able to develop into ovaries and produce mature eggs. When females were treated with E2 promoted BmVg/BmVn protein accumulation in hemolymph, ovaries and eggs. However, BmVg transcription was decreased in female fat bodies. An E2 analog was identified in the hemolymph of day 3 wandering silkworms using high-performance liquid chromatography. Estradiol titers from fifth late-instar larvae to pupal stage were determined by enzyme-linked immunosorbent assay. The results suggested that silkworms synthesized a vertebrate E2 analog. This study found that E2 promoted the synthesis of BmVg, a female typical protein in silkworms. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Sex differences and estrogen regulation of BDNF gene expression, but not propeptide content, in the developing hippocampus.

    Science.gov (United States)

    Kight, Katherine E; McCarthy, Margaret M

    2017-01-02

    Sex differences in adult brain function are frequently determined developmentally through the actions of steroid hormones during sensitive periods of prenatal and early postnatal life. In rodents, various cellular end points of the developing brain are affected by estradiol that is derived from the aromatization of circulating testosterone and/or synthesized within the brain. We have previously described a sex difference in neurogenesis in the hippocampus of neonatal rats that is modulated by estradiol. In this report, we examined a potential downstream regulator of the effects of estradiol on hippocampal cell proliferation by measuring gene expression of brain-derived neurotrophin (BDNF) in male and female neonatal rats in response to estradiol. Males had higher baseline BDNF gene expression in dentate gyrus and CA1 regions of the hippocampus compared with females. Neonatal administration of exogenous estradiol resulted in opposite effects on BDNF expression in these areas of the neonatal hippocampus, such that BDNF transcripts increased in CA1 but decreased in dentate. Blocking endogenous estradiol signaling by antagonizing estrogen receptors decreased BDNF expression in the dentate of males, but not females, and had no effect in CA1. Interestingly, this sex difference and response to estradiol was not mirrored by translational output, as no differences in BDNF precursor peptide were observed. The sex- and region-specific effects of estradiol on BDNF expression in the neonatal hippocampus suggest a complex functional relationship between these pleiotropic factors in regulating developmental neurogenesis. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  2. Differential regulation of HIF-1α and HIF-2α in neuroblastoma: Estrogen-related receptor alpha (ERRα) regulates HIF2A transcription and correlates to poor outcome

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    Hamidian, Arash; Stedingk, Kristoffer von; Munksgaard Thorén, Matilda; Mohlin, Sofie; Påhlman, Sven, E-mail: sven.pahlman@med.lu.se

    2015-06-05

    Hypoxia-inducible factors (HIFs) are differentially regulated in tumor cells. While the current paradigm supports post-translational regulation of the HIF-α subunits, we recently showed that hypoxic HIF-2α is also transcriptionally regulated via insulin-like growth factor (IGF)-II in the childhood tumor neuroblastoma. Here, we demonstrate that transcriptional regulation of HIF-2α seems to be restricted to neural cell-derived tumors, while HIF-1α is canonically regulated at the post-translational level uniformly across different tumor forms. Enhanced expression of HIF2A mRNA at hypoxia is due to de novo transcription rather than increased mRNA stability, and chemical stabilization of the HIF-α proteins at oxygen-rich conditions unexpectedly leads to increased HIF2A transcription. The enhanced HIF2A levels do not seem to be dependent on active HIF-1. Using a transcriptome array approach, we identified members of the Peroxisome proliferator-activated receptor gamma coactivator (PGC)/Estrogen-related receptor (ERR) complex families as potential regulators of HIF2A. Knockdown or inhibition of one of the members, ERRα, leads to decreased expression of HIF2A, and high expression of the ERRα gene ESRRA correlates with poor overall and progression-free survival in a clinical neuroblastoma material consisting of 88 tumors. Thus, targeting of ERRα and pathways regulating transcriptional HIF-2α are promising therapeutic avenues in neuroblastoma. - Highlights: • Transcriptional control of HIF-2α is restricted to neural cell-derived tumors. • Enhanced transcription of HIF2A is not due to increased mRNA stability. • Chemical stabilization of the HIF-α subunits leads to increased HIF2A transcription. • ERRα regulates HIF2A mRNA expression in neuroblastoma. • High expression of ESRRA correlates to poor outcome in neuroblastoma.

  3. Estrogenic regulation of histamine receptor subtype H1 expression in the ventromedial nucleus of the hypothalamus in female rats.

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    Hiroko Mori

    Full Text Available Female sexual behavior is controlled by central estrogenic action in the ventromedial nucleus of the hypothalamus (VMN. This region plays a pivotal role in facilitating sex-related behavior in response to estrogen stimulation via neural activation by several neurotransmitters, including histamine, which participates in this mechanism through its strong neural potentiating action. However, the mechanism through which estrogen signaling is linked to the histamine system in the VMN is unclear. This study was undertaken to investigate the relationship between estrogen and histamine receptor subtype H1 (H1R, which is a potent subtype among histamine receptors in the brain. We show localization of H1R exclusively in the ventrolateral subregion of the female VMN (vl VMN, and not in the dorsomedial subregion. In the vl VMN, abundantly expressed H1R were mostly colocalized with estrogen receptor α. Intriguingly, H1R mRNA levels in the vl VMN were significantly elevated in ovariectomized female rats treated with estrogen benzoate. These data suggest that estrogen can amplify histamine signaling by enhancing H1R expression in the vl VMN. This enhancement of histamine signaling might be functionally important for allowing neural excitation in response to estrogen stimulation of the neural circuit and may serve as an accelerator of female sexual arousal.

  4. A Suppressive Antagonism Evidences Progesterone and Estrogen Receptor Pathway Interaction with Concomitant Regulation of Hand2, Bmp2 and ERK during Early Decidualization.

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    Ana C Mestre-Citrinovitz

    Full Text Available Progesterone receptor and estrogen receptor participate in growth and differentiation of the different rat decidual regions. Steroid hormone receptor antagonists were used to study steroid regulation of decidualization. Here we describe a suppressive interaction between progesterone receptor (onapristone and estrogen receptor (ICI182780 antagonists and their relation to a rescue phenomenon with concomitant regulation of Hand2, Bmp2 and p-ERK1/2 during the early decidualization steps. Phenotypes of decidua development produced by antagonist treatments were characterized by morphology, proliferation, differentiation, angiogenesis and expression of signaling molecules. We found that suppression of progesterone receptor activity by onapristone treatment resulted in resorption of the implantation sites with concomitant decrease in progesterone and estrogen receptors, PCNA, KI67 antigen, DESMIN, CCND3, CX43, Prl8a2, and signaling players such as transcription factor Hand2, Bmp2 mRNAs and p-ERK1/2. Moreover, FGF-2 and Vegfa increased as a consequence of onapristone treatment. Implantation sites from antagonist of estrogen receptor treated rats developed all decidual regions, but showed an anomalous blood vessel formation at the mesometrial part of the decidua. The deleterious effect of onapristone was partially counteracted by the impairment of estrogen receptor activity with rescue of expression levels of hormone steroid receptors, proliferation and differentiation markers, and the induction of a probably compensatory increase in signaling molecules Hand2, Bmp2 and ERK1/2 activation compared to oil treated controls. This novel drug interaction during decidualization could be applied to pathological endometrial cell proliferation processes to improve therapies using steroid hormone receptor targets.

  5. Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer.

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    Paris, O; Ferraro, L; Grober, O M V; Ravo, M; De Filippo, M R; Giurato, G; Nassa, G; Tarallo, R; Cantarella, C; Rizzo, F; Di Benedetto, A; Mottolese, M; Benes, V; Ambrosino, C; Nola, E; Weisz, A

    2012-09-20

    Estrogen effects on mammary epithelial and breast cancer (BC) cells are mediated by the nuclear receptors ERα and ERβ, transcription factors that display functional antagonism with each other, with ERβ acting as oncosuppressor and interfering with the effects of ERα on cell proliferation, tumor promotion and progression. Indeed, hormone-responsive, ERα+ BC cells often lack ERβ, which when present associates with a less aggressive clinical phenotype of the disease. Recent evidences point to a significant role of microRNAs (miRNAs) in BC, where specific miRNA expression profiles associate with distinct clinical and biological phenotypes of the lesion. Considering the possibility that ERβ might influence BC cell behavior via miRNAs, we compared miRNome expression in ERβ+ vs ERβ- hormone-responsive BC cells and found a widespread effect of this ER subtype on the expression pattern of these non-coding RNAs. More importantly, the expression pattern of 67 miRNAs, including 10 regulated by ERβ in BC cells, clearly distinguishes ERβ+, node-negative, from ERβ-, metastatic, mammary tumors. Molecular dissection of miRNA biogenesis revealed multiple mechanisms for direct regulation of this process by ERβ+ in BC cell nuclei. In particular, ERβ downregulates miR-30a by binding to two specific sites proximal to the gene and thereby inhibiting pri-miR synthesis. On the other hand, the receptor promotes miR-23b, -27b and 24-1 accumulation in the cell by binding in close proximity of the corresponding gene cluster and preventing in situ the inhibitory effects of ERα on pri-miR maturation by the p68/DDX5-Drosha microprocessor complex. These results indicate that cell autonomous regulation of miRNA expression is part of the mechanism of action of ERβ in BC cells and could contribute to establishment or maintenance of a less aggressive tumor phenotype mediated by this nuclear receptor.

  6. Chicken pleiotrophin: regulation of tissue specific expression by estrogen in the oviduct and distinct expression pattern in the ovarian carcinomas.

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    Jin-Young Lee

    Full Text Available Pleiotrophin (PTN is a developmentally-regulated growth factor which is widely distributed in various tissues and also detected in many kinds of carcinomas. However, little is known about the PTN gene in chickens. In the present study, we found chicken PTN to be highly conserved with respect to mammalian PTN genes (91-92.6% and its mRNA was most abundant in brain, heart and oviduct. This study focused on the PTN gene in the oviduct where it was detected in the glandular (GE and luminal (LE epithelial cells. Treatment of young chicks with diethylstilbesterol induced PTN mRNA and protein in GE and LE, but not in other cell types of the oviduct. Further, several microRNAs, specifically miR-499 and miR-1709 were discovered to influence PTN expression via its 3'-UTR which suggests that post-transcriptional regulation influences PTN expression in chickens. We also compared expression patterns and CpG methylation status of the PTN gene in normal and cancerous ovaries from chickens. Our results indicated that PTN is most abundant in the GE of adenocarcinoma of cancerous, but not normal ovaries of hens. Bisulfite sequencing revealed that 30- and 40% of -1311 and -1339 CpG sites are demethylated in ovarian cancer cells, respectively. Collectively, these results indicate that chicken PTN is a novel estrogen-induced gene expressed mainly in the oviductal epithelia implicating PTN regulation of oviduct development and egg formation, and also suggest that PTN is a biomarker for epithelial ovarian carcinoma that could be used for diagnosis and monitoring effects of therapies for the disease.

  7. Paternal retrieval behavior regulated by brain estrogen synthetase (aromatase in mouse sires that engage in communicative interactions with pairmates

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    Shirin eAkther

    2015-12-01

    Full Text Available Parental behaviors involve complex social recognition and memory processes and interactive behavior with children that can greatly facilitate healthy human family life. Fathers play a substantial role in child care in a small but significant number of mammals, including humans. However, the brain mechanism that controls male parental behavior is much less understood than that controlling female parental behavior. Fathers of non-monogamous laboratory ICR mice are an interesting model for examining the factors that influence paternal responsiveness because sires can exhibit maternal-like parental care (retrieval of pups when separated from their pups along with their pairmates because of olfactory and auditory signals from the dams. Here we tested whether paternal behavior is related to femininity by the aromatization of testosterone. For this purpose, we measured the immunoreactivity of aromatase (cytochrome P450 family 19 (CYP19, which synthesizes estrogen from androgen, in nine brain regions of the sire. We observed higher levels of aromatase expression in these areas of the sire brain when they engaged in communicative interactions with dams in separate cages. The capacity of sires to retrieve pups was increased following a period of five days spent with the pups as a whole family after parturition, whereas the acquisition of this ability was suppressed in sires treated daily with an aromatase inhibitor. These results suggest that brain aromatization regulates the initiation, development, and maintenance of paternal behavior in the ICR mice.

  8. Nuclear c-Abl-mediated tyrosine phosphorylation induces chromatin structural changes through histone modifications that include H4K16 hypoacetylation

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    Aoyama, Kazumasa; Fukumoto, Yasunori; Ishibashi, Kenichi; Kubota, Sho; Morinaga, Takao; Horiike, Yasuyoshi; Yuki, Ryuzaburo; Takahashi, Akinori; Nakayama, Yuji; Yamaguchi, Naoto, E-mail: nyama@p.chiba-u.ac.jp

    2011-12-10

    c-Abl tyrosine kinase, which is ubiquitously expressed, has three nuclear localization signals and one nuclear export signal and can shuttle between the nucleus and the cytoplasm. c-Abl plays important roles in cell proliferation, adhesion, migration, and apoptosis. Recently, we developed a pixel imaging method for quantitating the level of chromatin structural changes and showed that nuclear Src-family tyrosine kinases are involved in chromatin structural changes upon growth factor stimulation. Using this method, we show here that nuclear c-Abl induces chromatin structural changes in a manner dependent on the tyrosine kinase activity. Expression of nuclear-targeted c-Abl drastically increases the levels of chromatin structural changes, compared with that of c-Abl. Intriguingly, nuclear-targeted c-Abl induces heterochromatic profiles of histone methylation and acetylation, including hypoacetylation of histone H4 acetylated on lysine 16 (H4K16Ac). The level of heterochromatic histone modifications correlates with that of chromatin structural changes. Adriamycin-induced DNA damage stimulates translocation of c-Abl into the nucleus and induces chromatin structural changes together with H4K16 hypoacetylation. Treatment with trichostatin A, a histone deacetylase inhibitor, blocks chromatin structural changes but not nuclear tyrosine phosphorylation by c-Abl. These results suggest that nuclear c-Abl plays an important role in chromatin dynamics through nuclear tyrosine phosphorylation-induced heterochromatic histone modifications.

  9. Estrogen receptor signal in regulation of B cell activation during diverse immune responses.

    Science.gov (United States)

    Asaba, Josaine; Bandyopadhyay, Mausumi; Kindy, Mark; Dasgupta, Subhajit

    2015-11-01

    The role of signalling through oestrogen receptors (ERs) in the regulation of B cell activation is an area of growing importance not only in terms protective immunity but also in the determination of the mechanisms of the onset of autoimmune disorders and cancers. The mode of signalling action of this single chain nuclear receptor protein molecule depends on its ability to bind to the promoters of Pax5, HOXC4 and apolipoprotein B RNA-editing enzyme activation-induced cytidine deaminase (AID) genes. ER-mediated transcriptional regulation induces class switch recombination of the immunoglobulin heavy chain variable (VH) to DH-JH genes and somatic hypermutation in developing B cells. The mode of action of ER is associated with BCR-signal pathways that involve the regulator proteins BAFF and APRIL. Additionally, the plasma membrane-bound G protein-coupled oestrogen receptor-1 (GEPR1) directs diverse cell signalling events in B cells that involve the MAPK pathways. These signals are immensely important during progenitor and precursor B cell activation. We have focused our goals on the medicinal aspects of ER-signalling mechanisms and their effects on polyclonal B cell activation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. ESTROGEN IN THE LIMBIC SYSTEM

    NARCIS (Netherlands)

    ter Horst, Gert J.; Litwack, G

    2010-01-01

    Estrogens are a group of steroid hormones that function as the primary female sex hormone. Estrogens not only have an important role in the regulation of the estrous or menstrual cycle but also control, for example, bone formation, the cardiovascular system, and cognitive functions. Estradiol (E2),

  11. The extracellular matrix, p53 and estrogen compete to regulate cell-surface Fas/Apo-1 suicide receptor expression in proliferating embryonic cerebral cortical precursors, and reciprocally, Fas-ligand modifies estrogen control of cell-cycle proteins

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    Newman Joseph M

    2004-03-01

    Full Text Available Abstract Background Apoptosis is important for normal cerebral cortical development. We previously showed that the Fas suicide receptor was expressed within the developing cerebral cortex, and that in vitro Fas activation resulted in caspase-dependent death. Alterations in cell-surface Fas expression may significantly influence cortical development. Therefore, in the following studies, we sought to identify developmentally relevant cell biological processes that regulate cell-surface Fas expression and reciprocal consequences of Fas receptor activation. Results Flow-cytometric analyses identified two distinct neural sub-populations that expressed Fas on their cell surface at high (FasHi or moderate (FasMod levels. The anti-apoptotic protein FLIP further delineated a subset of Fas-expressing cells with potential apoptosis-resistance. FasMod precursors were mainly in G0, while FasHi precursors were largely apoptotic. However, birth-date analysis indicated that neuroblasts express the highest levels of cell-surface Fas at the end of S-phase, or after their final round of mitosis, suggesting that Fas expression is induced at cell cycle checkpoints or during interkinetic nuclear movements. FasHi expression was associated with loss of cell-matrix adhesion and anoikis. Activation of the transcription factor p53 was associated with induction of Fas expression, while the gonadal hormone estrogen antagonistically suppressed cell-surface Fas expression. Estrogen also induced entry into S-phase and decreased the number of Fas-expressing neuroblasts that were apoptotic. Concurrent exposure to estrogen and to soluble Fas-ligand (sFasL suppressed p21/waf-1 and PCNA. In contrast, estrogen and sFasL, individually and together, induced cyclin-A expression, suggesting activation of compensatory survival mechanisms. Conclusions Embryonic cortical neuronal precursors are intrinsically heterogeneous with respect to Fas suicide-sensitivity. Competing intrinsic (p53

  12. The regulation of Hh/Gli1 signaling cascade involves Gsk3β- mediated mechanism in estrogen-derived endometrial hyperplasia.

    Science.gov (United States)

    Kaushal, Jyoti Bala; Sankhwar, Pushplata; Kumari, Suparna; Popli, Pooja; Shukla, Vinay; Hussain, Mohd Kamil; Hajela, Kanchan; Dwivedi, Anila

    2017-07-26

    The present study was undertaken to explore the functional involvement of Hh signaling and its regulatory mechanism in endometrial hyperplasia. Differential expression of Hh signaling molecules i.e., Ihh, Shh, Gli1 or Gsk3β was observed in endometrial hyperplasial (EH) cells as compared to normal endometrial cells. Estradiol induced the expression of Hh signaling molecules and attenuated the expression of Gsk3β whereas anti-estrogen (K1) or progestin (MPA) suppressed these effects in EH cells. Cyclopamine treatment or Gli1 siRNA knockdown suppressed the growth of EH cells and reduced the expression of proliferative markers. Estradiol also induced the nuclear translocation of Gli1 which was suppressed by both MPA and K1 in EH cells. While exploring non-canonical mechanism, LY-294002 (Gsk3β activator) caused a decrease in Gli1 expression indicating the involvement of Gsk3β in Gli1 regulation. Further, Gsk3β silencing promoted the expression and nuclear translocation of Gli1 demonstrating that Gsk3β serves as a negative kinase regulator of Gli1 in EH cells. Similar attenuation of Hh signaling molecules was observed in rats with uterine hyperplasia undergoing anti-estrogen treatment. The study suggested that Hh/Gli1 cascade (canonical pathway) as well as Gsk3β-Gli1 crosstalk (non-canonical pathway) play crucial role in estrogen-dependent cell proliferation in endometrial hyperplasia.

  13. IGF-1 gene expression is differentially regulated by estrogen receptors α and β in mouse endometrial stromal cells and ovarian granulosa cells.

    Science.gov (United States)

    Ogo, Yuki; Taniuchi, Shusuke; Ojima, Fumiya; Hayashi, Sayo; Murakami, Itsuo; Saito, Yuka; Takeuchi, Sakae; Kudo, Toshiyuki; Takahashi, Sumio

    2014-01-01

    Insulin-like growth factor 1 (IGF-1) is involved in regulations of reproductive functions in rats and mice. IGF-1 expression is regulated by estrogen in several reproductive organs including the uterus and ovary. Two types of estrogen receptor (ERα and ERβ) are expressed in mouse uteri and ovaries, and it is unclear whether they differently mediate IGF-1 gene transcription. To clarify the roles of ERα and ERβ, mouse endometrial stromal cells and ovarian granulosa cells were treated with ligands specific for individual estrogen receptors. In endometrial stromal cells, propyl-pyrazole-triol (PPT; ERα-selective agonist) increased Igf1 mRNA expression, which was suppressed by methyl-piperidino-pyrazole (MPP, ERα-selective antagonist), while diarylpropionitrile (DPN, ERβ-potency selective agonist) increased Igf1 mRNA expression, which was inhibited by MPP but not by 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-α]pyrimidin-3-yl]phenol (PHTPP; ERβ antagonist). PHTPP enhanced the DPN-induced increase in Igf1 mRNA expression. In ovarian granulosa cells, E2 and DPN decreased Igf1 mRNA expression, whereas PPT did not affect Igf1 mRNA levels. In these cells, PHTPP inhibited the DPN-induced decrease in Igf1 mRNA expression. These results suggest that ERα facilitates Igf1 transcription, whereas ERβ appears to inhibit Igf1 gene transcription in mouse endometrial stromal cells and ovarian granulosa cells.

  14. The influence of high and low levels of estrogen on diurnal urine regulation in young women

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    Bie Peter

    2008-11-01

    Full Text Available Abstract Background Sex hormones have a pronounced effect on arginine vasopressin (AVP, and therefore on the diurnal water homeostasis. Low and high levels of plasma-estradiol as seen in the follicular phase of the menstrual cycle may therefore alter the diurnal regulation of urine production. Furthermore the structural resemblance of oxytocin to vasopressin has led to speculations about the possible antidiuretic properties of oxytocin under normal physiological conditions. To elucidate the influence of high and low p-estradiol on the regulation of the diurnal urine production, 15 normal menstruating women (21–33 y underwent two circadian in-patient investigations, both situated in follicular phase. Methods Admitting the participants solely in the follicular phase resulted in high and low plasma-estradiol whereas plasma-progesterone was similar. Urine and blood samples were taken at predetermined time points to determine plasma AVP, plasma oxytocin, plasma aldosterone, plasma natriuretic peptide (ANP, urinary solute excretions, and urinary excretions of prostaglandin E2 (PGE-2 and aquaporin-2 (AQP-2. Blood pressure was measured every hour. Results Plasma AVP, plasma aldosterone and plasma ANP were unaffected by the different levels of estradiol. All had marked circadian variations whereas oxytocin did not display any circadian rhythm. High estradiol resulted in lower p-osmolality and p-sodium reflecting the downward resetting of the osmoreceptors. Oxytocin did not correlate with either diuresis or urine osmolality. The diurnal urine production was similar in the two groups as were urine osmolality, excretion of PGE-2 and AQP-2. AQP-2 does not have a circadian rhythm and is not significantly correlated to either AVP or oxytocin under normal physiological conditions. Conclusion High and low level of estradiol has no influence on the circadian rhythm of AVP or the subsequent urine production. High p-estradiol resets the osmoreceptors for AVP

  15. The coordinated p53 and estrogen receptor cis-regulation at an FLT1 promoter SNP is specific to genotoxic stress and estrogenic compound.

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    Yari Ciribilli

    Full Text Available BACKGROUND: Recently, we established that a C>T single nucleotide polymorphism (SNP in the promoter of the VEGF receptor FLT1 gene generates a (1/2 site p53 response element (RE-T that results in p53 responsiveness of the promoter. The transcriptional control required an estrogen receptor (ER (1/2 site response element (ERE1 225 nt upstream to the RE-T. METHODOLOGY/PRINCIPAL FINDINGS: Here we report the identification of a second ER (1/2 site (ERE2 located 145 bp downstream of the RE-T and establish that both EREs can impact p53-mediated transactivation of FLT1-T in a manner that is cell type and ER level dependent. Gene reporter assays and ChIP experiments conducted in the breast cancer-derived MCF7 cells revealed that the ERE2 site was sufficient for p53-mediated ERalpha recruitment and transactivation of the FLT1-T promoter/reporter construct. Surprisingly, unlike the case for other p53 target promoters, p53-mediated transactivation of FLT1-T constructs or expression of the endogenous FLT1 gene, as well as binding of p53 and ER at the promoter constructs, was inducible by doxorubicin but not by 5-fluorouracil. Furthermore, ER activity at FLT1-T was differentially affected by ER ligands, compared to a control TFF1/pS2 ER target promoter. The p53-related transcription factors (TFs p73 and p63 had no effect on FLT1 transactivation. CONCLUSIONS/SIGNIFICANCE: We establish a new dimension to the p53 master regulatory network where p53-mediated transcription from a (1/2 site RE can be determined by ER binding at one or more cis-acting EREs in manner that is dependent on level of ER protein, the type of ER ligand and the specific p53-inducing agent.

  16. Identification of a Hormone-regulated Dynamic Nuclear Actin Network Associated with Estrogen Receptor α in Human Breast Cancer Cell Nuclei*

    Science.gov (United States)

    Ambrosino, Concetta; Tarallo, Roberta; Bamundo, Angela; Cuomo, Danila; Franci, Gianluigi; Nassa, Giovanni; Paris, Ornella; Ravo, Maria; Giovane, Alfonso; Zambrano, Nicola; Lepikhova, Tatiana; Jänne, Olli A.; Baumann, Marc; Nyman, Tuula A.; Cicatiello, Luigi; Weisz, Alessandro

    2010-01-01

    Estrogen receptor α (ERα) is a modular protein of the steroid/nuclear receptor family of transcriptional regulators that upon binding to the hormone undergoes structural changes, resulting in its nuclear translocation and docking to specific chromatin sites. In the nucleus, ERα assembles in multiprotein complexes that act as final effectors of estrogen signaling to the genome through chromatin remodeling and epigenetic modifications, leading to dynamic and coordinated regulation of hormone-responsive genes. Identification of the molecular partners of ERα and understanding their combinatory interactions within functional complexes is a prerequisite to define the molecular basis of estrogen control of cell functions. To this end, affinity purification was applied to map and characterize the ERα interactome in hormone-responsive human breast cancer cell nuclei. MCF-7 cell clones expressing human ERα fused to a tandem affinity purification tag were generated and used to purify native nuclear ER-containing complexes by IgG-Sepharose affinity chromatography and glycerol gradient centrifugation. Purified complexes were analyzed by two-dimensional DIGE and mass spectrometry, leading to the identification of a ligand-dependent multiprotein complex comprising β-actin, myosins, and several proteins involved in actin filament organization and dynamics and/or known to participate in actin-mediated regulation of gene transcription, chromatin dynamics, and ribosome biogenesis. Time course analyses indicated that complexes containing ERα and actin are assembled in the nucleus early after receptor activation by ligands, and gene knockdown experiments showed that gelsolin and the nuclear isoform of myosin 1c are key determinants for assembly and/or stability of these complexes. Based on these results, we propose that the actin network plays a role in nuclear ERα actions in breast cancer cells, including coordinated regulation of target gene activity, spatial and functional

  17. Identification of a hormone-regulated dynamic nuclear actin network associated with estrogen receptor alpha in human breast cancer cell nuclei.

    Science.gov (United States)

    Ambrosino, Concetta; Tarallo, Roberta; Bamundo, Angela; Cuomo, Danila; Franci, Gianluigi; Nassa, Giovanni; Paris, Ornella; Ravo, Maria; Giovane, Alfonso; Zambrano, Nicola; Lepikhova, Tatiana; Jänne, Olli A; Baumann, Marc; Nyman, Tuula A; Cicatiello, Luigi; Weisz, Alessandro

    2010-06-01

    Estrogen receptor alpha (ERalpha) is a modular protein of the steroid/nuclear receptor family of transcriptional regulators that upon binding to the hormone undergoes structural changes, resulting in its nuclear translocation and docking to specific chromatin sites. In the nucleus, ERalpha assembles in multiprotein complexes that act as final effectors of estrogen signaling to the genome through chromatin remodeling and epigenetic modifications, leading to dynamic and coordinated regulation of hormone-responsive genes. Identification of the molecular partners of ERalpha and understanding their combinatory interactions within functional complexes is a prerequisite to define the molecular basis of estrogen control of cell functions. To this end, affinity purification was applied to map and characterize the ERalpha interactome in hormone-responsive human breast cancer cell nuclei. MCF-7 cell clones expressing human ERalpha fused to a tandem affinity purification tag were generated and used to purify native nuclear ER-containing complexes by IgG-Sepharose affinity chromatography and glycerol gradient centrifugation. Purified complexes were analyzed by two-dimensional DIGE and mass spectrometry, leading to the identification of a ligand-dependent multiprotein complex comprising beta-actin, myosins, and several proteins involved in actin filament organization and dynamics and/or known to participate in actin-mediated regulation of gene transcription, chromatin dynamics, and ribosome biogenesis. Time course analyses indicated that complexes containing ERalpha and actin are assembled in the nucleus early after receptor activation by ligands, and gene knockdown experiments showed that gelsolin and the nuclear isoform of myosin 1c are key determinants for assembly and/or stability of these complexes. Based on these results, we propose that the actin network plays a role in nuclear ERalpha actions in breast cancer cells, including coordinated regulation of target gene

  18. Transcriptional activity of human brain estrogen receptor-α splice variants: evidence for cell type-specific regulation

    NARCIS (Netherlands)

    Ishunina, T. A.; Sluiter, A. A.; Swaab, D. F.; Verwer, R. W. H.

    2013-01-01

    Estrogen receptor α (ERα) isoforms with complex types of alternative splicing are naturally present in the human brain and may affect canonical receptor signaling. In the present study we investigated transcriptional activity of common ERα splice variants from this group with different molecular

  19. WISP-2 gene in human breast cancer: estrogen and progesterone inducible expression and regulation of tumor cell proliferation.

    Science.gov (United States)

    Banerjee, Snigdha; Saxena, Neela; Sengupta, Krishanu; Tawfik, Ossama; Mayo, Matthew S; Banerjee, Sushanta K

    2003-01-01

    WISP-2 mRNA and protein was overexpressed in preneoplastic and cancerous cells of human breast. Statistical analyses show a significant association between WISP-2 expression and estrogen receptor (ER) positivity. In normal breast, the expression was virtually undetected. The studies showed that WISP-2 is an estrogen-induced early response gene in MCF-7 cells and the expression was continuously increased to reach a maximum level at 24 h. The estrogen effect was inhibited by a pure antiestrogen (ICI 182,780). Human mammary epithelial cells, in which WISP-2 expression was undetected or minimally detected, responded to 17beta-estradiol by upregulating the WISP-2 gene after transfection with ER-alpha, providing further evidences that WISP-2 expression is mediated through ER-alpha. Overexpression of WISP-2 mRNA by estrogen may be accomplished by both transcriptional activation and stabilization. MCF-7 cells exposed to progesterone had a rapid but transient increase in WISP-2 expression, and PR antagonist RU38486 blocked this mRNA induction. In combination with estradiol, progesterone acted as an antagonist inhibiting the expression of WISP-2 mRNA. Moreover, disruption of WISP-2 signaling in MCF-7 cells by use of antisense oligomers caused a significant reduction in tumor cell proliferation. The results are consistent with the conclusion that WISP-2 expression is a requirement for breast tumor cells proliferation.

  20. WISP-2 Gene in Human Breast Cancer: Estrogen and Progesterone Inducible Expression and Regulation of Tumor Cell Proliferation

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    Snigdha Banerjee

    2003-01-01

    Full Text Available WISP-2 mRNA and protein was overexpressed in preneoplastic and cancerous cells of human breast. Statistical analyses show a significant association between WISP-2 expression and estrogen receptor (ER positivity. In normal breast, the expression was virtually undetected. The studies showed that WISP-2 is an estrogen-induced early response gene in MCF-7 cells and the expression was continuously increased to reach a maximum level at 24 h. The estrogen effect was inhibited by a pure antiestrogen (ICI 182,780. Human mammary epithelial cells, in which WISP-2 expression was undetected or minimally detected, responded to 17β-estradiol by upregulating the WISP-2 gene after transfection with ER-α, providing further evidences that WISP-2 expression is mediated through ER-α. Overexpression of WISP-2 mRNA by estrogen may be accomplished by both transcriptional activation and stabilization. MCF-7 cells exposed to progesterone had a rapid but transient increase in WISP-2 expression, and PR antagonist RU38486 blocked this mRNA induction. In combination with estradiol, progesterone acted as an antagonist inhibiting the expression of WISP-2 mRNA. Moreover, disruption of WISP-2 signaling in MCF-7 cells by use of antisense oligomers caused a significant reduction in tumor cell proliferation. The results are consistent with the conclusion that WISP-2 expression is a requirement for breast tumor cells proliferation.

  1. WISP-2 Gene in Human Breast Cancer: Estrogen and Progesterone Inducible Expression and Regulation of Tumor Cell Proliferation1

    Science.gov (United States)

    Banerjee, Snigdha; Saxena, Neela; Sengupta, Krishanu; Tawfik, Ossama; Mayo, Matthew S; Banerjee, Sushanta K

    2003-01-01

    Abstract WISP-2 mRNA and protein was overexpressed in preneoplastic and cancerous cells of human breast. Statistical analyses show a significant association between WISP-2 expression and estrogen receptor (ER) positivity. In normal breast, the expression was virtually undetected. The studies showed that WISP-2 is an estrogen-induced early response gene in MCF-7 cells and the expression was continuously increased to reach a maximum level at 24 h. The estrogen effect was inhibited by a pure antiestrogen (ICI 182,780). Human mammary epithelial cells, in which WISP-2 expression was undetected or minimally detected, responded to 17β-estradiol by upregulating the WISP-2 gene after transfection with ER-α, providing further evidences that WISP-2 expression is mediated through ER-α. Overexpression of WISP-2 mRNA by estrogen may be accomplished by both transcriptional activation and stabilization. MCF-7 cells exposed to progesterone had a rapid but transient increase in WISP-2 expression, and PR antagonist RU38486 blocked this mRNA induction. In combination with estradiol, progesterone acted as an antagonist inhibiting the expression of WISP-2 mRNA. Moreover, disruption of WISP-2 signaling in MCF-7 cells by use of antisense oligomers caused a significant reduction in tumor cell proliferation. The results are consistent with the conclusion that WISP-2 expression is a requirement for breast tumor cells proliferation. PMID:12659671

  2. Sex Steroid Hormones Matter for Learning and Memory: Estrogenic Regulation of Hippocampal Function Inmale and Female Rodents

    Science.gov (United States)

    Frick, Karyn M.; Kim, Jaekyoon; Tuscher, Jennifer J.; Fortress, Ashley M.

    2015-01-01

    Ample evidence has demonstrated that sex steroid hormones, such as the potent estrogen 17ß-estradiol (E[subscript 2]), affect hippocampal morphology, plasticity, and memory in male and female rodents. Yet relatively few investigators who work with male subjects consider the effects of these hormones on learning and memory. This review describes…

  3. RNA Regulation by Estrogen

    Science.gov (United States)

    2011-08-01

    POU5F1P4 POU class 5 homeobox 1 pseudogene 4 3.03 220366_at ELSPBP1 epididymal sperm binding protein 1 3.03 220849_at LOC1001324 72 hypothetical...member 5 4.92 207800_at AKAP5 A kinase (PRKA) anchor protein 5 4.92 216779_at CYLC1 cylicin, basic protein of sperm head cytoskeleton 1 4.92...ODF1 outer dense fiber of sperm tails 1 3.73 203645_s_at CD163 CD163 molecule 3.73 218033_s_at SNN stannin 3.73 222095_s_at Fam163a family with

  4. RNA Regulation of Estrogen

    Science.gov (United States)

    2010-08-01

    epididymal sperm binding protein 1 3.03 220849_at LOC1001324 72 hypothetical LOC100132472; hypothetical LOC79999; hypothetical LOC388436 3.03 220849_at...4.92 216779_at CYLC1 cylicin, basic protein of sperm head cytoskeleton 1 4.92 208604_s_at HOXA3 homeobox A3 4.92 217235_x_at IGLV2-23 immunoglobulin...G antigen 12C; G antigen 5; G antigen 6; G antigen 7; G antigen 8 3.73 214485_at ODF1 outer dense fiber of sperm tails 1 3.73 203645_s_at CD163 CD163

  5. Ginsenoside Rd promotes non-amyloidogenic pathway of amyloid precursor protein processing by regulating phosphorylation of estrogen receptor alpha.

    Science.gov (United States)

    Yan, Xiaodong; Hu, Gengyao; Yan, Weiming; Chen, Tao; Yang, Feng; Zhang, Xiao; Zhao, Gang; Liu, Juanfang

    2017-01-01

    Previous study demonstrated that Ginsenoside Rd. (GS-Rd) could improve cognitive and memory function in animal model of Alzheimer's disease. This study was aimed to investigate whether GS-Rd could improve non-amyloidogenic pathway by activating estrogen receptor (ER). 10mg/kg GS-Rd in ovariectomy (OVX)+GS-Rd group and equivalent volume of saline in sham operated group and OVX group were administrated intraperitoneally for two months, respectively. The Morris Water Maze was used to examine cognitive function of rats, with sAPPα and Aβ levels in the hippocampi measured. The culture medium of HT22 hippocampal neuronal cells were incubated with GS-Rd, ER antagonist ICI182.780, MAPK inhibitor PD98059, or PI3Kinhibitor LY294002, respectively. sAPPα levels was measured, and expression of α-secretase, sAPPα, β-secretase, Aβ, phosphorylation form of AKT (p-AKT), total AKT, p-ERK, total ERK, p-ERα, total ERα, p-ERβ and total ERβ were examined by Western blot to explore the estrogenic-like activity of GS-Rd. GS-Rd attenuate cognitive and memory impairment, increased levels of sAPPα and reduced extracellular Aβ of OVX rats. In HT22, GS-Rd could upregulate sAPPα level, which can be inhibited by inhibitor of MAPK and PI3K pathway. In addition, inhibitor of estrogen receptor prevented GS-Rd triggered release of sAPPα and activation of MAPK and PI3K pathways. GS-Rd could increase expression of α-secretase and sAPPα, while decrease expression of β-secretase and Aβ. Besides, GS-Rd promoted phosphorylation of estrogen receptor alpha at Ser118 residue. Our findings show that GS-Rd enhances learning and memory function of OVX rats by activating estrogen-like activity. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Immunocytochemical determination of the estrogen-regulated proteins Mr 24,000, Mr 52,000 and DF3 breast cancer associated antigen: clinical value in advanced breast cancer and correlation with estrogen receptor.

    Science.gov (United States)

    Damstrup, L; Andersen, J; Kufe, D W; Hayes, D F; Poulsen, H S

    1992-01-01

    The Mr 24,000 and Mr 52,000 estrogen-regulated cytosol proteins, and the breast cancer-associated antigen DF3 have been studied in an immunocytochemical assay. Primary tumor specimens from 119 patients with advanced breast cancer who received endocrine therapy have been studied. Monoclonal antibodies were used for the detection of the proteins in formalin-fixed paraffin-embedded blocks. No correlation between Mr 52,000-positive specimens and the presence of estrogen receptor (ER) could be established (p = 0.87, chi-square test) whereas a statistically significant association between Mr 24,000 (p = 0.0002), DF3 antigen (p = 0.044) and ER was demonstrated. No intercorrelation was found between Mr 24,000 and Mr 52,000 or DF3 (p = 0.63, 0.98 and 0.12 respectively). Clinical response was evaluated for immunocytochemical findings, Mr 24,000 (p = 0.37), Mr 52,000 (p = 0.61) and DF3 (p = 0.68) showed no association whereas ER was statistically correlated (p = 0.00005). Neither overall survival nor disease-free survival correlated to Mr 24,000 (p = 0.18 and 0.75 respectively, logrank test), Mr 52,000 (p = 0.095 and 0.38), or DF3 (p = 0.22 and 0.13) staining, whereas ER-positive tumors did (p = 0.00005). Discrimination between ER-positive responders and ER-positive non-responders was not possible using either Mr 52,000, Mr 24,000 or DF3 staining. Based on our findings we conclude that immunocytochemical staining for Mr 52,000, Mr 24,000 or DF3 cannot be used as a marker to predict response to endocrine therapy in patients with advanced or recurrent breast cancer.

  7. Mutual interaction of kisspeptin, estrogen and bone morphogenetic protein-4 activity in GnRH regulation by GT1-7 cells

    Science.gov (United States)

    Terasaka, Tomohiro; Otsuka, Fumio; Tsukamoto, Naoko; Nakamura, Eri; Inagaki, Kenichi; Toma, Kishio; Ogura-Ochi, Kanako; Glidewell-Kenney, Christine; Lawson, Mark A.; Makino, Hirofumi

    2014-01-01

    Reproduction is integrated by interaction of neural and hormonal signals converging on hypothalamic neurons for controlling gonadotropin-releasing hormone (GnRH). Kisspeptin, the peptide product of the kiss1 gene and the endogenous agonist for the GRP54 receptor, plays a key role in the regulation of GnRH secretion. In the present study, we investigated the interaction between kisspeptin, estrogen and BMPs in the regulation of GnRH production by using mouse hypothalamic GT1-7 cells. Treatment with kisspeptin increased GnRH mRNA expression and GnRH protein production in a concentrationdependent manner. The expression levels of kiss1 and GPR54 were not changed by kisspeptin stimulation. Kisspeptin induction of GnRH was suppressed by co-treatment with BMPs, with BMP-4 action being the most potent for suppressing the kisspeptin effect. The expression of kisspeptin receptor, GPR54, was suppressed by BMPs, and this effect was reversed in the presence of kisspeptin. It was also revealed that BMP-induced Smad1/5/8 phosphorylation and Id-1 expression were suppressed and inhibitory Smad6/7 was induced by kisspeptin. In addition, estrogen induced GPR54 expression, while kisspeptin increased the expression levels of ERα and ERβ, suggesting that the actions of estrogen and kisspeptin are mutually enhanced in GT1-7 cells. Moreover, kisspeptin stimulated MAPKs and AKT signaling, and ERK signaling was functionally involved in the kisspeptin-induced GnRH expression. BMP-4 was found to suppress kisspeptin-induced GnRH expression by reducing ERK signaling activity. Collectively, the results indicate that the axis of kisspeptin-induced GnRH production is bi-directionally controlled, being augmented by an interaction between ERα/β and GPR54 signaling and suppressed by BMP-4 action in GT1-7 neuron cells. PMID:23880664

  8. The exonuclease activity of hPMC2 is required for transcriptional regulation of the QR gene and repair of estrogen-induced abasic sites.

    Science.gov (United States)

    Krishnamurthy, N; Ngam, C R; Berdis, A J; Montano, M M

    2011-11-24

    We have previously reported that the expression of antioxidative stress enzymes is upregulated by trans-hydroxytamoxifen (TOT) in breast epithelial cell lines providing protection against estrogen-induced DNA damage. This regulation involves Estrogen Receptor β (ERβ) recruitment to the Electrophile Response Element (EpRE) and a novel protein, human homolog of Xenopus gene which Prevents Mitotic Catastrophe (hPMC2). We have also demonstrated that ERβ and hPMC2 are required for TOT-dependent recruitment of poly (ADP-ribose) polymerase 1 (PARP-1) and Topoisomerase IIβ (Topo IIβ) to the EpRE. Sequence analysis reveals that the C-terminus of hPMC2 encodes a putative exonuclease domain. Using in vitro kinetic assays, we found that hPMC2 is a 3'-5' non-processive exonuclease that degrades both single-stranded and double-stranded substrates. Mutation of two conserved carboxylate residues drastically reduced the exonuclease activity of hPMC2, indicating the relative importance of the catalytic residues. Western blot analysis of breast cancer cell lines for Quinone Reductase (QR) levels revealed that the intrinsic exonuclease activity of hPMC2 was required for TOT-induced QR upregulation. Chromatin immunoprecipitation (ChIP) assays also indicated that hPMC2 was involved in the formation of strand breaks observed with TOT treatment and is specific for the EpRE-containing region of the QR gene. We also determined that the transcription factor NF-E2-related factor-2 (Nrf2) is involved in the specificity of hPMC2 for the EpRE. In addition, we determined that the catalytic activity of hPMC2 is required for repair of abasic sites that result from estrogen-induced DNA damage. Thus, our study provides a mechanistic basis for transcriptional regulation by hPMC2 and provides novel insights into its role in cancer prevention.

  9. Regulated Ubiquitinylation-Dependent Corepressor and Coactivator Complex Exchange as a Potential Target in Estrogen-Dependent Breast Cancer

    Science.gov (United States)

    2006-09-01

    engaged by apo-estrogen recep- tor-alpha isoforms have divergent outcomes. EMBO J. 23, 3653–3666. Metzger, E., Wissmann, M., Yin, N., Muller , J.M...S. Cheng†‡, Mingjie Jin§, Dongyan Liu§, Chris Benner*‡, Dong Wang*, Zhen Ye*, Marina Bibikova¶, Jian-Bing Fan¶, Lingxun Duan§, Christopher K. Glass

  10. Increased Immunostaining of Fibulin-1, an Estrogen-Regulated Protein in the Stroma of Human Ovarian Epithelial Tumors

    OpenAIRE

    Roger, Pascal; Pujol, Pascal; Lucas, Annick; Baldet, Pierre; Rochefort, Henri

    1998-01-01

    Fibulin-1, an extracellular matrix protein, is secreted by human ovarian metastatic cancer cell lines under estrogen stimulation. Fibulin-1 expression was quantified by immunohistochemistry and computer-aided image analysis in 44 human ovarian epithelial tumors and 14 normal ovaries. The fibulin-1 staining intensity in proximal stroma, close to the surface of epithelial cells and tumor cells, progressively increased from normal ovaries to serous carcinomas. In all lesions, excluding cystadeno...

  11. Natural antioxidants exhibit chemopreventive characteristics through the regulation of CNC b-Zip transcription factors in estrogen-induced breast carcinogenesis.

    Science.gov (United States)

    Chatterjee, Anwesha; Ronghe, Amruta; Singh, Bhupendra; Bhat, Nimee K; Chen, Jie; Bhat, Hari K

    2014-12-01

    The objective of the present study was to characterize the role of resveratrol (Res) and vitamin C (VC) in prevention of estrogen-induced breast cancer through regulation of cap "n"collar (CNC) b-zip transcription factors. Human breast epithelial cell line MCF-10A was treated with 17β-estradiol (E2) and VC or Res with or without E2. mRNA and protein expression levels of CNC b-zip transcription factors nuclear factor erythroid 2-related factor 1 (Nrf1), nuclear factor erythroid 2 related factor 2 (Nrf2), nuclear factor erythroid 2 related factor 3 (Nrf3), and Nrf2-regulated antioxidant enzymes superoxide dismutase 3 (SOD3) and quinone oxidoreductase 1 (NQO1) were quantified. The treatment with E2 suppressed, whereas VC and Res prevented E2-mediated decrease in the expression levels of SOD3, NQO1, Nrf2 mRNA, and protein in MCF-10A cells. The treatment with E2, Res, or VC significantly increased mRNA and protein expression levels of Nrf1. 17β-Estradiol treatment significantly increased but VC or Res decreased Nrf3 mRNA and protein expression levels. Our studies demonstrate that estrogen-induced breast cancer might be prevented through upregulation of antioxidant enzymes via Nrf-dependent pathways. © 2014 Wiley Periodicals, Inc.

  12. Estrogen Promotes Hepatic Synthesis of Long-Chain Polyunsaturated Fatty Acids by Regulating ELOVL5 at Post-Transcriptional Level in Laying Hens.

    Science.gov (United States)

    Zhang, Meng; Li, Cui-Cui; Li, Fang; Li, Hong; Liu, Xiao-Jun; Loor, Juan J; Kang, Xiang-Tao; Sun, Gui-Rong

    2017-06-30

    The very long chain fatty acid elongase (ELOVL) plays an important role in the synthesis of long-chain polyunsaturated fatty acids (LCPUFA). Previous studies suggest that chicken could be an alternate source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In this study, we detected that ELOVL5, which plays a key role in the biosynthesis of omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFA), was highly expressed in the liver of laying hens and increased rapidly after sexual maturity. Bioinformatic analysis revealed ELOVL fatty acid elongase 5 (ELOVL5) gene as a putative target of miR-218-5p, miR-19a-3p, miR-19b-3p, miR-30a-5p, miR-30b-5p, and miR-30e-5p. We demonstrated estrogen downregulated microRNA (miRNA), and that ELOVL5 is a direct target of miR-218-5p, which was located in intron 14 of the Slit guidance ligand 2 (SLIT2) gene and co-expressed with the host gene. Overall, estrogen enhanced hepatic synthesis of LCPUFA by functioning as a negative regulator of miRNA thereby augmenting the expression of these miRNA target genes, especially ELOVL5, which plays a key role in the biosynthesis of n-3 and n-6 LCPUFA. This study provides a novel model for the use of estrogen in the poultry industry as an inducer of ELOVL5 expression to enhance hepatic n-3 and n-6 LCPUFA synthesis at the post-transcriptional level.

  13. [Fluid shear stress and raloxifene stimulates the proliferation of osteoblast through regulating the expresstion of β-catenin and estrogen receptor α].

    Science.gov (United States)

    Tang, Wan-rog; Liu, Ying; Li, Li-hua; Wu, Zeng-bo; He, Yuo

    2014-11-01

    To investigate how the fluid shear stress and raloxifene alone or in combination affect the proliferation of murine pre-osteoblast MC3T3-E1. MC3T3-E1 cells cultured in vitro were treated with the fluid shearing stress and raloxifene alone or in combination, and the MC3T3-E1 cells without treatment were set as control (O group), treated with estrogen receptor antagonist ICI-182780 (10-7 mol/L, I group) were set as negative control group. The cells were observed underoptical inverted microscope from cell shape, size, and nuclear shape to quantity respectively before harvested. The levels of mRNA and protein of β-catenin and estrogen receptor alpha (ERα) were detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blot respectively. (1) As compared with those of the control group and negative control group, the cell proliferation, the expression of ERα mRNA and protein, and protein expression of β-catenin significantly increased in the groups of raloxifene, fluid shearing stress and raloxifene combination fluid shearing stress (Praloxifene group compared with O group (P>0.05), increased significantly in groups of fluid shear stress and raloxifene combination fluid shear stress. (2) The cells number, the expression of β-catenin and ERα were not changed significantly between raloxifene group and fluid shearing stress group (P> 0. 05), but all test parameters in groups of raloxifene combination fluid shearing stress were higher than that of the previous two groups (Praloxifene, the selective estrogen receptor modulator, were verifed to be able to promote MC3T3-E1 proliferation, increase the expression of β-catenin and ERα, and the combination functioned synergicly significantly. Fluid shear stress and raloxifene may possiblely affect the osteoblast proliferation by regulating the signaling pathways of Wnt/β-catenin and ER.

  14. The LAR protein tyrosine phosphatase enables PDGF beta-receptor activation through attenuation of the c-Abl kinase activity.

    NARCIS (Netherlands)

    Zheng, W.; Lennartsson, J.; Hendriks, W.J.A.J.; Heldin, C.H.; Hellberg, C.

    2011-01-01

    The receptor tyrosine phosphatase (RPTP) LAR negatively regulates the activity of several receptor tyrosine kinases. To investigate if LAR affects the platelet-derived growth factor (PDGF) receptor signaling, mouse embryonic fibroblasts (MEFs) from mice where the LAR phosphatase domains were deleted

  15. Distinct Effects of Estrogen on Mouse Maternal Behavior: The Contribution of Estrogen Synthesis in the Brain.

    Directory of Open Access Journals (Sweden)

    Gen Murakami

    Full Text Available Estrogen surge following progesterone withdrawal at parturition plays an important role in initiating maternal behavior in various rodent species. Systemic estrogen treatment shortens the latency to onset of maternal behavior in nulliparous female rats that have not experienced parturition. In contrast, nulliparous laboratory mice show rapid onset of maternal behavior without estrogen treatment, and the role of estrogen still remains unclear. Here the effect of systemic estrogen treatment (for 2 h, 1 day, 3 days, and 7 days after progesterone withdrawal was examined on maternal behavior of C57BL/6 mice. This estrogen regimen led to different effects on nursing, pup retrieval, and nest building behaviors. Latency to nursing was shortened by estrogen treatment within 2 h. Moreover, pup retrieval and nest building were decreased. mRNA expression was also investigated for estrogen receptor α (ERα and for genes involved in regulating maternal behavior, specifically, the oxytocin receptor (OTR and vasopressin receptor in the medial amygdala (MeA and medial preoptic area (MPOA. Estrogen treatment led to decreased ERα mRNA in both regions. Although OTR mRNA was increased in the MeA, OTR and vasopressin receptor mRNA were reduced in the MPOA, showing region-dependent transcription regulation. To determine the mechanisms for the actions of estrogen treatment, the contribution of estrogen synthesis in the brain was examined. Blockade of estrogen synthesis in the brain by systemic letrozole treatment in ovariectomized mice interfered with pup retrieval and nest building but not nursing behavior, indicating different contributions of estrogen synthesis to maternal behavior. Furthermore, letrozole treatment led to an increase in ERα mRNA in the MeA but not in the MPOA, suggesting that involvement of estrogen synthesis is brain region dependent. Altogether, these results suggest that region-dependent estrogen synthesis leads to differential transcriptional

  16. Glutamate-induced apoptosis in primary cortical neurons is inhibited by equine estrogens via down-regulation of caspase-3 and prevention of mitochondrial cytochrome c release

    Directory of Open Access Journals (Sweden)

    Zhang YueMei

    2005-02-01

    Full Text Available Abstract Background Apoptosis plays a key role in cell death observed in neurodegenerative diseases marked by a progressive loss of neurons as seen in Alzheimer's disease. Although the exact cause of apoptosis is not known, a number of factors such as free radicals, insufficient levels of nerve growth factors and excessive levels of glutamate have been implicated. We and others, have previously reported that in a stable HT22 neuronal cell line, glutamate induces apoptosis as indicated by DNA fragmentation and up- and down-regulation of Bax (pro-apoptotic, and Bcl-2 (anti-apoptotic genes respectively. Furthermore, these changes were reversed/inhibited by estrogens. Several lines of evidence also indicate that a family of cysteine proteases (caspases appear to play a critical role in neuronal apoptosis. The purpose of the present study is to determine in primary cultures of cortical cells, if glutamate-induced neuronal apoptosis and its inhibition by estrogens involve changes in caspase-3 protease and whether this process is mediated by Fas receptor and/or mitochondrial signal transduction pathways involving release of cytochrome c. Results In primary cultures of rat cortical cells, glutamate induced apoptosis that was associated with enhanced DNA fragmentation, morphological changes, and up-regulation of pro-caspase-3. Exposure of cortical cells to glutamate resulted in a time-dependent cell death and an increase in caspase-3 protein levels. Although the increase in caspase-3 levels was evident after 3 h, cell death was only significantly increased after 6 h. Treatment of cells for 6 h with 1 to 20 mM glutamate resulted in a 35 to 45% cell death that was associated with a 45 to 65% increase in the expression of caspase-3 protein. Pretreatment with caspase-3-protease inhibitor z-DEVD or pan-caspase inhibitor z-VAD significantly decreased glutamate-induced cell death of cortical cells. Exposure of cells to glutamate for 6 h in the presence or

  17. 17β estradiol regulation of connexin 43-based gap junction and mechanosensitivity through classical estrogen receptor pathway in osteocyte-like MLO-Y4 cells.

    KAUST Repository

    Ren, Jian

    2013-04-01

    Connexin 43 (Cx43) plays an essential role in osteocyte mechanotransduction. Although estrogen involves in the adaptive responses of bone cells to mechanical loadings, its effects on osteocytic Cx43-based gap junction intercellular communication (GJIC) remain obscure. We found that 17β estradiol (E2) up-regulated Cx43, and enhanced GJIC in osteocyte-like MLO-Y4 cells in fluorescence recovery after photobleaching (FRAP) assay. Combination of E2 pre-treatment and oscillating fluid flow (OFF) further enhanced Cx43 expression and mitogen-activated protein kinase (MAPK) phosphorylation, comparing to E2 or OFF treatment alone. Both blocking of classical estrogen receptors (ERα/β) by fulvestrant and ERα knockdown by small interfering RNA inhibited E2-mediated Cx43 increase, while a GPR30-specific agonist G-1 failed to promote Cx43 expression. Our results suggest that the presence of E2 enhanced Cx43-based GJIC mainly via ERα/β pathway, and sensitized osteocytes to mechanical loading. © 2012 Elsevier Inc. All rights reserved.

  18. 17β estradiol regulation of connexin 43-based gap junction and mechanosensitivity through classical estrogen receptor pathway in osteocyte-like MLO-Y4 cells.

    Science.gov (United States)

    Ren, Jian; Wang, Xu-Hui; Wang, Guang-Chao; Wu, Jun-Hua

    2013-04-01

    Connexin 43 (Cx43) plays an essential role in osteocyte mechanotransduction. Although estrogen involves in the adaptive responses of bone cells to mechanical loadings, its effects on osteocytic Cx43-based gap junction intercellular communication (GJIC) remain obscure. We found that 17β estradiol (E2) up-regulated Cx43, and enhanced GJIC in osteocyte-like MLO-Y4 cells in fluorescence recovery after photobleaching (FRAP) assay. Combination of E2 pre-treatment and oscillating fluid flow (OFF) further enhanced Cx43 expression and mitogen-activated protein kinase (MAPK) phosphorylation, comparing to E2 or OFF treatment alone. Both blocking of classical estrogen receptors (ERα/β) by fulvestrant and ERα knockdown by small interfering RNA inhibited E2-mediated Cx43 increase, while a GPR30-specific agonist G-1 failed to promote Cx43 expression. Our results suggest that the presence of E2 enhanced Cx43-based GJIC mainly via ERα/β pathway, and sensitized osteocytes to mechanical loading. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Estrogen-Induced Maldevelopment of the Penis Involves Down-Regulation of Myosin Heavy Chain 11 (MYH11) Expression, a Biomarker for Smooth Muscle Cell Differentiation1

    Science.gov (United States)

    Okumu, L.A.; Bruinton, Sequoia; Braden, Tim D.; Simon, Liz; Goyal, Hari O.

    2012-01-01

    ABSTRACT Cavernous smooth muscle cells are essential components in penile erection. In this study, we investigated effects of estrogen exposure on biomarkers for smooth muscle cell differentiation in the penis. Neonatal rats received diethylstilbestrol (DES), with or without the estrogen receptor (ESR) antagonist ICI 182,780 (ICI) or the androgen receptor (AR) agonist dihydrotestosterone (DHT), from Postnatal Days 1 to 6. Tissues were collected at 7, 10, or 21 days of age. The smooth muscle cell biomarker MYH11 was studied in depth because microarray data showed it was significantly down-regulated, along with other biomarkers, in DES treatment. Quantitative real time-PCR and Western blot analyses showed 50%–80% reduction (P ≤ 0.05) in Myh11 expression in DES-treated rats compared to that in controls; and ICI and DHT coadministration mitigated the decrease. Temporally, from 7 to 21 days of age, Myh11 expression was onefold increased (P ≥ 0.05) in DES-treated rats versus threefold increased (P ≤ 0.001) in controls, implying the long-lasting inhibitory effect of DES on smooth muscle cell differentiation. Immunohistochemical localization of smooth muscle alpha actin, another biomarker for smooth muscle cell differentiation, showed fewer cavernous smooth muscle cells in DES-treated animals than in controls. Additionally, DES treatment significantly up-regulated Esr1 mRNA expression and suppressed the neonatal testosterone surge by 90%, which was mitigated by ICI coadministration but not by DHT coadministration. Collectively, results provided evidence that DES treatment in neonatal rats inhibited cavernous smooth muscle cell differentiation, as shown by down-regulation of MYH11 expression at the mRNA and protein levels and by reduced immunohistochemical staining of smooth muscle alpha actin. Both the ESR and the AR pathways probably mediate this effect. PMID:22976277

  20. STI571 reduces TRAIL-induced apoptosis in colon cancer cells: c-Abl activation by the death receptor leads to stress kinase-dependent cell death

    Directory of Open Access Journals (Sweden)

    Huang Duen-Yi

    2012-03-01

    Full Text Available Abstract Background In an effort to achieve better cancer therapies, we elucidated the combination cancer therapy of STI571 (an inhibitor of Bcr-Abl and clinically used for chronic myelogenous leukemia and TNF-related apoptosis-inducing ligand (TRAIL, a developing antitumor agent in leukemia, colon, and prostate cancer cells. Methods Colon cancer (HCT116, SW480, prostate cancer (PC3, LNCaP and leukemia (K562 cells were treated with STI571 and TRAIL. Cell viability was determined by MTT assay and sub-G1 appearance. Protein expression and kinase phosphorylation were determined by Western blotting. c-Abl and p73 activities were inhibited by target-specific small interfering (siRNA. In vitro kinase assay of c-Abl was conducted using CRK as a substrate. Results We found that STI571 exerts opposite effects on the antitumor activity of TRAIL. It enhanced cytotoxicity in TRAIL-treated K562 leukemia cells and reduced TRAIL-induced apoptosis in HCT116 and SW480 colon cancer cells, while having no effect on PC3 and LNCaP cells. In colon and prostate cancer cells, TRAIL caused c-Abl cleavage to the active form via a caspase pathway. Interestingly, JNK and p38 MAPK inhibitors effectively blocked TRAIL-induced toxicity in the colon, but not in prostate cancer cells. Next, we found that STI571 could attenuate TRAIL-induced c-Abl, JNK and p38 activation in HCT116 cells. In addition, siRNA targeting knockdown of c-Abl and p73 also reduced TRAIL-induced cytotoxicity, rendering HCT116 cells less responsive to stress kinase activation, and masking the cytoprotective effect of STI571. Conclusions All together we demonstrate a novel mediator role of p73 in activating the stress kinases p38 and JNK in the classical apoptotic pathway of TRAIL. TRAIL via caspase-dependent action can sequentially activate c-Abl, p73, and stress kinases, which contribute to apoptosis in colon cancer cells. Through the inhibition of c-Abl-mediated apoptotic p73 signaling, STI571 reduces

  1. Prolactin-induced protein (PIP regulates proliferation of luminal A type breast cancer cells in an estrogen-independent manner.

    Directory of Open Access Journals (Sweden)

    Sanjeev K Baniwal

    Full Text Available Prolactin-induced Protein (PIP, an aspartyl protease unessential for normal mammalian cell function, is required for the proliferation and invasion of some breast cancer (BCa cell types. Because PIP expression is particularly high in the Luminal A BCa subtype, we investigated the roles of PIP in the related T47D BCa cell line. Nucleic acid and antibody arrays were employed to screen effects of PIP silencing on global gene expression and activation of receptor tyrosine kinases (RTKs, respectively. Expression of PIP-stimulated genes, as defined in the T47D cell culture model, was well correlated with the expression of PIP itself across a cohort of 557 mRNA profiles of diverse BCa tumors, and bioinformatics analysis revealed cJUN and cMYC as major nodes in the PIP-dependent gene network. Among 71 RTKs tested, PIP silencing resulted in decreased phosphorylation of focal adhesion kinase (FAK, ephrin B3 (EphB3, FYN, and hemopoietic cell kinase (HCK. Ablation of PIP also abrogated serum-induced activation of the downstream serine/threonine kinases AKT, ERK1/2, and JNK1. Consistent with these results, PIP-depleted cells exhibited defects in adhesion to fibronectin, cytoskeletal stress fiber assembly and protein secretion. In addition, PIP silencing abrogated the mitogenic response of T47D BCa cells to estradiol (E2. The dependence of BCa cell proliferation was unrelated, however, to estrogen signaling because: 1 PIP silencing did not affect the transcriptional response of estrogen target genes to hormone treatment, and 2 PIP was required for the proliferation of tamoxifen-resistant BCa cells. Pharmacological inhibition of PIP may therefore serve the bases for both augmentation of existing therapies for hormone-dependent tumors and the development of novel therapeutic approaches for hormone-resistant BCa.

  2. Mitochondria: Target organelles for estrogen action

    Directory of Open Access Journals (Sweden)

    Małgorzata Chmielewska

    2017-06-01

    Full Text Available Estrogens belong to a group of sex hormones, which have been shown to act in multidirectional way. Estrogenic effects are mediated by two types of intracellular receptors: estrogen receptor 1 (ESR1 and estrogen receptor 2 (ESR2. There are two basic mechanisms of estrogen action: 1 classical-genomic, in which the ligand-receptor complex acts as a transcriptional factor and 2 a nongenomic one, which is still not fully understood, but has been seen to lead to distinct biological effects, depending on tissue and ligand type. It is postulated that nongenomic effects may be associated with membrane signaling and the presence of classical nuclear receptors within the cell membrane. Estrogens act in a multidirectional way also within cell organelles. It is assumed that there is a mechanism which manages the migration of ESR into the mitochondrial membrane, wherein the exogenous estrogen affect the morphology of mitochondria. Estrogen, through its receptor, can directly modulate mitochondrial gene expression. Moreover, by regulating the level of reactive oxygen species, estrogens affect the biology of mitochondria. The considerations presented in this paper indicate the pleiotropic effects of estrogens, which represent a multidirectional pathway of signal transduction.

  3. Three nuclear and two membrane estrogen receptors in basal teleosts, Anguilla sp.: Identification, evolutionary history and differential expression regulation

    DEFF Research Database (Denmark)

    Lafont, Anne Gaëlle; Rousseau, Karine; Tomkiewicz, Jonna

    2016-01-01

    expressed in the eel, but with differential patterns of tissue expression and regulation. ESR1 only is consistently up-regulated in vivo in female eel BPG-liver axis during induced sexual maturation, and also up-regulated in vitro by estradiol in eel hepatocyte primary cultures. This first comparative study...

  4. Estrogen receptor alpha and beta regulate actin polymerization and spatial memory through an SRC-1/mTORC2-dependent pathway in the hippocampus of female mice.

    Science.gov (United States)

    Zhao, Yangang; He, Li; Zhang, Yuanyuan; Zhao, Jikai; Liu, Zhi; Xing, Fangzhou; Liu, Mengying; Feng, Ziqi; Li, Wei; Zhang, Jiqiang

    2017-11-01

    Aging-related decline of estrogens, especially 17β-estradiol (E2), has been shown to play an important role in the impairment of learning and memory in dementias, such as Alzheimer's disease (AD), but the underlying molecular mechanisms are poorly understood. In this study, we first demonstrated decreases in E2 signaling (aromatase, classic estrogen receptor ERα and ERβ and their coactivator SRC-1), mTORC2 signaling (Rictor and phospho-AKTser473) and actin polymerization (phospho-Cofilin, Profilin-1 and the F-actin/G-actin ratio) in the hippocampus of old female mice compared with those levels detected in the adult hippocampus. We then showed that ERα and ERβ antagonists induced a significant decrease in SRC-1, mTORC2 signaling, actin polymerization, and CA1 spine density, as well as impairments of learning and memory; however, ovariectomy-induced changes of these parameters could be significantly reversed by treatment with ER agonists. We further showed that expression of SRC-1, mTORC2 signaling and actin polymerization could be upregulated by E2 treatment, and the effects of E2 were blocked by the ER antagonists but mimicked by the agonists. We also showed that the lentivirus-mediated SRC-1 knockdown significantly inhibited the agonist-activated mTORC2 signaling and actin polymerization, and the lentivirus-mediated Rictor knockdown also significantly inhibited the agonist-activated actin polymerization. Finally, we demonstrated that the ERα and ERβ antagonists induced a disruption in actin polymerization and an impairment of spatial memory, which were rescued by activation of mTORC2. Taken together, the above results clearly demonstrated an mTORC2-dependent regulation of actin polymerization that contributed to the effects of ERα and ERβ on spatial learning, which may provide a novel target for the prevention and treatment of E2-related dementia in the aged population. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Uterine and placental expression of TRPV6 gene is regulated via progesterone receptor- or estrogen receptor-mediated pathways during pregnancy in rodents

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    Choi Kyung-Chul

    2009-05-01

    Full Text Available Abstract Transient receptor potential cation channel, subfamily V, member 6 (TRPV6 is an epithelial Ca2+ channel protein expressed in calcium absorbing organs. In the present study, we investigated the expression and regulation of uterine and placental TRPV6 during gestation in rodents. Uterine TRPV6 peaked at pregnancy day (P 0.5, P5.5 and, P13.5 and was detected in uterine epithelium and glands of rats, while placental TRPV6 mRNA levels increased in mid-gestation. Uterine and placental TRPV6 mRNA levels in rats appear to cyclically change during pregnancy, suggesting that TRPV6 may participate in the implantation process. In addition, uterine TRPV6 mRNA is only expressed in placenta-unattached areas of the uterus, and uterine TRPV6 immunoreactivity was observed in luminal and glandular epithelial cells. In the placenta, TRPV6 was detected in the labyrinth and spongy zone. These results may indicate that TRPV6 has at least two functions: implantation of the embryo and maintenance of pregnancy. To investigate the pathway(s mediating TRPV6 expression in rodents, anti-steroid hormone antagonists were injected prior to maximal TRPV6 expression. In rats, TRPV6 expression was reduced by RU486 (an anti-progesterone through progesterone receptors, and ICI 182,780 (an anti-estrogen blocked TRPV6 expression via estrogen receptors in mice. The juxtaposition of uterine and placental TRPV6 expressed in these tissues supports the notion that TRPV6 participates in transferring calcium ions between the maternal and fetal compartments. Taken together, TRPV6 gene may function as a key element in controlling calcium transport in the uterus between the embryo and the placenta during pregnancy.

  6. Signaling function of PSGL-1 in neutrophil: tyrosine-phosphorylation-dependent and c-Abl-involved alteration in the F-actin-based cytoskeleton.

    Science.gov (United States)

    Ba, Xueqing; Chen, Cuixia; Gao, Yanguang; Zeng, Xianlu

    2005-02-01

    P-selectin glycoprotein ligand-1 (PSGL-1) is the best-characterized selectin ligand that has been demonstrated to mediate leukocytes rolling on endothelium and leukocytes recruitment into inflamed tissue in vivo. In addition to its direct role in leukocyte capturing, PSGL-1 also functions as a signal-transducing receptor. The present work showed that after cross-linking of PSGL-1 with KPL1, an anti-PSGL-1 monoclonal antibody, PSGL-1 linked to the cytoskeleton and became a detergent-insoluble component in activated neutrophils. The antibody cross-linking led to the polymerization and redistribution of F-actin-based cytoskeleton, and this alteration of cytoskeleton was spatiotemporally related to the polarization of PSGL-1. PSGL-1's polarization was cytoskeleton-dependent because it was eliminated by cytochalasin B. Furthermore, the polymerization and redistribution of F-actin filaments were tyrosine-phosphorylation-dependent since the alteration of F-actin-based cytoskeleton was severely blocked by genistein, a universal tyrosine kinase inhibitor. STI571, a small molecule inhibitor for cytoplasmic tyrosine kinase c-Abl, also inhibited the alteration of F-actin-based cytoskeleton, and c-Abl was redistributed to where F-actin concentrated in the activated neutrophils. The results suggested that cross-linking of PSGL-1 induces the phosphorylation-dependent and c-Abl-involved alteration of F-actin-based cytoskeleton in neutrophils. 2004 Wiley-Liss, Inc.

  7. Estrogen receptor alpha and nuclear factor Y coordinately regulate the transcription of the SUMO-conjugating UBC9 gene in MCF-7 breast cancer cells.

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    Shibo Ying

    Full Text Available UBC9 encodes a protein that conjugates small ubiquitin-related modifier (SUMO to target proteins thereby changing their functions. Recently, it was noted that UBC9 expression and activity play a role in breast tumorigenesis and response to anticancer drugs. However, the underlying mechanism is poorly understood. To investigate the transcriptional regulation of the UBC9 gene, we identified and characterized its promoter and cis-elements. Promoter activity was tested using luciferase reporter assays. The binding of transcription factors to the promoter was detected by chromatin immunoprecipitation (ChIP, and their functional role was confirmed by siRNA knockdown. UBC9 mRNA and protein levels were measured by quantitative reverse transcription PCR and Western blot analysis, respectively. An increased expression of UBC9 mRNA and protein was found in MCF-7 breast cancer cells treated with 17β-estradiol (E2. Analysis of various deletion mutants revealed a 137 bp fragment upstream of the transcription initiation site to be sufficient for reporter gene transcription. Mutations of putative estrogen receptor α (ER-α (one imperfect estrogen response element, ERE and/or nuclear factor Y (NF-Y binding sites (two CCAAT boxes markedly reduced promoter activity. Similar results were obtained in ER-negative MDA-MB-231 cells except that the ERE mutation did not affect promoter activity. Additionally, promoter activity was stimulated upon E2 treatment and overexpression of ER-α or NF-YA in MCF-7 cells. ChIP confirmed direct binding of both transcription factors to the UBC9 promoter in vivo. Furthermore, UBC9 expression was diminished by ER-α and NF-Y siRNAs on the mRNA and protein levels. In conclusion, we identified the proximal UBC9 promoter and provided evidence that ER-α and NF-Y regulate UBC9 expression on the transcriptional level in response to E2 in MCF-7 cells. These findings may contribute to a better understanding of the regulation of UBC9 in ER

  8. Estrogen receptor alpha and nuclear factor Y coordinately regulate the transcription of the SUMO-conjugating UBC9 gene in MCF-7 breast cancer cells.

    Science.gov (United States)

    Ying, Shibo; Dünnebier, Thomas; Si, Jing; Hamann, Ute

    2013-01-01

    UBC9 encodes a protein that conjugates small ubiquitin-related modifier (SUMO) to target proteins thereby changing their functions. Recently, it was noted that UBC9 expression and activity play a role in breast tumorigenesis and response to anticancer drugs. However, the underlying mechanism is poorly understood. To investigate the transcriptional regulation of the UBC9 gene, we identified and characterized its promoter and cis-elements. Promoter activity was tested using luciferase reporter assays. The binding of transcription factors to the promoter was detected by chromatin immunoprecipitation (ChIP), and their functional role was confirmed by siRNA knockdown. UBC9 mRNA and protein levels were measured by quantitative reverse transcription PCR and Western blot analysis, respectively. An increased expression of UBC9 mRNA and protein was found in MCF-7 breast cancer cells treated with 17β-estradiol (E2). Analysis of various deletion mutants revealed a 137 bp fragment upstream of the transcription initiation site to be sufficient for reporter gene transcription. Mutations of putative estrogen receptor α (ER-α) (one imperfect estrogen response element, ERE) and/or nuclear factor Y (NF-Y) binding sites (two CCAAT boxes) markedly reduced promoter activity. Similar results were obtained in ER-negative MDA-MB-231 cells except that the ERE mutation did not affect promoter activity. Additionally, promoter activity was stimulated upon E2 treatment and overexpression of ER-α or NF-YA in MCF-7 cells. ChIP confirmed direct binding of both transcription factors to the UBC9 promoter in vivo. Furthermore, UBC9 expression was diminished by ER-α and NF-Y siRNAs on the mRNA and protein levels. In conclusion, we identified the proximal UBC9 promoter and provided evidence that ER-α and NF-Y regulate UBC9 expression on the transcriptional level in response to E2 in MCF-7 cells. These findings may contribute to a better understanding of the regulation of UBC9 in ER

  9. Estrogen receptor (ER)α-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression.

    Science.gov (United States)

    Drew, Brian G; Hamidi, Habib; Zhou, Zhenqi; Villanueva, Claudio J; Krum, Susan A; Calkin, Anna C; Parks, Brian W; Ribas, Vicent; Kalajian, Nareg Y; Phun, Jennifer; Daraei, Pedram; Christofk, Heather R; Hewitt, Sylvia C; Korach, Kenneth S; Tontonoz, Peter; Lusis, Aldons J; Slamon, Dennis J; Hurvitz, Sara A; Hevener, Andrea L

    2015-02-27

    Obesity is associated with increased breast cancer (BrCA) incidence. Considering that inactivation of estrogen receptor (ER)α promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissue-specific sites of ERα action to combat metabolic-related disease, including BrCA, is of clinical importance. To study the role of ERα in adipose tissue we generated fat-specific ERα knock-out (FERKO) mice. Herein we show that ERα deletion increased adipocyte size, fat pad weight, and tissue expression and circulating levels of the secreted glycoprotein, lipocalin 2 (Lcn2), an adipokine previously associated with BrCA development. Chromatin immunoprecipitation and luciferase reporter studies showed that ERα binds the Lcn2 promoter to repress its expression. Because adipocytes constitute an important cell type of the breast microenvironment, we examined the impact of adipocyte ERα deletion on cancer cell behavior. Conditioned medium from ERα-null adipocytes and medium containing pure Lcn2 increased proliferation and migration of a subset of BrCA cells in culture. The proliferative and promigratory effects of ERα-deficient adipocyte-conditioned medium on BrCA cells was reversed by Lcn2 deletion. BrCA cell responsiveness to exogenous Lcn2 was heightened in cell types where endogenous Lcn2 expression was minimal, but components of the Lcn2 signaling pathway were enriched, i.e. SLC22A17 and 3-hydroxybutyrate dehydrogenase (BDH2). In breast tumor biopsies from women diagnosed with BrCA we found that BDH2 expression was positively associated with adiposity and circulating Lcn2 levels. Collectively these data suggest that reduction of ERα expression in adipose tissue promotes adiposity and is linked with the progression and severity of BrCA via increased adipocyte-specific Lcn2 production and enhanced tumor cell Lcn2 sensitivity. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Antiestrogenic activity of flavnoid phytochemicals mediated via c-Jun N-terminal protein kinase pathway. Cell-type specific regulation of estrogen receptor alpha

    Science.gov (United States)

    Flavonoid phytochemicals act as both agonists and antagonists of the human estrogen receptors (ERs). While a number of these compounds act by directly binding to the ER, certain phytochemicals, such as the flavonoid compounds chalcone and flavone, elicit antagonistic effects on estrogen signaling in...

  11. Up-regulation of type II collagen gene by 17β-estradiol in articular chondrocytes involves Sp1/3, Sox-9, and estrogen receptor α.

    Science.gov (United States)

    Maneix, Laure; Servent, Aurélie; Porée, Benoît; Ollitrault, David; Branly, Thomas; Bigot, Nicolas; Boujrad, Noureddine; Flouriot, Gilles; Demoor, Magali; Boumediene, Karim; Moslemi, Safa; Galéra, Philippe

    2014-11-01

    The existence of a link between estrogen deprivation and osteoarthritis (OA) in postmenopausal women suggests that 17β-estradiol (17β-E2) may be a modulator of cartilage homeostasis. Here, we demonstrate that 17β-E2 stimulates, via its receptor human estrogen receptor α 66 (hERα66), type II collagen expression in differentiated and dedifferentiated (reflecting the OA phenotype) articular chondrocytes. Transactivation of type II collagen gene (COL2A1) by ligand-independent transactivation domain (AF-1) of hERα66 was mediated by "GC" binding sites of the -266/-63-bp promoter, through physical interactions between ERα, Sp1/Sp3, Sox9, and p300, as demonstrated in chromatin immunoprecipitation (ChIP) and Re-Chromatin Immuno-Precipitation (Re-ChIP) assays in primary and dedifferentiated cells. 17β-E2 and hERα66 increased the DNA-binding activities of Sp1/Sp3 and Sox-9 to both COL2A1 promoter and enhancer regions. Besides, Sp1, Sp3, and Sox-9 small interfering RNAs (siRNAs) prevented hERα66-induced transactivation of COL2A1, suggesting that these factors and their respective cis-regions are required for hERα66-mediated COL2A1 up-regulation. Our results highlight the genomic pathway by which 17β-E2 and hERα66 modulate Sp1/Sp3 heteromer binding activity and simultaneously participate in the recruitment of the essential factors Sox-9 and p300 involved respectively in the chondrocyte-differentiated status and COL2A1 transcriptional activation. These novel findings could therefore be attractive for tissue engineering of cartilage in OA, by the fact that 17β-E2 could promote chondrocyte redifferentiation. 17β-E2 up-regulates type II collagen gene expression in articular chondrocytes. An ERα66/Sp1/Sp3/Sox-9/p300 protein complex mediates this stimulatory effect. This heteromeric complex interacts and binds to Col2a1 promoter and enhancer in vivo. Our findings highlight a new regulatory mechanism for 17β-E2 action in chondrocytes. 17β-E2 might be an attractive

  12. Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ERα).

    Science.gov (United States)

    Pham, Duyen H; Tan, Chuan C; Homan, Claire C; Kolc, Kristy L; Corbett, Mark A; McAninch, Dale; Fox, Archa H; Thomas, Paul Q; Kumar, Raman; Gecz, Jozef

    2017-06-01

    De novo and inherited mutations of X-chromosome cell adhesion molecule protocadherin 19 (PCDH19) cause frequent, highly variable epilepsy, autism, cognitive decline and behavioural problems syndrome. Intriguingly, hemizygous null males are not affected while heterozygous females are, contradicting established X-chromosome inheritance. The disease mechanism is not known. Cellular mosaicism is the likely driver. We have identified p54nrb/NONO, a multifunctional nuclear paraspeckle protein with known roles in nuclear hormone receptor gene regulation, as a PCDH19 protein interacting partner. Using breast cancer cells we show that PCDH19-NONO complex is a positive co-regulator of ERα-mediated gene expression. Expression of mutant PCDH19 affects at least a subset of known ERα-regulated genes. These data are consistent with our findings that genes regulated by nuclear hormone receptors and those involved in the metabolism of neurosteroids in particular are dysregulated in PCDH19-epilepsy girls and affected mosaic males. Overall we define and characterize a novel mechanism of gene regulation driven by PCDH19, which is mediated by paraspeckle constituent NONO and is ERα-dependent. This PCDH19-NONO-ERα axis is of relevance not only to PCDH19-epilepsy and its comorbidities but likely also to ERα and generally nuclear hormone receptor-associated cancers. © The Author 2017. Published by Oxford University Press.

  13. NRF2/long noncoding RNA ROR signaling regulates mammary stem cell expansion and protects against estrogen genotoxicity.

    Science.gov (United States)

    Zhang, Yongshu; Xia, Jixiang; Li, Qinglin; Yao, Yuan; Eades, Gabriel; Gernapudi, Ramkishore; Duru, Nadire; Kensler, Thomas W; Zhou, Qun

    2014-11-07

    Long noncoding RNAs (lncRNAs) have emerged as key regulators of gene expression in embryonic stem cell (ESC) self-renewal and differentiation. In ESCs, lncRNAs are regulated at the genetic level via transcription factor binding to lncRNA gene promoters. Here we demonstrate that the key cytoprotective transcription factor NRF2 controls lncRNA expression in mammary stem cells. By profiling lncRNAs in wild-type and NRF2 knockdown mammary stem cells, we demonstrate that the lncRNA ROR, a regulator of embryonic stem cell pluripotency, is overexpressed upon NRF2 knockdown. We performed promoter analyses and examined predicted NRF2 binding elements in the ROR promoter using luciferase reporter constructs of a ROR promoter deletion series. Our studies revealed that NRF2 binds to two specific NRF2 response elements flanking the ROR promoter and that these two NRF2 response elements are equally important to suppress ROR transcription. In addition, we identified associated H3K27me3 chromatin modification and EZH2 binding at the ROR promoter that was dependent on NRF2 binding. We observed that NRF2 knockdown or ROR overexpression leads to increased stem cell self-renewal in mammary stem cells. Furthermore, we demonstrate Nrf2 regulation of the mammary stem cell population in vivo. These observations provide further evidence for the critical role of NRF2 in maintaining normal stem cell subpopulations in mammary epithelium. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Androgens and estrogens synergistically regulate the expression of doublecortin and enhance neuronal recruitment in the song system of adult female canaries.

    Science.gov (United States)

    Yamamura, Takashi; Barker, Jennifer M; Balthazart, Jacques; Ball, Gregory F

    2011-06-29

    Vocal control nuclei in songbirds display seasonal changes in volume that are regulated by testosterone (T) and its androgenic (5α-dihydrotestosterone; DHT) or estrogenic (17β-estradiol; E(2)) metabolites. In male canaries, T regulates expression of the microtubule-associated protein doublecortin (DCX), a marker of neurogenesis. We examined the effect of T and its two metabolites alone or in combination on DCX expression in adult female canaries. Treatment with T or with DHT+E(2) increased HVC volume and neuron numbers as well as the total numbers of fusiform (migrating) and round (differentiating) DCX neurons in the nucleus but generally not in adjacent areas. DHT or E(2) alone did not increase these measures but increased the density of fusiform DCX cells per section. Similar results were observed in area X, although some effects did not reach significance, presumably because plasticity in X is mediated transsynaptically and follows HVC changes with some delay. There was no effect of any treatment on the total number of neurons in area X, and no change in DCX cell densities was detected in the lateral magnocellular nucleus of the anterior nidopallium, nor in other parts of the nidopallium. DHT and E(2) by themselves thus increase density of DCX cells migrating through HVC but are not sufficient in isolation to induce the recruitment of these newborn neurons in the nucleus. These effects are generally not observed in the rest of the nidopallium, implying that steroids only act on the attraction and recruitment of new neurons in HVC without having any major effects on their production at the ventricle wall.

  15. MDH2 Stimulated by Estrogen-GPR30 Pathway Down-Regulated PTEN Expression Promoting the Proliferation and Invasion of Cells in Endometrial Cancer

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    Yan Zhuang

    2017-04-01

    Full Text Available PURPOSE: The relationship between endometrial carcinoma and cellular metabolism is unknown. In endometrial cancer, mutation rate of PTEN has been reported very high. Malate dehydrogenase 2 (MDH2 is one of the isoforms of malate dehydrogenase, which is involved in citric acid cycle in mitochondria. Our study aimed to investigate the role MDH2 played in PTEN-regulated endometrial carcinoma. METHODS: To reveal the expression of MDH2 and the co-localization of PTEN and MDH2, immunohistochemistry and immunofluorescent staining were used. Western blot, Real-time PCR, RNA interference and overexpression plasmid DNA transfection were performed to investigate the relationship between PTEN and MDH2 as well as the impact of E2 on the expression of PTEN and MDH2, while CCK8, transwell and flow cytometric analysis were carried out to evaluate the proliferation, migration and invasion and apoptosis of endometrial carcinoma cell lines. RESULTS: Our results demonstrated that as a metabolism related enzyme, MDH2 was overexpressed in endometrial carcinoma tissues and related to the grade of the cancer (P = .038. Western blot, Real-time PCR and immunofluorescent staining revealed MDH2 inhibited the expression of PTEN and was co-localized with PTEN in the cytoplasm of endometrial carcinoma. Proliferation, transwell and apoptosis assay suggested that MDH2 enhanced the proliferation, migration and invasion but inhibited the apoptosis of endometrial cancer cell line through suppressing PTEN. Furthermore, E2 inhibited the expression level of PTEN but enhanced MDH2 via GPR30. CONCLUSIONS: Our study demonstrated that MDH2, stimulated by estrogen, was involved in the development of PTEN-regulated endometrial carcinoma through GPR30-related pathway.

  16. Estrogen and Osteoporosis.

    Science.gov (United States)

    Lindsay, Robert

    1987-01-01

    This article reviews the use of estrogen in the prevention and treatment of osteoporosis. Dosage levels, interactions with other factors, side effects, and the mechanism of estrogen action are discussed. (Author/MT)

  17. Estrogen-gut microbiome axis: Physiological and clinical implications.

    Science.gov (United States)

    Baker, James M; Al-Nakkash, Layla; Herbst-Kralovetz, Melissa M

    2017-09-01

    Low levels of gonadal circulating estrogen observed in post-menopausal women can adversely impact a diverse range of physiological factors, with clinical implications for brain cognition, gut health, the female reproductive tract and other aspects of women's health. One of the principal regulators of circulating estrogens is the gut microbiome. This review aims to shed light on the role of the gut microbiota in estrogen-modulated disease. The gut microbiota regulates estrogens through secretion of β-glucuronidase, an enzyme that deconjugates estrogens into their active forms. When this process is impaired through dysbiosis of gut microbiota, characterized by lower microbial diversity, the decrease in deconjugation results in a reduction of circulating estrogens. The alteration in circulating estrogens may contribute to the development of conditions discussed herein: obesity, metabolic syndrome, cancer, endometrial hyperplasia, endometriosis, polycystic ovary syndrome, fertility, cardiovascular disease (CVD) and cognitive function. The bi-directional relationship between the metabolic profile (including estrogen levels) and gut microbiota in estrogen-driven disease will also be discussed. Promising therapeutic interventions manipulating the gut microbiome and the metabolic profile of estrogen-driven disease, such as bariatric surgery and metformin, will be detailed. Modulation of the microbiome composition subsequently impacts the metabolic profile, and vice versa, and has been shown to alleviate many of the estrogen-modulated disease states. Last, we highlight promising research interventions in the field, such as dietary therapeutics, and discuss areas that provide exciting unexplored topics of study. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Estrogens and aging skin

    OpenAIRE

    Thornton, M. Julie

    2013-01-01

    Estrogen deficiency following menopause results in atrophic skin changes and acceleration of skin aging. Estrogens significantly modulate skin physiology, targeting keratinocytes, fibroblasts, melanocytes, hair follicles and sebaceous glands, and improve angiogenesis, wound healing and immune responses. Estrogen insufficiency decreases defense against oxidative stress; skin becomes thinner with less collagen, decreased elasticity, increased wrinkling, increased dryness and reduced vascularity...

  19. Expression of calbindin-D28k and its regulation by estrogen in the human endometrium during the menstrual cycle

    Directory of Open Access Journals (Sweden)

    Leung Peter CK

    2011-03-01

    Full Text Available Abstract Human endometrium resists embryo implantation except during the 'window of receptivity'. A change in endometrial gene expression is required for the development of receptivity. Uterine calbindin-D28k (CaBP-28k is involved in the regulation of endometrial receptivity by intracellular Ca2+. Currently, this protein is known to be mainly expressed in brain, kidneys, and pancreas, but potential role(s of CaBP-28k in the human uterus during the menstrual cycle remain to be clarified. Thus, in this study we demonstrated the expression of CaBP-28k in the human endometrium in distinct menstrual phases. During the human menstrual cycle, uterine expression levels of CaBP-28k mRNA and protein increased in the proliferative phase and fluctuated in these tissues, compared with that observed in other phases. We assessed the effects of two sex-steroid hormones, 17beta-estradiol (E2 and progesterone (P4, on the expression of CaBP-28k in Ishikawa cells. A significant increase in the expression of CaBP-28k mRNA was observed at the concentrations of E2 (10(-9 to -7 M. In addition, spatial expression of CaBP-28k protein was detected by immunohistochemistry. CaBP-28k was abundantly localized in the cytoplasm of the luminal and glandular epithelial cells during the proliferative phases (early-, mid-, late- and early-secretory phase of menstrual cycle. Taken together, these results indicate that CaBP-28k, a uterine calcium binding protein, is abundantly expressed in the human endometrium, suggesting that uterine expression of CaBP-28k may be involved in reproductive function during the human menstrual cycle.

  20. [Regulation of [12Asp]K-ras4B on transcriptional activity of estrogen receptor in endometrial carcinoma HEC-1A cell lines].

    Science.gov (United States)

    Gui, Li-ming; Wei, Li-hui; Xu, Ming-xu; Wang, Jian-liu; Zhong, Ying-cheng; Li, Xiao-ping; Tu, Zheng; Sun, Peng-ming; Ma, Da-long

    2004-01-01

    To investigate the effect of mutant-type [(12)Asp]K-ras4B gene on the expression of estrogen receptor (ER) alpha and beta and their transcriptional activity as a transcription factor in endometrial carcinoma HEC-1A cell line. (1) Effect of [(12)Asp]K-ras4B on the expression of ER alpha and beta were determined using Western blot assay. (2) Eukaryotic expression plasmid pGL3-luciferase-ERE containing luciferase report gene and estrogen receptor element (ERE) was constructed, and co-transfected into NIH3T3 and HEC-1A cell lines with pEGFP-N1 to examine the effect of [(12)Asp]K-ras4B on ER transcription that is regulated by estradiol. In addition, they were transfected into pSV5-HER0 (containing full length wide type ERalpha cDNA) and pCMV-rafS621A (inhibiting raf kinase) plasmids to test the effect of [(12)Asp]K-ras4B/raf signal pathway on transcriptional activity of ER proteins. (1) Protein level of ERs expressed in pcDI transfected control cells was low while it was increased for 3.6-fold (97 +/- 25, 349 +/- 67, P ras4B NIH3T3 cells after transfection. (2) In pcDI-[(12)Asp]K-ras4B NIH3T3 cells, the ratios for ERalpha and and ERbeta levels before transfection of rafS621A plasmids to that after the transfection, were 2.4:1 (724 +/- 45, 310 +/- 46, P HEC-1A cells, these ratios were 2.1:1 (566 +/- 22, 279 +/- 30, P ras4B NIH3T3 cells, 19-fold (141 +/- 39, 2644 +/- 331, P HEC-1A cells, respectively, when compared with those in the absence of E(2). (4) In pSV5-HER0 transfected pcDI-[(12)Asp] K-ras4B NIH3T3 cells and HEC-1A cells, compared to the untransfected cells, the ER transcriptional activity in the transfected cells increased markedly. The luciferase activity was increased for 8-fold (1048 +/- 91, 8099 +/- 452, P HEC-1A cells and pcDI-[(12)Asp]K-ras4B NIH3T3 cells. The ratio of luciferase activities in pcDI-[(12)Asp]K-ras4B NIH3T3 and HEC-1A cells, before and after transfection was 7.8:1 (1184 +/- 168, 152 +/- 27, P ras4B can enhance the expression of ERalpha and

  1. 17β-Estradiol regulates cell proliferation, colony formation, migration, invasion and promotes apoptosis by upregulating miR-9 and thus degrades MALAT-1 in osteosarcoma cell MG-63 in an estrogen receptor-independent manner

    Energy Technology Data Exchange (ETDEWEB)

    Fang, Dengfeng; Yang, Hui; Lin, Jing; Teng, Yi; Jiang, Yingying; Chen, Jiao; Li, Yu, E-mail: yuli_scu@163.com

    2015-02-20

    In bone, different concentration of estrogen leads to various of physiological processes in osteoblast, such as the proliferation, migration, and apoptosis in an estrogen receptor-dependent manner. But little was known about the estrogen effects on osteosarcoma (OS). In this study, OS cell MG-63 was treated with low (1 nM) or high (100 nM) dose of 17β-Estradiol (E2) with the presence or absence of estrogen receptor α (ERα), for evaluating the E2 effects on proliferation, migration, invasion, colony formation and apoptosis. Consistent with a previous study, high dose of E2 treatment dramatically downregulated expressing level of long non-coding RNA metastasis associated lung adenocarcinoma transcript 1 (MALAT-1). The observation of upregulation of miR-9 after a high dose of E2 treatment indicated the cause of MALAT-1 reduction. Downregulation of MALAT-1 promoted the combination of SFPQ/PTBP2 complex. It was also observed that the proliferation, migration, invasion, colony formation and apoptosis of OS cells were remarkably affected by high dose of E2 treatment, but not by low dose, in an ERα independent manner. Furthermore, the abolishment of the effects on these physiological processes caused by ectopic expression of miR-9 ASOs suggested the necessity of miR-9 in MALAT-1 regulation. Here we found that the high dose of E2 treatment upregulated miR-9 thus posttranscriptionally regulated MALAT-1 RNA level in OS cells, and then the downregulation of MALAT-1 inhibited cell proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) processes in the E2-dose dependent and ER-independent ways. - Highlights: • E2 affects osteosarcoma cell MG-63 in an Estrogen receptor-independent way. • High dose of E2 treatment upregulates miR-9 which target to MALAT-1 RNA. • Upregulated miR-9 degrades MALAT-1 and thus affects combination of SFPQ/PTBP2. • E2 treatment block cell proliferation, colony formation, mobility, and enhance apoptosis.

  2. Estrogen induction of telomerase activity through regulation of the mitogen-activated protein kinase (MAPK dependent pathway in human endometrial cancer cells.

    Directory of Open Access Journals (Sweden)

    Chunxiao Zhou

    Full Text Available Given that prolonged exposure to estrogen and increased telomerase activity are associated with endometrial carcinogenesis, our objective was to evaluate the interaction between the MAPK pathway and estrogen induction of telomerase activity in endometrial cancer cells. Estradiol (E2 induced telomerase activity and hTERT mRNA expression in the estrogen receptor (ER-α positive, Ishikawa endometrial cancer cell line. UO126, a highly selective inhibitor of MEK1/MEK2, inhibited telomerase activity and hTERT mRNA expression induced by E2. Similar results were also found after transfection with ERK 1/2-specific siRNA. Treatment with E2 resulted in rapid phosphorylation of p44/42 MAPK and increased MAPK activity which was abolished by UO126. The hTERT promoter contains two estrogen response elements (EREs, and luciferase assays demonstrate that these EREs are activated by E2. Exposure to UO126 or ERK 1/2-specific siRNA in combination with E2 counteracted the stimulatory effect of E2 on luciferase activity from these EREs. These findings suggest that E2-induction of telomerase activity is mediated via the MAPK pathway in human endometrial cancer cells.

  3. Growth regulation by estrogen in breast cancer 1 (GREB1) is a novel progesterone-responsive gene required for human endometrial stromal decidualization.

    Science.gov (United States)

    Camden, Alison J; Szwarc, Maria M; Chadchan, Sangappa B; DeMayo, Francesco J; O'Malley, Bert W; Lydon, John P; Kommagani, Ramakrishna

    2017-09-01

    Is Growth Regulation by Estrogen in Breast Cancer 1 (GREB1) required for progesterone-driven endometrial stromal cell decidualization? GREB1 is a novel progesterone-responsive gene required for progesterone-driven human endometrial stromal cell (HESC) decidualization. Successful establishment of pregnancy requires HESCs to transform from fibroblastic to epithelioid cells in a process called decidualization. This process depends on the hormone progesterone, but the molecular mechanisms by which it occurs have not been determined. Primary and transformed HESCs in which GREB1 expression was knocked down were decidualized in culture for up to 6 days. Wild-type and progesterone receptor (PR) knockout mice were treated with progesterone, and their uteri were assessed for levels of GREB1 expression. Analysis of previous data included data mining of expression profile data sets and in silico transcription factor-binding analysis. Endometrial biopsies obtained from healthy women of reproductive age during the proliferative phase (Days 8-12) of their menstrual cycle were used for isolating HESCs. Experiments were carried out with early passage (no more than four passages) HESCs isolated from at least three subjects. Transcript levels of decidualization markers prolactin (PRL) and insulin-like growth factor-binding protein-1 (IGFBP-1) were detected by quantitative RT-PCR as readouts for HESC decidualization. Cells were also imaged by phase-contrast microscopy. To assess the requirement for GREB1, PR and SRC-2, cells were transfected with specifically targeted small interfering RNAs. Results are shown as mean and SE from three replicates of one representative patient-derived primary endometrial cell line. Experiments were also conducted with transformed HESCs. Progesterone treatment of mice and transformed HESCs led to an ~5-fold (5.6 ± 0.81, P endometrial function and dysfunction should be assessed by using knock-out mouse models. Identification and functional analysis of

  4. Metabolism of ethynyl estrogens.

    Science.gov (United States)

    Helton, E D; Goldzieher, J W

    1977-09-01

    The pharmacokinetics and metabolic conversion of the ethynylated estrogens are reviewed. Special emphasis is given to the comparative pharmacokinetics of ethynyl-estradiol in different populations of women. Similarly, the variability of ethynyl-estradiol and mestranol metabolism in humans resulting from presentation of radio-labeled steroid and purification of the metabolic products is presented and discussed. The concepts of estrogen hepatotoxicity are reviewed with respect to the known phenomenon of estrogen oxidative metabolism and covalent binding. Recent evidence for the metabolic removal of the 17alpha-ethynyl group is discussed, and its relationship to estrogen hepatoxicity is considered and related to the covalent binding phenomenon.

  5. Estrogen turns down "the AIRE".

    Science.gov (United States)

    Bakhru, Pearl; Su, Maureen A

    2016-04-01

    Genetic alterations are known drivers of autoimmune disease; however, there is a much higher incidence of autoimmunity in women, implicating sex-specific factors in disease development. The autoimmune regulator (AIRE) gene contributes to the maintenance of central tolerance, and complete loss of AIRE function results in the development of autoimmune polyendocrinopathy syndrome type 1. In this issue of the JCI, Dragin and colleagues demonstrate that AIRE expression is downregulated in females as the result of estrogen-mediated alterations at the AIRE promoter. The association between estrogen and reduction of AIRE may at least partially account for the elevated incidence of autoimmune disease in women and has potential implications for sex hormone therapy.

  6. Estrogen Deficiency and the Origin of Obesity during Menopause

    Directory of Open Access Journals (Sweden)

    Fernando Lizcano

    2014-01-01

    Full Text Available Sex hormones strongly influence body fat distribution and adipocyte differentiation. Estrogens and testosterone differentially affect adipocyte physiology, but the importance of estrogens in the development of metabolic diseases during menopause is disputed. Estrogens and estrogen receptors regulate various aspects of glucose and lipid metabolism. Disturbances of this metabolic signal lead to the development of metabolic syndrome and a higher cardiovascular risk in women. The absence of estrogens is a clue factor in the onset of cardiovascular disease during the menopausal period, which is characterized by lipid profile variations and predominant abdominal fat accumulation. However, influence of the absence of these hormones and its relationship to higher obesity in women during menopause are not clear. This systematic review discusses of the role of estrogens and estrogen receptors in adipocyte differentiation, and its control by the central nervous systemn and the possible role of estrogen-like compounds and endocrine disruptors chemicals are discussed. Finally, the interaction between the decrease in estrogen secretion and the prevalence of obesity in menopausal women is examined. We will consider if the absence of estrogens have a significant effect of obesity in menopausal women.

  7. Estrogen Deficiency and the Origin of Obesity during Menopause.

    Science.gov (United States)

    Lizcano, Fernando; Guzmán, Guillermo

    2014-01-01

    Sex hormones strongly influence body fat distribution and adipocyte differentiation. Estrogens and testosterone differentially affect adipocyte physiology, but the importance of estrogens in the development of metabolic diseases during menopause is disputed. Estrogens and estrogen receptors regulate various aspects of glucose and lipid metabolism. Disturbances of this metabolic signal lead to the development of metabolic syndrome and a higher cardiovascular risk in women. The absence of estrogens is a clue factor in the onset of cardiovascular disease during the menopausal period, which is characterized by lipid profile variations and predominant abdominal fat accumulation. However, influence of the absence of these hormones and its relationship to higher obesity in women during menopause are not clear. This systematic review discusses of the role of estrogens and estrogen receptors in adipocyte differentiation, and its control by the central nervous systemn and the possible role of estrogen-like compounds and endocrine disruptors chemicals are discussed. Finally, the interaction between the decrease in estrogen secretion and the prevalence of obesity in menopausal women is examined. We will consider if the absence of estrogens have a significant effect of obesity in menopausal women.

  8. The Modified Human DNA Repair Enzyme O6-Methylguanine-DNA Methyltransferase Is a Negative Regulator of Estrogen Receptor-Mediated Transcription upon Alkylation DNA Damage

    OpenAIRE

    Teo, Alvin K. C.; Oh, Hue Kian; Ali, Rahmen B.; Li, Benjamin F. L.

    2001-01-01

    Cell proliferation requires precise control to prevent mutations from replication of (unrepaired) damaged DNA in cells exposed spontaneously to mutagens. Here we show that the modified human DNA repair enzyme O6-methylguanine-DNA methyltransferase (R-MGMT), formed from the suicidal repair of the mutagenic O6-alkylguanine (6RG) lesions by MGMT in the cells exposed to alkylating carcinogens, functions in such control by preventing the estrogen receptor (ER) from transcription activation that me...

  9. The prolyl isomerase Pin1 acts synergistically with CDK2 to regulate the basal activity of estrogen receptor α in breast cancer.

    Directory of Open Access Journals (Sweden)

    Chiara Lucchetti

    Full Text Available 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.

  10. Estrogen Receptor Beta Expression in the Mouse Forebrain: Age and Sex Differences

    OpenAIRE

    Zuloaga, Damian G.; Zuloaga, Kristen L.; Hinds, Laura R.; Carbone, David L.; Handa, Robert J.

    2014-01-01

    Estrogen receptors regulate multiple brain functions including stress, sexual, and memory associated behaviors as well as control of neuroendocrine and autonomic function. During development, estrogen signaling is involved in programming adult sex differences in physiology and behavior. Expression of estrogen receptor alpha changes across development in a region specific fashion. By contrast, estrogen receptor beta (ERβ) is expressed in many brain regions, yet few studies have explored sex an...

  11. AKT1 as the PageRank hub gene is associated with melanoma and its functional annotation is highly related to the estrogen signaling pathway that may regulate the growth of melanoma.

    Science.gov (United States)

    Zhao, Jingjing; Zeng, Xue; Song, Ping; Wu, Xiaohong; Shi, Hongbo

    2016-10-01

    In order to detect the disease-associated genes and their gene interaction function and association with melanoma mechanisms, we identified a total of 1,310 differentially expressed genes (DEGs) from the Gene Expression Omnibus database GSE3189 with FDR 2 using the R package. After constructing the gene interaction network by STRING with the selected DEGs, we applied a statistical approach to identify the topological hub genes with PageRank score. Forty-four genes were identified in this network and AKT1 was selected as the most important hub gene. The AKT1 gene encodes a serine‑threonine protein kinase (AKT). High expression of AKT is involved in the resistance of cell apoptosis as well as adaptive resistance to treatment in melanoma. Our results indicated that AKT1 with a higher expression in melanoma showed enriched binding sites in the negative regulation of response to external stimulus, which enables cells to adapt to changes in external stimulation for survival. Another finding was that AKT regulated the lipid metabolic process and may be involved in melanoma progression and promotion of tumor growth through gene enrichment function analysis. Two highlighted pathways were detected in our study: i) the estrogen signaling pathway modulates the immune tolerance and resistance to cell apoptosis, which contributes to the growth of melanoma and ii) the RAP1 signaling pathway which regulates focal adhesion (FA) negative feedback to cell migration and invasion in melanoma. Our studies highlighted the top differentially expressed gene AKT1 and its correlation with the estrogen signaling and RAP1 signaling pathways to alter the proliferation and apoptosis of melanoma cells. Analysis of the enrichment functions of genes associated with melanoma will help us find the exact mechanism of melanoma and advance the full potential of newly targeted cancer therapy.

  12. [Estrogens and vascular thrombosis].

    Science.gov (United States)

    Colmou, A

    1982-09-01

    The incidence of thromboses among young women has increased with widespread use of oral contraceptives (OCs) due to the significant thromboembolic risk of estrogen. Estrogens intervene at the vascular, platelet, and plasma levels as a function of hormonal variations in the menstrual cycle, increasing the aggregability of the platelets and thrombocytes, accelerating the formation of clots, and decreasing the amount of antithrombin III. Estrogens are used in medicine to treat breast and prostate cancers and in gynecology to treat dysmenorrhea, during the menopause, and in contraception. Smoking, cardiovascular disease and hypertension, hypercholesterolemia, and diabetes are contraindicators to estrogen use. Thrombosis refers to blockage of a blood vessel by a clot or thrombus. Before estrogens are prescribed, a history of phlebitis, obesity, hyperlipidemia, or significant varicosities should be ruled out. A history of venous thrombosis, hyperlipoproteinemia, breast nodules, serious liver condition, allergies to progesterone, and some ocular diseases of vascular origin definitively rule out treatment with estrogens. A family history of infarct, embolism, diabetes, cancer, or vascular accidents at a young age signals a need for greater patient surveillance. All patients receiving estrogens should be carefully observed for signs of hypertension, hypercholesterolemia, hypercoagulability, or diabetes. Nurses have a role to play in carefully eliciting the patient's history of smoking, personal and family medical problems, and previous and current laboratory results, as well as in informing the patients of the risks and possible side effects of OCs, especially for those who smoke. Nurses should educate patients receiving estrogens, especially those with histories of circulatory problems, to avoid standing in 1 position for prolonged periods, avoid heat which is a vasodilator, avoid obesity, excercise regularly, wear appropriate footgear, and follow other good health

  13. Estrogen and the central control of body fluid balance.

    Science.gov (United States)

    Curtis, Kathleen S

    2009-05-25

    Body fluid volume and electrolyte concentration are maintained at optimal levels by complex behavioral and physiological mechanisms that are integrated and coordinated by the central nervous system. From initial studies of estrogen effects on salt and water intake in the 1970s and later investigations of the role of estrogen in cardiovascular and neuroendocrine function, it has become increasingly clear that body fluid volume and osmotic regulation are affected by estrogen. In the early 1990s, estrogen receptors were identified throughout the central nervous system, in areas including circumventricular organs that detect humoral signals associated with body fluid challenges, and hypothalamic and hindbrain nuclei involved in behavioral, neuroendocrine, and cardiovascular responses to body fluid challenges. Taken together, the body of evidence amassed from more than 40 years of investigations suggests that the central actions of estrogen influence body fluid regulation and, more specifically, compensatory responses to perturbations of osmotic or volume balance in two interrelated ways. Estrogen alter the detection of signals by the central nervous system and, at the same time, act within central pathways to modify neurotransmitter systems that mediate specific responses to osmotic or volume challenges. This review focuses on the central actions of estrogen in influencing the cardiovascular, neuroendocrine, and behavioral processes that subserve body fluid regulation.

  14. KBERG: KnowledgeBase for Estrogen Responsive Genes

    DEFF Research Database (Denmark)

    Tang, Suisheng; Zhang, Zhuo; Tan, Sin Lam

    2007-01-01

    Estrogen has a profound impact on human physiology affecting transcription of numerous genes. To decipher functional characteristics of estrogen responsive genes, we developed KnowledgeBase for Estrogen Responsive Genes (KBERG). Genes in KBERG were derived from Estrogen Responsive Gene Database...... (ERGDB) and were analyzed from multiple aspects. We explored the possible transcription regulation mechanism by capturing highly conserved promoter motifs across orthologous genes, using promoter regions that cover the range of [-1200, +500] relative to the transcription start sites. The motif detection......-friendly system that provides links to other relevant resources such as ERGDB, UniGene, Entrez Gene, HomoloGene, GO, eVOC and GenBank, and thus offers a platform for functional exploration and potential annotation of genes responsive to estrogen. KBERG database can be accessed at http://research.i2r.a-star.edu.sg/kberg....

  15. Estrogen induces endometrial cancer cell proliferation and invasion by regulating the fat mass and obesity-associated gene via PI3K/AKT and MAPK signaling pathways.

    Science.gov (United States)

    Zhang, Zhenbo; Zhou, Dongmei; Lai, Yunli; Liu, Yongjuan; Tao, Xiang; Wang, Qianqian; Zhao, Guixu; Gu, Hongqin; Liao, Hong; Zhu, Yaping; Xi, Xiaowei; Feng, Youji

    2012-06-01

    Obesity is generally acknowledged as a risk factor for endometrial cancer, as accumulated adipocytes partly contribute to the increased production of estrogen which is involved in dysregulated cell growth and metastasis in early endometrial carcinogenesis. Thus we evaluated in this study expression of the fat mass and obesity-associated (FTO) gene in endometrial tumor tissues and further explored its role in β-estradiol (E2)-induced endometrial cancer cell proliferation and invasion. IHC staining showed that FTO overexpressed in endometrial carcinoma. Additionally, E2-induced FTO via activation of the PI3K/AKT and MPAK signal pathways contributed to enhanced proliferation and invasion. Therefore, this study provides a new insight on the mechanisms of E2-induced proliferation and invasion and the link between obesity and endometrial cancer, implying the possibility of using FTO as a potential therapeutic target for the treatment of endometrial cancer. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  16. Steroid estrogens, conjugated estrogens and estrogenic activity in farm dairy shed effluents

    Energy Technology Data Exchange (ETDEWEB)

    Gadd, Jennifer B., E-mail: j.gadd@niwa.co.n [Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch 8140 (New Zealand); Tremblay, Louis A., E-mail: tremblayl@landcareresearch.co.n [Landcare Research, PO Box 40, Lincoln, 7640 (New Zealand); Northcott, Grant L., E-mail: grant.northcott@plantandfood.co.n [Plant and Food Research, Private Bag 3123, Waikato Mail Centre, Hamilton 3240 (New Zealand)

    2010-03-15

    Agricultural wastes are a source of steroid estrogens and, if present, conjugated estrogens may add to the estrogen load released to soil and aquatic environments. Dairy shed effluent samples were collected from 18 farms for analysis of steroid estrogens by GC-MS, conjugated estrogens by LC-MS-MS, and estrogenic activity by E-screen in vitro bioassay. 17alpha-estradiol was found at highest concentrations (median 730 ng l{sup -1}), followed by estrone (100 ng l{sup -1}) and 17beta-estradiol (24 ng l{sup -1}). Conjugated estrogens (estrone-3-sulfate, 17alpha-estradiol-3-sulfate and 17beta-estradiol-3,17-disulfate) were measured in most samples (12-320 ng l{sup -1}). Median estrogenic activity was 46 ng l{sup -1} 17beta-estradiol equivalents. Conjugated estrogens contributed up to 22% of the total estrogen load from dairy farming, demonstrating their significance. Steroid estrogens dominated overall estrogenic activity measured in the samples. Significantly, 17alpha-estradiol contributed 25% of overall activity, despite potency 2% that of 17beta-estradiol, highlighting the importance in environmental risk assessments of this previously neglected compound. - In rural ecosystems, 17alpha-estradiol and conjugated estrogens are significant sources of environmental estrogens from agricultural wastes.

  17. Estrogen, progesterone, and genistein differentially regulate levels of expression of α-, β-, and γ-epithelial sodium channel (ENaC) and α-sodium potassium pump (Na⁺/K⁺-ATPase) in the uteri of sex steroid-deficient rats.

    Science.gov (United States)

    Chinigarzadeh, Asma; Muniandy, Sekaran; Salleh, Naguib

    2015-10-01

    Estrogen, progesterone, and genistein could induce changes in uterine fluid volume and Na(+) concentration. Progesterone upregulates expression of epithelial sodium channel (ENaC) and Na(+)/K(+)-ATPase which contributed toward these changes. However, effects of estrogen and genistein were unknown. This study therefore investigated changes in expression of these proteins in the uterus under estrogen, progesterone, and genistein influences to further understand mechanisms underlying sex steroids and phytoestrogen effects on uterine fluid Na(+) regulation. In this study, uteri of ovariectomized female rats receiving 7-day treatment with genistein (25, 50, and 100 mg/kg/day), estrogen (0.8 × 10(-4) mg/kg/day), or progesterone (4 mg/kg/day) were harvested, and expression levels of α-, β-, and γ-ENaC proteins and messenger RNAs (mRNAs) and α-Na(+)/K(+)-ATPase protein were determined by Western blotting (proteins) and real-time polymerase chain reaction (mRNA). Meanwhile, distribution of α-, β-, and γ-ENaC and α-Na(+)/K(+)-ATPase proteins in the uterus was identified by immunohistochemistry. Our findings indicated that expression of α-, β-, and γ-ENaC proteins and mRNAs and α-Na(+)/K(+)-ATPase protein were enhanced under progesterone influence. Lower expressions were noted under estrogen and genistein influences compared to progesterone. Under estrogen, progesterone, and genistein influences, α- and β-ENaC were distributed at apical membrane and γ-ENaC was distributed at apical and basolateral membranes of uterine luminal epithelia. Under progesterone influence, α-Na(+)/K(+)-ATPase was highly expressed at basolateral membrane. In conclusion, high expression of α-, β-, and γ-ENaC and α-Na(+)/K(+)-ATPase under progesterone influence would contribute toward increased uterine fluid Na(+) reabsorption, whereas lesser expression of these proteins under estrogen and genistein influences would contribute toward lower reabsorption of uterine fluid Na

  18. Estrogen-dependent changes in estrogen receptor-β mRNA expression in middle-aged female rat brain.

    Science.gov (United States)

    Yamaguchi, Naoko; Yuri, Kazunari

    2014-01-16

    During aging, estrogen production and circulating levels of estrogen are markedly decreased in females. Although several differences exist in the process of reproductive aging between women and female rats, the results of many studies suggest that the female rat, especially the middle-aged or aged ovariectomized female, is an important animal model of hormone loss in women. In target tissues including the brain, the actions of estrogen are mediated mainly via the alpha and beta subtypes of the estrogen receptor (ER-α and ER-β). Estrogen treatment is known to change the expression of ER-α mRNA and protein in specific regions of the brain in middle-aged female rodents. In contrast, we do not know if estrogen regulates the expression of ER-β in the brain at this stage of life. In the present study, we performed in situ hybridization on brain sections of ovariectomized and estrogen-treated middle-aged female rats to reveal the effects of estrogen on the expression of ER-β throughout the brain. Our results showed that estrogen treatment decreased the number of ER-β mRNA-positive cells in the mitral cell and external plexiform layers of the olfactory bulb, central amygdaloid nucleus, medial geniculate nucleus, posterior hypothalamic nucleus, suprachiasmatic nucleus, and reticular part of the substantia nigra. As compared to the results of previous studies of young females, our data revealed that the regions in which expression of ER-β mRNA expression is affected by estrogen differ in middle age. These results suggest that the effects of estrogen on ER-β expression change with age. © 2013 Published by Elsevier B.V.

  19. Skeletal Muscle Estrogen Receptor Activation in Response to Eccentric Exercise Up-Regulates Myogenic-Related Gene Expression Independent of Differing Serum Estradiol Levels Occurring during the Human Menstrual Cycle

    Directory of Open Access Journals (Sweden)

    Mackenzie Haines, Sarah K. McKinley-Barnard, Thomas L. Andre, Josh J. Gann, Paul S. Hwang, Darryn S. Willoughby

    2018-03-01

    Full Text Available This study sought to determine if the differences in serum estradiol we have previously observed to occur during the mid-follicular (MF and mid-luteal (ML phases of the female menstrual cycle could be attributed to estrogen-induced receptor activation and subsequent effects on myogenic-related genes which may otherwise impact muscle regeneration in response to eccentric exercise. Twenty-two physically-active females (20.9 ± 1.4 years, 63.5 ± 9.0 kg, 1.65 ± 0.08 m underwent an eccentric exercise bout of the knee extensors during the MF and ML phases of their 28-day menstrual cycle. Prior to (PRE, at 6 (6HRPOST, and 24 (24HRPOST hours post-exercise for each session, participants had muscle biopsies obtained. Skeletal muscle estradiol and estrogen receptor-α (ER-α content and ER-DNA binding were determined with ELISA. Real-time PCR was used to assess ER-α, Myo-D, and cyclin D1 mRNA expression. Data were analyzed utilizing a 2 x 3 repeated measures univariate analyses of variance (ANOVA for each criterion variable (p ≤ .05. Skeletal muscle estradiol levels were not significantly impacted by either menstrual phase (p > 0.05; however, both ER-α mRNA and protein were significantly increased during MF (p < 0.05. ER-DNA binding and Myo-D mRNA expression increased significantly in both menstrual phases in response to exercise but were not different from one another; however, cyclin D1 mRNA expression was significantly greater during MF. This study demonstrates that skeletal muscle ER-α activation in response to eccentric exercise up-regulates myogenic-related gene expression independent of serum estradiol levels occurring during the human menstrual cycle.

  20. Estrogens increase the expression of fibulin-1, an extracellular matrix protein secreted by human ovarian cancer cells

    NARCIS (Netherlands)

    Clinton, GM; Rougeot, C; Derancourt, J; Roger, P; Defrenne, A; Godyna, S; Argraves, WS; Rochefort, H

    1996-01-01

    Ovarian cancers have a high ability to invade the peritoneal cavity and some are stimulated by estrogens, In an attempt to understand the mode of action of estrogens on these cancer cells and to develop new markers, we have characterized estrogen-regulated proteins, This study,vas aimed at

  1. Channel catfish (Ictalurus punctatus) leukocytes express estrogen receptor isoforms ERα and ERβ2 and are functionally modulated by estrogens

    Science.gov (United States)

    Iwanowicz, Luke R.; Stafford, James L.; Patiño, Reynaldo; Bengten, Eva; Miller, Norman W.; Blazer, Vicki

    2014-01-01

    Estrogens are recognized as modulators of immune responses in mammals and teleosts. While it is known that the effects of estrogens are mediated via leukocyte-specific estrogen receptors (ERs) in humans and mice, leucocyte-specific estrogen receptor expression and the effects of estrogens on this cell population is less explored and poorly understood in teleosts. Here in, we verify that channel catfish (Ictalurus punctaus) leukocytes express ERα and ERβ2. Transcripts of these isoforms were detected in tissue-associated leukocyte populations by PCR, but ERβ2 was rarely detected in PBLs. Expression of these receptors was temporally regulated in PBLs following polyclonal activation by concanavalin A, lipopolysaccharide or alloantigen based on evaluation by quantitative and end-point PCR. Examination of long-term leukocyte cell lines demonstrated that these receptors are differentially expressed depending on leukocyte lineage and phenotype. Expression of ERs was also temporally dynamic in some leukocyte lineages and may reflect stage of cell maturity. Estrogens affect the responsiveness of channel catfish peripheral blood leukocytes (PBLs) to mitogens in vitro. Similarly, bactericidal activity and phorbol 12-myristate 13-acetate induced respiratory burst was modulated by 17β-estradiol. These actions were blocked by the pure ER antagonist ICI 182780 indicating that response is, in part, mediated via ERα. In summary, estrogen receptors are expressed in channel catfish leukocytes and participate in the regulation of the immune response. This is the first time leukocyte lineage expression has been reported in teleost cell lines.

  2. The Role of Estrogens in Control of Energy Balance and Glucose Homeostasis

    Science.gov (United States)

    Clegg, Deborah J.; Hevener, Andrea L.

    2013-01-01

    Estrogens play a fundamental role in the physiology of the reproductive, cardiovascular, skeletal, and central nervous systems. In this report, we review the literature in both rodents and humans on the role of estrogens and their receptors in the control of energy homeostasis and glucose metabolism in health and metabolic diseases. Estrogen actions in hypothalamic nuclei differentially control food intake, energy expenditure, and white adipose tissue distribution. Estrogen actions in skeletal muscle, liver, adipose tissue, and immune cells are involved in insulin sensitivity as well as prevention of lipid accumulation and inflammation. Estrogen actions in pancreatic islet β-cells also regulate insulin secretion, nutrient homeostasis, and survival. Estrogen deficiency promotes metabolic dysfunction predisposing to obesity, the metabolic syndrome, and type 2 diabetes. We also discuss the effect of selective estrogen receptor modulators on metabolic disorders. PMID:23460719

  3. Androgenic and estrogenic regulation of Atrogin-1, MuRF1 and myostatin expression in different muscle types of male mice.

    Science.gov (United States)

    De Naeyer, H; Lamon, S; Russell, A P; Everaert, I; De Spaey, A; Vanheel, B; Taes, Y; Derave, W

    2014-04-01

    The molecular factors targeted by androgens and estrogens on muscle mass are not fully understood. The current study aimed to explore gene and protein expression of Atrogin-1, MuRF1, and myostatin in an androgen deprivation-induced muscle atrophy model. We examined the effects of Orx either with or without testosterone (T) or estradiol (E2) administration on Atrogin-1 gene expression, and MuRF1 and myostatin gene and protein expression. Measurements were made in soleus (SOL), extensor digitorum longus (EDL) and levator ani/bulbocavernosus (LA/BC) of male C57BL/6 mice. Thirty days of Orx resulted in a reduction in weight gain and muscle mass. These effects were prevented by T. In LA/BC, Atrogin-1 and MuRF1 mRNA was increased throughout 30 days of Orx, which was fully reversed by T and partially by E2 administration. In EDL and SOL, a less pronounced upregulation of both genes was only detectable at the early stages of Orx. Myostatin mRNA levels were downregulated in LA/BC and upregulated in EDL following Orx. T, but not E2, reversed these effects. No changes in protein levels of MuRF1 and myostatin were found in EDL at any time point following Orx. The atrophy in SOL and EDL in response to androgen deprivation, and its restoration by T, is accompanied by only minimal changes in atrogenes and myostatin gene expression. The marked differences in muscle atrophy and atrogene and myostatin mRNA between LA/BC and the locomotor muscles suggest that the murine LA/BC is not an optimal model to study Orx-induced muscle atrophy.

  4. High salivary estrogen and risk of developing pregnancy gingivitis.

    Science.gov (United States)

    Gürsoy, Mervi; Gürsoy, Ulvi Kahraman; Sorsa, Timo; Pajukanta, Riitta; Könönen, Eija

    2013-09-01

    Estrogen regulates the cellular functions of several tissues that may disturb the host response against bacteria. The present aim is to evaluate the contribution of estrogen to the severity of gingival inflammation during pregnancy. Salivary estrogen levels from 30 pregnant and 24 non-pregnant females were related to their periodontal health parameters, including visible plaque index (VPI) and bleeding on probing (BOP) from six sites per tooth. The pregnant group was examined three times during pregnancy and twice during postpartum, and the non-pregnant group was examined three times, once per subsequent month. Salivary estrogen levels increased significantly during the second (P high estrogen and high VPI levels had the highest frequency of pregnancy gingivitis. During the second and third trimesters, simultaneously enhanced estrogen levels and VPI scores brought an additional risk of developing gingivitis compared with a high VPI score alone. The present findings suggest that, during pregnancy, the estrogen level determines the magnitude of gingival inflammation developed against microbial plaque at the gingival margin.

  5. Estrogens mediate cardiac hypertrophy in a stimulus-dependent manner.

    Science.gov (United States)

    Haines, Christopher D; Harvey, Pamela A; Leinwand, Leslie A

    2012-09-01

    The incidence of cardiac hypertrophy, an established risk factor for heart failure, is generally lower in women compared with men, but this advantage is lost after menopause. Although it is widely believed that estrogens are cardioprotective, there are contradictory reports, including increased cardiac events in postmenopausal women receiving estrogens and enhanced cardiac protection from ischemic injury in female mice without estrogens. We exposed aromatase knockout (ArKO) mice, which produce no estrogens, to both pathologic and physiologic stimuli. This model allows an investigation into the effects of a complete, chronic lack of estrogens in male and female hearts. At baseline, female ArKO mice had normal-sized hearts but decreased cardiac function and paradoxically increased phosphorylation of many progrowth kinases. When challenged with the pathological stimulus, isoproterenol, ArKO females developed 2-fold more hypertrophy than wild-type females. In contrast, exercise-induced physiological hypertrophy was unaffected by the absence of estrogens in either sex, although running performance was blunted in ArKO females. Thus, loss of estrogen signaling in females, but not males, impairs cardiac function and sensitizes the heart to pathological insults through up-regulation of multiple hypertrophic pathways. These findings provide insight into the apparent loss of cardioprotection after menopause and suggest that caution is warranted in the long-term use of aromatase inhibitors in the setting of breast cancer prevention.

  6. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation.

    Science.gov (United States)

    Ghoussaini, Maya; French, Juliet D; Michailidou, Kyriaki; Nord, Silje; Beesley, Jonathan; Canisus, Sander; Hillman, Kristine M; Kaufmann, Susanne; Sivakumaran, Haran; Moradi Marjaneh, Mahdi; Lee, Jason S; Dennis, Joe; Bolla, Manjeet K; Wang, Qin; Dicks, Ed; Milne, Roger L; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A; Beckmann, Matthias W; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Alonso, M Rosario; Pita, Guillermo; Neuhausen, Susan L; Anton-Culver, Hoda; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Tessier, Daniel C; Vincent, Daniel; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Ito, Hidemi; Dörk, Thilo; Bogdanova, Natalia V; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Wu, Anna H; Van Den Berg, David; Lambrechts, Diether; Floris, Giuseppe; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Monica; Couch, Fergus J; Hallberg, Emily; Giles, Graham G; Haiman, Christopher A; Le Marchand, Loic; Goldberg, Mark S; Teo, Soo H; Yip, Cheng Har; Borresen-Dale, Anne-Lise; Zheng, Wei; Cai, Qiuyin; Winqvist, Robert; Pylkäs, Katri; Andrulis, Irene L; Devilee, Peter; Tollenaar, Rob A E M; García-Closas, Montserrat; Figueroa, Jonine; Hall, Per; Czene, Kamila; Brand, Judith S; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J; Koppert, Linetta B; Li, Jingmei; Shu, Xiao-Ou; Zheng, Ying; Cox, Angela; Cross, Simon S; Shah, Mitul; Rhenius, Valerie; Choi, Ji-Yeob; Kang, Daehee; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Luccarini, Craig; Conroy, Don M; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Olswold, Curtis; Slager, Susan; Shen, Chen-Yang; Hou, Ming-Feng; Swerdlow, Anthony; Schoemaker, Minouk J; Simard, Jacques; Pharoah, Paul D P; Kristensen, Vessela; Chenevix-Trench, Georgia; Easton, Douglas F; Dunning, Alison M; Edwards, Stacey L

    2016-10-06

    Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  7. Estrogens and male reproduction: a new concept

    Directory of Open Access Journals (Sweden)

    S. Carreau

    2007-06-01

    Full Text Available The mammalian testis serves two main functions: production of spermatozoa and synthesis of steroids; among them estrogens are the end products obtained from the irreversible transformation of androgens by a microsomal enzymatic complex named aromatase. The aromatase is encoded by a single gene (cyp19 in humans which contains 18 exons, 9 of them being translated. In rats, the aromatase activity is mainly located in Sertoli cells of immature rats and then in Leydig cells of adult rats. We have demonstrated that germ cells represent an important source of estrogens: the amount of P450arom transcript is 3-fold higher in pachytene spermatocytes compared to gonocytes or round spermatids; conversely, aromatase activity is more intense in haploid cells. Male germ cells of mice, bank voles, bears, and monkeys express aromatase. In humans, we have shown the presence of a biologically active aromatase and of estrogen receptors (alpha and ß in ejaculated spermatozoa and in immature germ cells in addition to Leydig cells. Moreover, we have demonstrated that the amount of P450arom transcripts is 30% lower in immotile than in motile spermatozoa. Alterations of spermatogenesis in terms of number and motility of spermatozoa have been described in men genetically deficient in aromatase. These last observations, together with our data showing a significant decrease of aromatase in immotile spermatozoa, suggest that aromatase could be involved in the acquisition of sperm motility. Thus, taking into account the widespread localization of aromatase and estrogen receptors in testicular cells, it is obvious that, besides gonadotrophins and androgens, estrogens produced locally should be considered to be physiologically relevant hormones involved in the regulation of spermatogenesis and spermiogenesis.

  8. Functional adaptation in female rats: the role of estrogen signaling.

    Directory of Open Access Journals (Sweden)

    Susannah J Sample

    Full Text Available Sex steroids have direct effects on the skeleton. Estrogen acts on the skeleton via the classical genomic estrogen receptors alpha and beta (ERα and ERβ, a membrane ER, and the non-genomic G-protein coupled estrogen receptor (GPER. GPER is distributed throughout the nervous system, but little is known about its effects on bone. In male rats, adaptation to loading is neuronally regulated, but this has not been studied in females.We used the rat ulna end-loading model to induce an adaptive modeling response in ovariectomized (OVX female Sprague-Dawley rats. Rats were treated with a placebo, estrogen (17β-estradiol, or G-1, a GPER-specific agonist. Fourteen days after OVX, rats underwent unilateral cyclic loading of the right ulna; half of the rats in each group had brachial plexus anesthesia (BPA of the loaded limb before loading. Ten days after loading, serum estrogen concentrations, dorsal root ganglion (DRG gene expression of ERα, ERβ, GPER, CGRPα, TRPV1, TRPV4 and TRPA1, and load-induced skeletal responses were quantified. We hypothesized that estrogen and G-1 treatment would influence skeletal responses to cyclic loading through a neuronal mechanism. We found that estrogen suppresses periosteal bone formation in female rats. This physiological effect is not GPER-mediated. We also found that absolute mechanosensitivity in female rats was decreased, when compared with male rats. Blocking of adaptive bone formation by BPA in Placebo OVX females was reduced.Estrogen acts to decrease periosteal bone formation in female rats in vivo. This effect is not GPER-mediated. Gender differences in absolute bone mechanosensitivity exist in young Sprague-Dawley rats with reduced mechanosensitivity in females, although underlying bone formation rate associated with growth likely influences this observation. In contrast to female and male rats, central neuronal signals had a diminished effect on adaptive bone formation in estrogen-deficient female rats.

  9. Estrogen modulates mesenchyme-epidermis interactions in the adult nipple.

    Science.gov (United States)

    Wu, Hsing-Jung; Oh, Ji Won; Spandau, Dan F; Tholpady, Sunil; Diaz, Jesus; Schroeder, Laura J; Offutt, Carlos D; Glick, Adam B; Plikus, Maksim V; Koyama, Sachiko; Foley, John

    2017-04-15

    Maintenance of specialized epidermis requires signals from the underlying mesenchyme; however, the specific pathways involved remain to be identified. By recombining cells from the ventral skin of the K14-PTHrP transgenic mice [which overexpress parathyroid hormone-related protein (PTHrP) in their developing epidermis and mammary glands] with those from wild type, we show that transgenic stroma is sufficient to reprogram wild-type keratinocytes into nipple-like epidermis. To identify candidate nipple-specific signaling factors, we compared gene expression signatures of sorted Pdgfrα-positive ventral K14-PTHrP and wild-type fibroblasts, identifying differentially expressed transcripts that are involved in WNT, HGF, TGFβ, IGF, BMP, FGF and estrogen signaling. Considering that some of the growth factor pathways are targets for estrogen regulation, we examined the upstream role of this hormone in maintaining the nipple. Ablation of estrogen signaling through ovariectomy produced nipples with abnormally thin epidermis, and we identified TGFβ as a negatively regulated target of estrogen signaling. Estrogen treatment represses Tgfβ1 at the transcript and protein levels in K14-PTHrP fibroblasts in vitro, while ovariectomy increases Tgfb1 levels in K14-PTHrP ventral skin. Moreover, ectopic delivery of Tgfβ1 protein into nipple connective tissue reduced epidermal proliferation. Taken together, these results show that specialized nipple epidermis is maintained by estrogen-induced repression of TGFβ signaling in the local fibroblasts. © 2017. Published by The Company of Biologists Ltd.

  10. Exercise, Eating, Estrogen, and Osteoporosis.

    Science.gov (United States)

    Brown, Jim

    1986-01-01

    Osteoporosis affects millions of people, especially women. Three methods for preventing or managing osteoporosis are recommended: (1) exercise; (2) increased calcium intake; and (3) estrogen replacement therapy. (CB)

  11. Estrogen and Progestin (Hormone Replacement Therapy)

    Science.gov (United States)

    ... Estrogen and progestin are two female sex hormones. Hormone replacement therapy works by replacing estrogen hormone that is no ... menopausal women. Progestin is added to estrogen in hormone replacement therapy to reduce the risk of uterine cancer in ...

  12. Identification of estrogen target genes during zebrafish embryonic development through transcriptomic analysis.

    Directory of Open Access Journals (Sweden)

    Ruixin Hao

    Full Text Available Estrogen signaling is important for vertebrate embryonic development. Here we have used zebrafish (Danio rerio as a vertebrate model to analyze estrogen signaling during development. Zebrafish embryos were exposed to 1 µM 17β-estradiol (E2 or vehicle from 3 hours to 4 days post fertilization (dpf, harvested at 1, 2, 3 and 4 dpf, and subjected to RNA extraction for transcriptome analysis using microarrays. Differentially expressed genes by E2-treatment were analyzed with hierarchical clustering followed by biological process and tissue enrichment analysis. Markedly distinct sets of genes were up and down-regulated by E2 at the four different time points. Among these genes, only the well-known estrogenic marker vtg1 was co-regulated at all time points. Despite this, the biological functional categories targeted by E2 were relatively similar throughout zebrafish development. According to knowledge-based tissue enrichment, estrogen responsive genes were clustered mainly in the liver, pancreas and brain. This was in line with the developmental dynamics of estrogen-target tissues that were visualized using transgenic zebrafish containing estrogen responsive elements driving the expression of GFP (Tg(5xERE:GFP. Finally, the identified embryonic estrogen-responsive genes were compared to already published estrogen-responsive genes identified in male adult zebrafish (Gene Expression Omnibus database. The expressions of a few genes were co-regulated by E2 in both embryonic and adult zebrafish. These could potentially be used as estrogenic biomarkers for exposure to estrogens or estrogenic endocrine disruptors in zebrafish. In conclusion, our data suggests that estrogen effects on early embryonic zebrafish development are stage- and tissue- specific.

  13. Estrogen signalling and the DNA damage response in hormone dependent breast cancers

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    C Elizabeth Caldon

    2014-05-01

    Full Text Available Estrogen is necessary for the normal growth and development of breast tissue, but high levels of estrogen are a major risk factor for breast cancer. One mechanism by which estrogen could contribute to breast cancer is via the induction of DNA damage. This perspective discusses the mechanisms by which estrogen alters the DNA damage response (DDR and DNA repair through the regulation of key effector proteins including ATM, ATR, CHK1, BRCA1 and p53 and the feedback on estrogen receptor signalling from these proteins. We put forward the hypothesis that estrogen receptor signalling converges to suppress effective DNA repair and apoptosis in favour of proliferation. This is important in hormone-dependent breast cancer as it will affect processing of estrogen-induced DNA damage, as well as other genotoxic insults. DDR and DNA repair proteins are frequently mutated or altered in estrogen responsive breast cancer which will further change the processing of DNA damage. Finally the action of estrogen signalling on DNA damage is also relevant to the therapeutic setting as the suppression of a DNA damage response by estrogen has the potential to alter the response of cancers to anti-hormone treatment or chemotherapy that induces DNA damage.

  14. Plasticity of Signaling by Spinal Estrogen Receptor α, κ-Opioid Receptor, and Metabotropic Glutamate Receptors over the Rat Reproductive Cycle Regulates Spinal Endomorphin 2 Antinociception: Relevance of Endogenous-Biased Agonism.

    Science.gov (United States)

    Liu, Nai-Jiang; Murugaiyan, Vijaya; Storman, Emiliya M; Schnell, Stephen A; Kumar, Arjun; Wessendorf, Martin W; Gintzler, Alan R

    2017-11-15

    We previously showed that intrathecal application of endomorphin 2 [EM2; the highly specific endogenous μ-opioid receptor (MOR) ligand] induces antinociception that varies with stage of the rat estrous cycle: minimal during diestrus and prominent during proestrus. Earlier studies, however, did not identify proestrus-activated signaling strategies that enable spinal EM2 antinociception. We now report that in female rats, increased spinal dynorphin release and κ-opioid receptor (KOR) signaling, as well as the emergence of glutamate-activated metabotropic glutamate receptor 1 (mGluR1) signaling, are critical to the transition from an EM2 nonresponsive state (during diestrus) to an analgesically responsive state (during proestrus). Differential signaling by mGluR1, depending on its activation by membrane estrogen receptor α (mERα; during diestrus) versus glutamate (during proestrus), concomitant with the ebb and flow of spinal dynorphin/KOR signaling, functions as a switch, preventing or promoting, respectively, spinal EM2 antinociception. Importantly, EM2 and glutamate-containing varicosities appose spinal neurons that express MOR along with mGluRs and mERα, suggesting that signaling mechanisms regulating analgesic effectiveness of intrathecally applied EM2 also pertain to endogenous EM2. Regulation of spinal EM2 antinociception by both the nature of the endogenous mGluR1 activator (i.e., endogenous biased agonism at mGluR1) and changes in spinal dynorphin/KOR signaling represent a novel mechanism for modulating analgesic responsiveness to endogenous EM2 (and perhaps other opioids). This points the way for developing noncanonical pharmacological approaches to pain management by harnessing endogenous opioids for pain relief.SIGNIFICANCE STATEMENT The current prescription opioid abuse epidemic underscores the urgency to develop alternative pharmacotherapies for managing pain. We find that the magnitude of spinal endomorphin 2 (EM2) antinociception not only varies

  15. Identification and Biological Evaluation of Coactivator Binding Inhibitors for the Estrogen Receptor

    Science.gov (United States)

    Gunther, Jillian Rebecca

    2009-01-01

    The physiologic effects of estrogen action through the estrogen receptor (ER) are widespread, as this hormone exerts actions in both reproductive (e.g., uterus) and non-reproductive (e.g., bone, brain) tissues in both men and women. As such, the regulation of the activity of this ligand-activated transcription factor is highly relevant to the…

  16. Expression of aromatase and estrogen receptor alpha in chondrosarcoma, but no beneficial effect of inhibiting estrogen signaling both in vitro and in vivo

    NARCIS (Netherlands)

    Meijer, D.; Gelderblom, Hans; Karperien, Hermanus Bernardus Johannes; Cleton-Jansen, A.M.; Hogendoorn, C.W.; Bovee, J.

    2011-01-01

    Background: Chondrosarcomas are malignant cartilage-forming tumors which are highly resistant to conventional chemotherapy and radiotherapy. Estrogen signaling is known to play an important role in proliferation and differentiation of chondrocytes and in growth plate regulation at puberty. Our

  17. Identification of estrogen responsive genes using esophageal squamous cell carcinoma (ESCC as a model

    Directory of Open Access Journals (Sweden)

    Essack Magbubah

    2012-10-01

    Full Text Available Abstract Background Estrogen therapy has positively impact the treatment of several cancers, such as prostate, lung and breast cancers. Moreover, several groups have reported the importance of estrogen induced gene regulation in esophageal cancer (EC. This suggests that there could be a potential for estrogen therapy for EC. The efficient design of estrogen therapies requires as complete as possible list of genes responsive to estrogen. Our study develops a systems biology methodology using esophageal squamous cell carcinoma (ESCC as a model to identify estrogen responsive genes. These genes, on the other hand, could be affected by estrogen therapy in ESCC. Results Based on different sources of information we identified 418 genes implicated in ESCC. Putative estrogen responsive elements (EREs mapped to the promoter region of the ESCC genes were used to initially identify candidate estrogen responsive genes. EREs mapped to the promoter sequence of 30.62% (128/418 of ESCC genes of which 43.75% (56/128 are known to be estrogen responsive, while 56.25% (72/128 are new candidate estrogen responsive genes. EREs did not map to 290 ESCC genes. Of these 290 genes, 50.34% (146/290 are known to be estrogen responsive. By analyzing transcription factor binding sites (TFBSs in the promoters of the 202 (56+146 known estrogen responsive ESCC genes under study, we found that their regulatory potential may be characterized by 44 significantly over-represented co-localized TFBSs (cTFBSs. We were able to map these cTFBSs to promoters of 32 of the 72 new candidate estrogen responsive ESCC genes, thereby increasing confidence that these 32 ESCC genes are responsive to estrogen since their promoters contain both: a/mapped EREs, and b/at least four cTFBSs characteristic of ESCC genes that are responsive to estrogen. Recent publications confirm that 47% (15/32 of these 32 predicted genes are indeed responsive to estrogen. Conclusion To the best of our knowledge our

  18. Identification of estrogen responsive genes using esophageal squamous cell carcinoma (ESCC) as a model

    KAUST Repository

    Essack, Magbubah

    2012-10-26

    Background: Estrogen therapy has positively impact the treatment of several cancers, such as prostate, lung and breast cancers. Moreover, several groups have reported the importance of estrogen induced gene regulation in esophageal cancer (EC). This suggests that there could be a potential for estrogen therapy for EC. The efficient design of estrogen therapies requires as complete as possible list of genes responsive to estrogen. Our study develops a systems biology methodology using esophageal squamous cell carcinoma (ESCC) as a model to identify estrogen responsive genes. These genes, on the other hand, could be affected by estrogen therapy in ESCC.Results: Based on different sources of information we identified 418 genes implicated in ESCC. Putative estrogen responsive elements (EREs) mapped to the promoter region of the ESCC genes were used to initially identify candidate estrogen responsive genes. EREs mapped to the promoter sequence of 30.62% (128/418) of ESCC genes of which 43.75% (56/128) are known to be estrogen responsive, while 56.25% (72/128) are new candidate estrogen responsive genes. EREs did not map to 290 ESCC genes. Of these 290 genes, 50.34% (146/290) are known to be estrogen responsive. By analyzing transcription factor binding sites (TFBSs) in the promoters of the 202 (56+146) known estrogen responsive ESCC genes under study, we found that their regulatory potential may be characterized by 44 significantly over-represented co-localized TFBSs (cTFBSs). We were able to map these cTFBSs to promoters of 32 of the 72 new candidate estrogen responsive ESCC genes, thereby increasing confidence that these 32 ESCC genes are responsive to estrogen since their promoters contain both: a/mapped EREs, and b/at least four cTFBSs characteristic of ESCC genes that are responsive to estrogen. Recent publications confirm that 47% (15/32) of these 32 predicted genes are indeed responsive to estrogen.Conclusion: To the best of our knowledge our study is the first

  19. Estradiol up-regulates L-type Ca2+channels via membrane-bound estrogen receptor / Phosphoinositide-3kinase / Akt / cAMP response element-binding protein signaling pathway.

    Science.gov (United States)

    Yang, Xiaoyan; Mao, Xiaofang; Xu, Gao; Xing, Shasha; Chattopadhyay, Ansuman; Jin, Si; Salama, Guy

    2018-01-09

    In long QT type-2 (LQT2), women are more prone to lethal arrhythmias called Torsade de Pointes (TdP) than men. We previously reported that 17-β-estradiol (E2) upregulates L-type Ca 2+ -channels and current (I Ca,L ) (∼30%) in rabbit ventricular myocytes by a classical genomic-mechanism mediated by estrogen-receptor-α (ER)α. In LQT2 ( I Kr -blockade or bradycardia), the higher Ca 2+ influx via I Ca,L , causes Ca 2+ -overload, spontaneous sarcoplasmic reticulum Ca 2+ -release, and re-activation of I Ca,L that trigger early afterdepolarizations (EADs) and TdP. The molecular mechanisms whereby E2 upregulates I Ca,L are poorly understood and are now investigated. H9C2 and rat myocytes were incubated with E2, ±ER antagonist, or inhibitors of downstream transcription factors 24 hours, followed by Western blots of Cav1.2α1C and voltage-clamp measurements of I Ca,L . Incubation of H9C2 cells with E2 (10∼100 nM) increased I Ca,L density and Cav1.2α1C expression which were suppressed by the ER-antagonist ICI-182,780 (1μM). Enhanced I Ca,L and Cav1.2α1C expression by E2 was suppressed by inhibitors of Pi3K (LY294002=30μM; pL via plasma-membrane ER, and activating a Pi3K, Akt and CREB signaling. The promoter regions of CACNA1C gene (human-rabbit-rat) contain adjacent/overlapping binding-sites for p-CREB and ERα which suggest a synergistic regulation by these pathways. Copyright © 2018. Published by Elsevier Inc.

  20. Arctigenin, a dietary phytoestrogen, induces apoptosis of estrogen receptor-negative breast cancer cells through the ROS/p38 MAPK pathway and epigenetic regulation.

    Science.gov (United States)

    Hsieh, Chia-Jung; Kuo, Po-Lin; Hsu, Ying-Chan; Huang, Ya-Fang; Tsai, Eing-Mei; Hsu, Ya-Ling

    2014-02-01

    This study investigates the anticancer effect of arctigenin (ATG), a natural lignan product of Arctium lappa L., in human breast cancer MDA-MB-231 cells. Results indicate that ATG inhibits MDA-MB-231 cell growth by inducing apoptosis in vitro and in vivo. ATG triggers the mitochondrial caspase-independent pathways, as indicated by changes in Bax/Bcl-2 ratio, resulting in AIF and EndoG nuclear translocation. ATG increased cellular reactive oxygen species (ROS) production by increasing p22(phox)/NADPH oxidase 1 interaction and decreasing glutathione level. ATG clearly increases the activation of p38 MAPK, but not JNK and ERK1/2. Antioxidant EUK-8, a synthetic catalytic superoxide and hydrogen peroxide scavenger, significantly decreases ATG-mediated p38 activation and apoptosis. Blocking p38 with a specific inhibitor suppresses ATG-mediated Bcl-2 downregulation and apoptosis. Moreover, ATG activates ATF-2, a transcription factor activated by p38, and then upregulates histone H3K9 trimethylation in the Bcl-2 gene promoter region, resulting in Bcl-2 downregulation. Taken together, the results demonstrate that ATG induces apoptosis of MDA-MB-231 cells via the ROS/p38 MAPK pathway and epigenetic regulation of Bcl-2 by upregulation of histone H3K9 trimethylation. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

  1. Estrogen mediated expression of nucleophosmin 1 in human endometrial carcinoma clinical stages through estrogen receptor-α signaling.

    Science.gov (United States)

    Zhou, Yunxiao; Shen, Jie; Xia, Liqun; Wang, Yanli

    2014-01-01

    Endometrial carcinoma is one of the most common gynecologic malignancies. Estrogen plays a critical role in its pathogenesis, but the underlying mechanism is not clear. Nucleophosmin 1 (NPM1), a multifunctional protein involved in many cellular activities, has been implicated in the tumorigenesis processes. However, the role of NPM1 in endometrial carcinogenesis remains to be elucidated. The present study was aimed to elucidate the role of NPM1 in different clinical stages of human endometrial carcinoma and the underlying mechanism of NPM1 action. The distribution and expression of NPM1 in normal endometrium, FIGO stages I to IV endometrial carcinoma tissues was analyzed using immunohistochemistry, RT-qPCR and Western blotting. The association between NPM1 expression and estrogen and estrogen receptor signaling was investigated in primary-cultured FIGO stage I endometrial adenocarcinoma cells. A strong positive correlation between NPM1 level and the clinical stage and histological grade of endometrial carcinomas was observed. Expression of NPM1 was up-regulated by estrogen in primary-cultured human endometrial adenocarcinoma cells. Furthermore, estrogen increased NPM1 level via estrogen receptor-α (ERα) signaling, nor estrogen receptor-β signaling. Expression of NPM1 was gradually increased with the increase of clinical stages of endometrial carcinomas. Overexpression of NPM1 may play a role in the effects of estrogen on the malignant progression of endometrioid adenocarcinoma via ERα signaling. These findings may extend our understanding of the oncogenesis of steroid hormone-related cancers and have significance for the diagnosis and treatment of this carcinoma.

  2. Estrogen and gastrointestinal malignancy.

    LENUS (Irish Health Repository)

    Hogan, A M

    2012-02-01

    The concept that E2 exerts an effect on the gastrointestinal tract is not new and its actions on intestinal mucosa have been investigated for at least three decades. An attempt to consolidate results of these investigations generates more questions than answers, thus suggesting that many unexplored avenues remain and that the full capabilities of this steroid hormone are far from understood. Evidence of its role in esophageal, gastric and gallbladder cancers is confusing and often equivocal. The most compelling evidence regards the protective role conferred by estrogen (or perhaps ERbeta) against the development and proliferation of colon cancer. Not only has the effect been described but also many mechanisms of action have been explored. It is likely that, along with surgery, chemotherapy and radiotherapy, hormonal manipulation will play an integral role in colon cancer management in the very near future.

  3. Effects of Estrogens on Adipokines and Glucose Homeostasis in Female Aromatase Knockout Mice.

    Directory of Open Access Journals (Sweden)

    Michelle L Van Sinderen

    Full Text Available The maintenance of glucose homeostasis within the body is crucial for constant and precise performance of energy balance and is sustained by a number of peripheral organs. Estrogens are known to play a role in the maintenance of glucose homeostasis. Aromatase knockout (ArKO mice are estrogen-deficient and display symptoms of dysregulated glucose metabolism. We aim to investigate the effects of estrogen ablation and exogenous estrogen administration on glucose homeostasis regulation. Six month-old female wildtype, ArKO, and 17β-estradiol (E2 treated ArKO mice were subjected to whole body tolerance tests, serum examination of estrogen, glucose and insulin, ex-vivo muscle glucose uptake, and insulin signaling pathway analyses. Female ArKO mice display increased body weight, gonadal (omental adiposity, hyperinsulinemia, and liver triglycerides, which were ameliorated upon estrogen treatment. Tolerance tests revealed that estrogen-deficient ArKO mice were pyruvate intolerant hence reflecting dysregulated hepatic gluconeogenesis. Analyses of skeletal muscle, liver, and adipose tissues supported a hepatic-based glucose dysregulation, with a down-regulation of Akt phosphorylation (a key insulin signaling pathway molecule in the ArKO liver, which was improved with E2 treatment. Concurrently, estrogen treatment lowered ArKO serum leptin and adiponectin levels and increased inflammatory adipokines such as tumour necrosis factor alpha (TNFα and interleukin 6 (IL6. Furthermore, estrogen deficiency resulted in the infiltration of CD45 macrophages into gonadal adipose tissues, which cannot be reversed by E2 treatment. This study describes the effects of estrogens on glucose homeostasis in female ArKO mice and highlights a primary phenotype of hepatic glucose dysregulation and a parallel estrogen modified adipokine profile.

  4. Role of mitochondrial oxidative stress to explain the different longevity between genders: protective effect of estrogens.

    Science.gov (United States)

    Viña, J; Sastre, J; Pallardó, F V; Gambini, J; Borrás, C

    2006-12-01

    Females live longer than males. Work from our laboratory has shown that this may be due to the up-regulation of longevity-associated genes by estrogens. Estrogens bind to the estrogen receptors and subsequently activate the mitogen activated protein kinase and nuclear factor kappa B signalling pathways, resulting in an up-regulation of antioxidant enzymes. Estrogen administration, however, has serious undesirable effects and of course, cannot be administered to males because of its powerful feminizing effects. Thus, we tested the effect of genistein, a phytoestrogen of high nutritional importance whose structure is similar to estradiol, on the regulation of the expression of antioxidant, longevity-related genes and consequently on oxidant levels in mammary gland tumour cells in culture. Phytoestrogens mimic the protective effect of oestradiol using the same signalling pathway. The critical importance of up-regulating antioxidant genes, by hormonal and dietary manipulations, to increase longevity is discussed.

  5. The Influence of Estrogens on the Biological and Therapeutic Actions of Growth Hormone in the Liver

    Directory of Open Access Journals (Sweden)

    Leandro Fernández-Pérez

    2012-07-01

    Full Text Available GH is main regulator of body growth and composition, somatic development, intermediate metabolism and gender-dependent dimorphism in mammals. The liver is a direct target of estrogens because it expresses estrogen receptors which are connected with development, lipid metabolism and insulin sensitivity, hepatic carcinogenesis, protection from drug-induced toxicity and fertility. In addition, estrogens can modulate GH actions in liver by acting centrally, regulating pituitary GH secretion, and, peripherally, by modulating GHR-JAK2-STAT5 signalling pathway. Therefore, the interactions of estrogens with GH actions in liver are biologically and clinically relevant because disruption of GH signaling may cause alterations of its endocrine, metabolic, and gender differentiated functions and it could be linked to dramatic impact in liver physiology during development as well as in adulthood. Finally, the interplay of estrogens with GH is relevant because physiological roles these hormones have in human, and the widespread exposition of estrogen or estrogen-related compounds in human. This review highlights the importance of these hormones in liver physiology as well as how estrogens modulate GH actions in liver which will help to improve the clinical use of these hormones.

  6. Estrogen deficiency attenuates fluid flow-induced [Ca2+]i oscillations and mechanoresponsiveness of MLO-Y4 osteocytes.

    Science.gov (United States)

    Deepak, Vishwa; Kayastha, Pushpalata; McNamara, Laoise M

    2017-07-01

    It has been proposed that estrogen regulates the mechanosensitivity of osteocytes; however, the effects of estrogen deficiency that arises during postmenopausal osteoporosis on mechanical stimulation-induced calcium signaling in osteocytes remain elusive. Here, we pretreated MLO-Y4 osteocytes with 10 nM E2 for 2, 3 and 5 d, then simulated postmenopausal conditions either by estrogen withdrawal (EW) from culture medium, or by inhibiting the estrogen receptor by using fulvestrant and estrogen (FE; ICI 182,780) in vitro We investigated [Ca2+]i oscillations and mechanobiologic responses of osteocytes (EW and FE) that were exposed to oscillatory fluid flow (OFF; 1 Pa, 0.5 Hz). We demonstrated that estrogen treatment enhanced OFF-induced [Ca2+]i oscillations and that this effect was abrogated both by FE and EW. Moreover, osteocytes in both estrogen-depleted groups (EW and FE) had reduced levels of NO and prostaglandin E2 release, down-regulated dentin matrix protein-1, sclerostin, osteopontin, osteocalcin, and alkaline phosphatase mRNA expression, and reduced F-actin fiber formation after OFF stimulation compared with estrogen-treated cells. We propose a link between estrogen deficiency and alterations in [Ca2+]i-mediated mechanosensitivity of osteocytes, which ultimately alter osteocyte function and differentiation.-Deepak, V., Kayastha, P., McNamara, L. M. Estrogen deficiency attenuates fluid flow-induced [Ca2+]i oscillations and mechanoresponsiveness of MLO-Y4 osteocytes. © FASEB.

  7. Estrogen Regulation of Messenger RNA Stability

    Science.gov (United States)

    1990-08-17

    H f / Slobin, L.I. and Jordan, P. (1984). "Translational repression of mRNA for eucaryotic elogation factors in Friend erythroleukemia cells ...101 19. In vitro Cell -Free Assay Conditions for Studying mRNA Turnover and Schematic of Characterization of Nuclease- Activity 106 20...hours for more stable species. The average half-time of turnover for mRNA in eukaryotic cells is 10-20 hours. This appears to be a weighted average of

  8. Potential mechanisms underlying estrogen-induced expression of the molluscan estrogen receptor (ER) gene

    Energy Technology Data Exchange (ETDEWEB)

    Tran, Thi Kim Anh [School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308 (Australia); Department of Agriculture, Forestry and Fisheries, Vinh University, 182 Le Duan St., Vinh City, Nghe An (Viet Nam); MacFarlane, Geoff R. [School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308 (Australia); Kong, Richard Yuen Chong [Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong Special Administrative Region (China); O’Connor, Wayne A. [New South Wales Department of Primary Industries, Port Stephens Fisheries Institute, Taylors Beach, NSW 2316 (Australia); Yu, Richard Man Kit, E-mail: Richard.Yu@newcastle.edu.au [School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308 (Australia)

    2016-10-15

    Highlights: • This is the first report on the putative promoter sequence of a molluscan ER gene. • The gene promoter contains putative binding sites for direct and indirect interaction with ER. • E2 upregulates ER gene expression in the ovary in vitro and in vivo. • E2-induced gene expression may require a novel ligand-dependent receptor. • The ER proximal promoter is hypomethylated regardless of gene expression levels. - Abstract: In vertebrates, estrogens and estrogen mimicking chemicals modulate gene expression mainly through a genomic pathway mediated by the estrogen receptors (ERs). Although the existence of an ER orthologue in the mollusc genome has been known for some time, its role in estrogen signalling has yet to be deciphered. This is largely due to its constitutive (ligand-independent) activation and a limited mechanistic understanding of its regulation. To fill this knowledge gap, we cloned and characterised an ER cDNA (sgER) and the 5′-flanking region of the gene from the Sydney rock oyster Saccostrea glomerata. The sgER cDNA is predicted to encode a 477-amino acid protein that contains a DNA-binding domain (DBD) and a ligand-binding domain (LBD) typically conserved among both vertebrate and invertebrate ERs. A comparison of the sgER LBD sequence with those of other ligand-dependent ERs revealed that the sgER LBD is variable at several conserved residues known to be critical for ligand binding and receptor activation. Ligand binding assays using fluorescent-labelled E2 and purified sgER protein confirmed that sgER is devoid of estrogen binding. In silico analysis of the sgER 5′-flanking sequence indicated the presence of three putative estrogen responsive element (ERE) half-sites and several putative sites for ER-interacting transcription factors, suggesting that the sgER promoter may be autoregulated by its own gene product. sgER mRNA is ubiquitously expressed in adult oyster tissues, with the highest expression found in the ovary

  9. DNA stabilization by the upregulation of estrogen signaling in BRCA gene mutation carriers

    Directory of Open Access Journals (Sweden)

    Suba Z

    2015-05-01

    Full Text Available Zsuzsanna Suba Surgical and Molecular Tumor Pathology Centre, National Institute of Oncology, Budapest, Hungary Abstract: Currently available scientific evidence erroneously suggests that mutagenic weakness or loss of the BRCA1/2 genes may liberate the proliferative effects of estrogen signaling, which provokes DNA damage and genomic instability. Conversely, BRCA mutation seems to be an imbalanced defect, crudely inhibiting the upregulation of estrogen receptor expression and liganded transcriptional activity, whereas estrogen receptor-repressor functions become predominant. In BRCA-proficient cases, estrogen signaling orchestrates the activity of cell proliferation and differentiation with high safety, while upregulating the expression and DNA-stabilizing impact of BRCA genes. In turn, BRCA proteins promote estrogen signaling by proper estrogen synthesis via CYP19 gene regulation and by induction of the appropriate expression and transcriptional activity of estrogen receptors. In this exquisitely organized regulatory system, the dysfunction of each player may jeopardize genome stability and lead to severe chronic diseases, such as cancer development. Female organs, such as breast, endometrium, and ovary, exhibiting regular cyclic proliferative activity are particularly vulnerable in case of disturbances in either estrogen signaling or BRCA-mediated DNA repair. BRCA mutation carrier women may apparently be healthy or exhibit clinical signs of deficient estrogen signaling in spite of hyperestrogenism. Even women who enjoy sufficient compensatory DNA-defending activities are at risk of tumor development because many endogenous and environmental factors may jeopardize the mechanisms of extreme compensatory processes. Natural estrogens have numerous benefits in tumor prevention and therapy even in BRCA mutation carriers. There are no toxic effects even in sky-high doses and all physiologic cellular functions are strongly upregulated, while malignant

  10. Estrogen modulates osteogenic activity and estrogen receptor mRNA in mesenchymal stem cells of women.

    Science.gov (United States)

    Chen, F-P; Hu, C-H; Wang, K-C

    2013-02-01

    To determine whether estrogen regulates mesenchymal stem cell (MSC) activity in bone marrow from osteoporotic postmenopausal women. MSCs were collected from bone marrows which were aspirated simultaneously during iliac bone graft procedures in spine fusion surgery in osteoporotic postmenopausal women. We investigated proliferation, differentiation, osteogenic activity, and estrogen receptor (ER) α and β mRNA expression of primary culture MSCs isolated from four osteoporotic postmenopausal women, treated in vitro with or without 17β-estradiol. The expression of alkaline phosphatase (ALP), osteocalcin, interleukin-6, ERα and ERβ mRNA was evaluated. The expression of ALP and osteocalcin mRNA was detected during the cultures of MSCs and was observed to increase up to day 20. As compared with MSCs not treated with estradiol, a significant increase in DNA content, ERα mRNA, and ALP mRNA expression was observed in cultures with estradiol. The mRNA expression of osteocalcin and interleukin-6 was significantly lower in MSCs treated with estradiol than those without estradiol. There was no significant difference in the mRNA expression of ERβ between MSCs cultured with and without estradiol. In the proper environment, MSCs from osteoporotic women can differentiate into osteoblasts and estrogen enhances the osteogenic activity possibly via ERα activity.

  11. Designer interface peptide grafts target estrogen receptor alpha dimerization

    Energy Technology Data Exchange (ETDEWEB)

    Chakraborty, S. [Laboratory of Computational Biophysics & Bioengineering, Department of Physics, Tougaloo College, Tougaloo, MS 39174 (United States); Asare, B.K. [Department of Pharmacology and Toxicology, University of Buffalo, Buffalo, NY 14214 (United States); Biswas, P.K., E-mail: pbiswas@tougaloo.edu [Laboratory of Computational Biophysics & Bioengineering, Department of Physics, Tougaloo College, Tougaloo, MS 39174 (United States); Rajnarayanan, R.V., E-mail: rajendra@buffalo.edu [Department of Pharmacology and Toxicology, University of Buffalo, Buffalo, NY 14214 (United States)

    2016-09-09

    The nuclear transcription factor estrogen receptor alpha (ERα), triggered by its cognate ligand estrogen, regulates a variety of cellular signaling events. ERα is expressed in 70% of breast cancers and is a widely validated target for anti-breast cancer drug discovery. Administration of anti-estrogen to block estrogen receptor activation is still a viable anti-breast cancer treatment option but anti-estrogen resistance has been a significant bottle-neck. Dimerization of estrogen receptor is required for ER activation. Blocking ERα dimerization is therefore a complementary and alternative strategy to combat anti-estrogen resistance. Dimer interface peptide “I-box” derived from ER residues 503–518 specifically blocks ER dimerization. Recently using a comprehensive molecular simulation we studied the interaction dynamics of ERα LBDs in a homo-dimer. Based on this study, we identified three interface recognition peptide motifs LDKITDT (ERα residues 479–485), LQQQHQRLAQ (residues 497–506), and LSHIRHMSNK (residues 511–520) and reported the suitability of using LQQQHQRLAQ (ER 497–506) as a template to design inhibitors of ERα dimerization. Stability and self-aggregation of peptide based therapeutics poses a significant bottle-neck to proceed further. In this study utilizing peptide grafted to preserve their pharmacophoric recognition motif and assessed their stability and potential to block ERα mediated activity in silico and in vitro. The Grafted peptides blocked ERα mediated cell proliferation and viability of breast cancer cells but did not alter their apoptotic fate. We believe the structural clues identified in this study can be used to identify novel peptidometics and small molecules that specifically target ER dimer interface generating a new breed of anti-cancer agents. - Highlights: • Designer peptide grafts retain core molecular recognition motif during MD simulations. • Designer peptide grafts with Poly-ALA helix form stable

  12. Estrogenic plant extracts reverse weight gain and fat accumulation without causing mammary gland or uterine proliferation.

    Directory of Open Access Journals (Sweden)

    Elise F Saunier

    Full Text Available Long-term estrogen deficiency increases the risk of obesity, diabetes and metabolic syndrome in postmenopausal women. Menopausal hormone therapy containing estrogens might prevent these conditions, but its prolonged use increases the risk of breast cancer, as wells as endometrial cancer if used without progestins. Animal studies indicate that beneficial effects of estrogens in adipose tissue and adverse effects on mammary gland and uterus are mediated by estrogen receptor alpha (ERα. One strategy to improve the safety of estrogens to prevent/treat obesity, diabetes and metabolic syndrome is to develop estrogens that act as agonists in adipose tissue, but not in mammary gland and uterus. We considered plant extracts, which have been the source of many pharmaceuticals, as a source of tissue selective estrogens. Extracts from two plants, Glycyrrhiza uralensis (RG and Pueraria montana var. lobata (RP bound to ERα, activated ERα responsive reporters, and reversed weight gain and fat accumulation comparable to estradiol in ovariectomized obese mice maintained on a high fat diet. Unlike estradiol, RG and RP did not induce proliferative effects on mammary gland and uterus. Gene expression profiling demonstrated that RG and RP induced estradiol-like regulation of genes in abdominal fat, but not in mammary gland and uterus. The compounds in extracts from RG and RP might constitute a new class of tissue selective estrogens to reverse weight gain, fat accumulation and metabolic syndrome in postmenopausal women.

  13. Estrogenic plant extracts reverse weight gain and fat accumulation without causing mammary gland or uterine proliferation.

    Science.gov (United States)

    Saunier, Elise F; Vivar, Omar I; Rubenstein, Andrea; Zhao, Xiaoyue; Olshansky, Moshe; Baggett, Scott; Staub, Richard E; Tagliaferri, Mary; Cohen, Isaac; Speed, Terence P; Baxter, John D; Leitman, Dale C

    2011-01-01

    Long-term estrogen deficiency increases the risk of obesity, diabetes and metabolic syndrome in postmenopausal women. Menopausal hormone therapy containing estrogens might prevent these conditions, but its prolonged use increases the risk of breast cancer, as wells as endometrial cancer if used without progestins. Animal studies indicate that beneficial effects of estrogens in adipose tissue and adverse effects on mammary gland and uterus are mediated by estrogen receptor alpha (ERα). One strategy to improve the safety of estrogens to prevent/treat obesity, diabetes and metabolic syndrome is to develop estrogens that act as agonists in adipose tissue, but not in mammary gland and uterus. We considered plant extracts, which have been the source of many pharmaceuticals, as a source of tissue selective estrogens. Extracts from two plants, Glycyrrhiza uralensis (RG) and Pueraria montana var. lobata (RP) bound to ERα, activated ERα responsive reporters, and reversed weight gain and fat accumulation comparable to estradiol in ovariectomized obese mice maintained on a high fat diet. Unlike estradiol, RG and RP did not induce proliferative effects on mammary gland and uterus. Gene expression profiling demonstrated that RG and RP induced estradiol-like regulation of genes in abdominal fat, but not in mammary gland and uterus. The compounds in extracts from RG and RP might constitute a new class of tissue selective estrogens to reverse weight gain, fat accumulation and metabolic syndrome in postmenopausal women.

  14. Inhibition of NF-κB transcriptional activity by the estrogen receptor - Insights into the molecular mechanism

    NARCIS (Netherlands)

    Quaedackers, Monique Elisabeth

    2006-01-01

    The steroid hormone estrogen plays a key role in the regulation of a wide variety of physiological processes, having profound effects on tissues throughout the human body. This becomes evident in postmenopausal women where estrogen deficiency is associated with increased risks for developing various

  15. Epithelial estrogen receptor 1 intrinsically mediates squamous differentiation in the mouse vagina.

    Science.gov (United States)

    Miyagawa, Shinichi; Iguchi, Taisen

    2015-10-20

    Estrogen-mediated actions in female reproductive organs are tightly regulated, mainly through estrogen receptor 1 (ESR1). The mouse vaginal epithelium cyclically exhibits cell proliferation and differentiation in response to estrogen and provides a unique model for analyzing the homeostasis of stratified squamous epithelia. To address the role of ESR1-mediated tissue events during homeostasis, we analyzed mice with a vaginal epithelium-specific knockout of Esr1 driven by keratin 5-Cre (K5-Esr1KO). We show here that loss of epithelial ESR1 in the vagina resulted in aberrant epithelial cell proliferation in the suprabasal cell layers and led to failure of keratinized differentiation. Gene expression analysis showed that several known estrogen target genes, including erbB growth factor ligands, were not induced by estrogen in the K5-Esr1KO mouse vagina. Organ culture experiments revealed that the addition of erbB growth factor ligands, such as amphiregulin, could activate keratinized differentiation in the absence of epithelial ESR1. Thus, epithelial ESR1 integrates estrogen and growth factor signaling to mediate regulation of cell proliferation in squamous differentiation, and our results provide new insights into estrogen-mediated homeostasis in female reproductive organs.

  16. WISP-2 as a novel estrogen-responsive gene in human breast cancer cells.

    Science.gov (United States)

    Inadera, H; Hashimoto, S; Dong, H Y; Suzuki, T; Nagai, S; Yamashita, T; Toyoda, N; Matsushima, K

    2000-08-18

    In order to search for novel estrogen-responsive genes, we performed serial analysis of gene expression (SAGE) for estrogen-treated MCF-7 human breast cancer cells. SAGE analysis of 31,000 and 30,856 tags from non-treated and 17 beta-estradiol (E2)-treated cells for 24 h, respectively, facilitated the identification of 15,037 different transcripts. Comparison of these two SAGE libraries indicated a remarkable similarity in expression profiles. Among the identified transcripts, four genes were found to be markedly increased for E2-treated cells compared with control cells. Three of the transcripts were cathepsin D, pS2 and high mobility group 1 protein, which have been described as estrogen-inducible genes. The fourth gene was WISP-2 (Wnt-1 inducible signaling pathway protein 2) which has recently been reported as an up-regulated gene in the mammary epithelial cell line C57 MG transformed by the Wnt-1 oncogene. The increase in WISP-2 mRNA was completely prevented by co-incubation with a pure anti-estrogen ICI 182,780, but not by coincubation with cycloheximide, indicating that WISP-2 is directly regulated by the estrogen receptor. The WISP-2 gene was also induced by treating with environmental estrogens, such as bisphenol-A or nonylphenol. This study represents the first comprehensive gene expression analysis of estrogen-treated human breast cancer cells. Copyright 2000 Academic Press.

  17. Expression of estrogen-induced genes and estrogen receptor β in pancreatic neuroendocrine tumors: implications for targeted therapy.

    Science.gov (United States)

    Estrella, Jeannelyn S; Ma, Ly T; Milton, Denái R; Yao, James C; Wang, Huamin; Rashid, Asif; Broaddus, Russell R

    2014-10-01

    The indolent nature and expression of progesterone receptor (PR), a well-known estrogen-induced gene, in a subset of pancreatic neuroendocrine tumors (PanNETs), raise the possibility of hormonal regulation in these tumors. Immunohistochemical expression of estrogen receptors (ERs) α and β as well as messenger RNA expression of estrogen-induced genes (PR, EIG121, IGF-1, IGF-1R, sFRP1, and sFRP4) by quantitative reverse transcription-polymerase chain reaction were examined in 131 World Health Organization grade G1 and G2 PanNETs and correlated their expression with clinicopathological features. Thirty-nine PanNETs (30%) showed high positive ERβ staining, and 87 cases (66%) had low positive ERβ staining; only 5 cases (4%) had no nuclear staining. Pancreatic neuroendocrine tumors with small size (P = 0.02), low World Health Organization grade (P = 0.02), and low American Joint Committee on Cancer stage (P = 0.006) more frequently showed high positive ERβ staining. Among the estrogen-induced genes studied, PanNETs had significantly higher expression of PR, EIG121, IGF-1, sFRP1, and sFRP4 compared with normal pancreas, independent of age or sex. High positive ERβ staining was associated with an increased expression of PR (P < 0.001) and EIG121 (P = 0.02). Our study showed that PanNETs with favorable prognostic features have higher ERβ expression, which is associated with up-regulated PR and EIG121 messenger RNA expression. Estrogen regulation in PanNETs could potentially help in risk stratification and provide a rational target for novel treatment strategies.

  18. Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells.

    Science.gov (United States)

    Benedek, Gil; Zhang, Jun; Nguyen, Ha; Kent, Gail; Seifert, Hilary A; Davin, Sean; Stauffer, Patrick; Vandenbark, Arthur A; Karstens, Lisa; Asquith, Mark; Offner, Halina

    2017-09-15

    Sex hormones promote immunoregulatory effects on multiple sclerosis. In the current study we evaluated the composition of the gut microbiota and the mucosal-associated regulatory cells in estrogen or sham treated female mice before and after autoimmune encephalomyelitis (EAE) induction. Treatment with pregnancy levels of estrogen induces changes in the composition and diversity of gut microbiota. Additionally, estrogen prevents EAE-associated changes in the gut microbiota and might promote the enrichment of bacteria that are associated with immune regulation. Our results point to a possible cross-talk between the sex hormones and the gut microbiota, which could promote neuroprotection. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Estrogenic modulation of inflammation-related genes in male rats following volume overload

    Science.gov (United States)

    McLarty, Jennifer L.; Meléndez, Giselle C.; Levick, Scott P.; Bennett, Shanté; Sabo-Attwood, Tara; Brower, Gregory L.

    2012-01-01

    Our laboratory has previously reported significant increases of the proinflammatory cytokine TNF-α in male hearts secondary to sustained volume overload. These elevated levels of TNF-α are accompanied by left ventricular (LV) dilatation and cardiac dysfunction. In contrast, estrogen has been shown to protect against this adverse cardiac remodeling in both female and male rats. The purpose of this study was to determine whether estrogen has an effect on inflammation-related genes that contribute to this estrogen-mediated cardioprotection. Myocardial volume overload was induced by aortocaval fistula in 8 wk old male Sprague-Dawley rats (n = 30), and genes of interest were identified using an inflammatory PCR array in Sham, Fistula, and Fistula + Estrogen-treated (0.02 mg/kg per day beginning 2 wk prior to fistula) groups. A total of 55 inflammatory genes were modified (≥2-fold change) at 3 days postfistula. The number of inflammatory gene was reduced to 21 genes by estrogen treatment, whereas 13 genes were comparably modulated in both fistula groups. The most notable were TNF-α, which was downregulated by estrogen, and the TNF-α receptors, which were differentially regulated by estrogen. Specific genes related to arachidonic acid metabolism were downregulated by estrogen, including cyclooxygenase-1 and -2. Finally, gene expression for the β1-integrin cell adhesion subunit was significantly upregulated in the LV of estrogen-treated animals. Protein levels reflected the changes observed at the gene level. These data suggest that estrogen provides its cardioprotective effects, at least in part, via genomic modulation of numerous inflammation-related genes. PMID:22274565

  20. Estrogen Metabolism and Breast Cancer

    African Journals Online (AJOL)

    pathway mediated by the generation and redox Cycling of reactive oxygen species through the metabolic effects of estrogen .... therapy. Several studies including the European. Organization for Research and Treatment of. Cancer ÇEORTC) trial,19 the ATAC (Arimidex, tamoxifen, alone or in combination) adjuvant breast.

  1. Combinations of physiologic estrogens with xenoestrogens alter calcium and kinase responses, prolactin release, and membrane estrogen receptor trafficking in rat pituitary cells

    Directory of Open Access Journals (Sweden)

    Watson Cheryl S

    2010-10-01

    Full Text Available Abstract Background Xenoestrogens such as alkylphenols and the structurally related plastic byproduct bisphenol A have recently been shown to act potently via nongenomic signaling pathways and the membrane version of estrogen receptor-α. Though the responses to these compounds are typically measured individually, they usually contaminate organisms that already have endogenous estrogens present. Therefore, we used quantitative medium-throughput screening assays to measure the effects of physiologic estrogens in combination with these xenoestrogens. Methods We studied the effects of low concentrations of endogenous estrogens (estradiol, estriol, and estrone at 10 pM (representing pre-development levels, and 1 nM (representing higher cycle-dependent and pregnancy levels in combinations with the same levels of xenoestrogens in GH3/B6/F10 pituitary cells. These levels of xenoestrogens represent extremely low contamination levels. We monitored calcium entry into cells using Fura-2 fluorescence imaging of single cells. Prolactin release was measured by radio-immunoassay. Extracellular-regulated kinase (1 and 2 phospho-activations and the levels of three estrogen receptors in the cell membrane (ERα, ERβ, and GPER were measured using a quantitative plate immunoassay of fixed cells either permeabilized or nonpermeabilized (respectively. Results All xenoestrogens caused responses at these concentrations, and had disruptive effects on the actions of physiologic estrogens. Xenoestrogens reduced the % of cells that responded to estradiol via calcium channel opening. They also inhibited the activation (phosphorylation of extracellular-regulated kinases at some concentrations. They either inhibited or enhanced rapid prolactin release, depending upon concentration. These latter two dose-responses were nonmonotonic, a characteristic of nongenomic estrogenic responses. Conclusions Responses mediated by endogenous estrogens representing different life stages are

  2. Identifying a Mechanism for Crosstalk Between the Estrogen and Glucocorticoid Receptors | Center for Cancer Research

    Science.gov (United States)

    Estrogen has long been known to play important roles in the development and progression of breast cancer. Its receptor (ER), a member of the steroid receptor family, binds to estrogen response elements (EREs) in DNA and regulates gene transcription. More recently, another steroid receptor family member, the glucocorticoid receptor (GR), has been implicated in breast cancer progression, and ER/GR status is an important predictor of breast cancer outcome.

  3. Control of fluid intake by estrogens in the female rat: role of the hypothalamus

    Directory of Open Access Journals (Sweden)

    Jessica eSantollo

    2015-03-01

    Full Text Available Body fluid homeostasis is maintained by a complex network of central and peripheral systems that regulate blood pressure, fluid and electrolyte excretion, and fluid intake. The behavioral components, which include well regulated water and saline intake, are influenced by a number of hormones and neuropeptides. Since the early 1970s, it has been known that the ovarian estrogens play an important role in regulating fluid intake in females by decreasing water and saline intake under a variety of hypovolemic conditions. Behavioral, electrophysiological, gene and protein expression studies have identified nuclei in the hypothalamus, along with nearby forebrain structures such as the subfornical organ, as sites of action involved in mediating these effects of estrogens and, importantly, all of these brain areas are rich with estrogen receptors. This review will discuss the multiple estrogen receptor (ER subtypes, found both in the cell nucleus and associated with the plasma membrane, that provide diversity in the mechanism through which estrogens can induce behavioral changes in fluid intake. We then focus on the relevant brain structures, hypothesized circuits, and various peptides, such as angiotensin, oxytocin, and vasopressin, implicated in the anti-dipsogenic and anti-natriorexigenic actions of the estrogens.

  4. DHEA metabolites activate estrogen receptors alpha and beta

    OpenAIRE

    Michael Miller, Kristy K.; Al-Rayyan, Numan; Ivanova, Margarita M.; Mattingly, Kathleen A.; Ripp, Sharon L.; KLINGE, CAROLYN M.; Prough, Russell A.

    2012-01-01

    Dehydroepiandrosterone (DHEA) levels were reported to associate with increased breast cancer risk in postmenopausal women, but some carcinogen-induced rat mammary tumor studies question this claim. The purpose of this study was to determine how DHEA and its metabolites affect estrogen receptors α or β (ERα or ERβ) -regulated gene transcription and cell proliferation. In transiently transfected HEK-293 cells, androstenediol, DHEA, and DHEA-S activated ERα. In ERβ transfected HepG2 cells, andro...

  5. Conservation of estrogen receptor function in invertebrate reproduction

    OpenAIRE

    Jones, Brande L.; Walker, Chris; Azizi, Bahareh; Tolbert, Laren; Williams, Loren Dean; Snell, Terry W.

    2017-01-01

    Background Rotifers are microscopic aquatic invertebrates that reproduce both sexually and asexually. Though rotifers are phylogenetically distant from humans, and have specialized reproductive physiology, this work identifies a surprising conservation in the control of reproduction between humans and rotifers through the estrogen receptor. Until recently, steroid signaling has been observed in only a few invertebrate taxa and its role in regulating invertebrate reproduction has not been clea...

  6. Chronic kidney disease and the involvement of estrogen hormones in its pathogenesis and progression.

    Science.gov (United States)

    Gluhovschi, Gh; Gluhovschi, A; Anastasiu, D; Petrica, Ligia; Gluhovschi, Cristina; Velciov, Silvia

    2012-01-01

    The kidney is under the influence of sexual hormones. Estrogens have a favourable role in the progression of some chronic renal diseases. Estrogen hormones act upon the nephron component cells, regulating several processes going on at this level. One of the most important actions of the estrogens is represented by the protective effect on the kidneys, estrogens attenuating glomerulosclerosis and tubulo-interstitial fibrosis. Thus, estrogens have nephroprotective effects. Phosphorus-calcium metabolism disturbances during chronic kidney disease are influenced by numerous regulatory factors: parathormone, vitamin D fibroblast growth factor, 23. Estrogens play an important part in disturbances of the phosphorus-calcium metabolism, co-operating with these factors. They exert favourable effects on renal osteodystrophy, the main consequence of phosphorus-calcium disturbances. Hormonal dysfunction in chronic kidney disease is clinically accompanied by sexual dysfunction that influences the life quality of these patients. In advanced stages of chronic kidney disease, especially in dialysed patients, these sexual dysfunctions can be more evident. Hormonal replacement therapy and estrogen therapy- receptor modulating therapy have an important role in correcting hormonal dysfunctions manifest in chronic kidney disease. Caution is necessary in case of a would-be pregnancy in patients with chronic kidney disease, given its risks and the complexity of the problem. Renal transplantation corrects to a great extent hormonal dysfunctions in chronic kidney disease.

  7. The Effects of Synthetic Estrogen Exposure on the Sexually Dimorphic Liver Transcriptome of the Sex-Role-Reversed Gulf Pipefish

    National Research Council Canada - National Science Library

    Rose, Emily; Flanagan, Sarah P; Jones, Adam G

    2015-01-01

    .... Here, we investigate gene expression patterns in the liver of the sex-role-reversed Gulf pipefish, because the liver is known to be sexually dimorphic and estrogen-regulated in species with conventional sex roles...

  8. A modulated empirical Bayes model for identifying topological and temporal estrogen receptor α regulatory networks in breast cancer

    Directory of Open Access Journals (Sweden)

    Zhao Yuming

    2011-05-01

    Full Text Available Abstract Background Estrogens regulate diverse physiological processes in various tissues through genomic and non-genomic mechanisms that result in activation or repression of gene expression. Transcription regulation upon estrogen stimulation is a critical biological process underlying the onset and progress of the majority of breast cancer. Dynamic gene expression changes have been shown to characterize the breast cancer cell response to estrogens, the every molecular mechanism of which is still not well understood. Results We developed a modulated empirical Bayes model, and constructed a novel topological and temporal transcription factor (TF regulatory network in MCF7 breast cancer cell line upon stimulation by 17β-estradiol stimulation. In the network, significant TF genomic hubs were identified including ER-alpha and AP-1; significant non-genomic hubs include ZFP161, TFDP1, NRF1, TFAP2A, EGR1, E2F1, and PITX2. Although the early and late networks were distinct ( Conclusions We identified a number of estrogen regulated target genes and established estrogen-regulated network that distinguishes the genomic and non-genomic actions of estrogen receptor. Many gene targets of this network were not active anymore in anti-estrogen resistant cell lines, possibly because their DNA methylation and histone acetylation patterns have changed.

  9. Targeted Radiotherapy of Estrogen Receptor Positive Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Raghavan Rajagopalan

    2006-08-31

    The overall objectives of the proposal were to develop estrogen receptor (ER) binding small molecule radiopharmaceuticals for targeted radiotherapy of ER positive (ER+) tumors. In particular, this proposal focused on embedding a {sup 186,188}Re or a {sup 32}P radionuclide into an estrogen steroidal framework by isosteric substitution such that the resulting structure is topologically similar to the estrogen (estrogen mimic). The estrogen mimic molecules expected to bind to the ER and exhibit biodistribution akin to that of native estrogen due to structural mimicry. It is anticipated that the {sup 186,188}Re- or a {sup 32}P-containing estrogen mimics will be useful for targeted molecular radiotherapy of ER+ tumors. It is well established that the in vivo target tissue uptake of estrogen like steroidal molecules is related to the binding of the steroids to sex hormone binding globulin (SHBG). SHBG is important in the uptake of estrogens and testosterone in target tissues by SHBG receptors on the cell surface. However, hitherto the design of estrogen like small molecule radiopharmaceuticals was focused on optimizing ER binding characteristics without emphasis on SHBG binding properties. Consequently, even the molecules with good ER affinity in vitro, performed poorly in biodistribution studies. Based on molecular modeling studies the proposal focused on developing estrogen mimics 1-3 which were topologically similar to native estrogens, and form hydrogen bonds in ER and SHBG in the same manner as those of native estrogens. To this end the technical objectives of the proposal focused on synthesizing the rhenium-estrone and estradiol mimics 1 and 2 respectively, and phosphorous estradiol mimic 3 and to assess their stability and in vitro binding characteristics to ER and SHBG.

  10. Identification of functional networks of estrogen- and c-Myc-responsive genes and their relationship to response to tamoxifen therapy in breast cancer.

    Directory of Open Access Journals (Sweden)

    Elizabeth A Musgrove

    Full Text Available BACKGROUND: Estrogen is a pivotal regulator of cell proliferation in the normal breast and breast cancer. Endocrine therapies targeting the estrogen receptor are effective in breast cancer, but their success is limited by intrinsic and acquired resistance. METHODOLOGY/PRINCIPAL FINDINGS: With the goal of gaining mechanistic insights into estrogen action and endocrine resistance, we classified estrogen-regulated genes by function, and determined the relationship between functionally-related genesets and the response to tamoxifen in breast cancer patients. Estrogen-responsive genes were identified by transcript profiling of MCF-7 breast cancer cells. Pathway analysis based on functional annotation of these estrogen-regulated genes identified gene signatures with known or predicted roles in cell cycle control, cell growth (i.e. ribosome biogenesis and protein synthesis, cell death/survival signaling and transcriptional regulation. Since inducible expression of c-Myc in antiestrogen-arrested cells can recapitulate many of the effects of estrogen on molecular endpoints related to cell cycle progression, the estrogen-regulated genes that were also targets of c-Myc were identified using cells inducibly expressing c-Myc. Selected genes classified as estrogen and c-Myc targets displayed similar levels of regulation by estrogen and c-Myc and were not estrogen-regulated in the presence of siMyc. Genes regulated by c-Myc accounted for 50% of all acutely estrogen-regulated genes but comprised 85% (110/129 genes in the cell growth signature. siRNA-mediated inhibition of c-Myc induction impaired estrogen regulation of ribosome biogenesis and protein synthesis, consistent with the prediction that estrogen regulates cell growth principally via c-Myc. The 'cell cycle', 'cell growth' and 'cell death' gene signatures each identified patients with an attenuated response in a cohort of 246 tamoxifen-treated patients. In multivariate analysis the cell death signature

  11. Effect of Topical Estrogen in the Mangement of Traumatic Facial Wounds

    Directory of Open Access Journals (Sweden)

    Seyed Amirhosein Ghazizadeh Hashemi

    2016-01-01

    Full Text Available Introduction: Acute skin wound healing is a complicated process comprising various phases. Recent animal studies have shown that steroid sex hormones such as estrogen maybe helpful in the regulation of several pathophysiologic stages that are involved in wound healing. In this study we examined the effects of topical estrogen in the treatment of traumatic facial wounds.   Materials and Methods: Patients referred to Luqman Hospital, Tehran with traumatic wounds were enrolled in this case-control study into two groups of equal size. From the second week of the study, topical estrogen (0.625 mg conjugated topical estrogen ointment was administered in the case group, while the control group received a Eucerin dressing only. The two groups were then compared in terms of wound healing rate on Day 7,14, and 30.   Results: Thirty patients with mean age of 16.02+36.23 years were compared in the control and estrogen-treated groups. After treatment, no scars or keloids were observed in either group. The wound area in the estrogen group was lower than that in the control group on Day 14 and 30, but the difference was not significant (P>0.05. Healing rates in the control group on Day  14 (7.1+42.3 vs.50.3+4.9 mm2 and Day 30 (1.9+93.5 vs. + 97.3+0.6 mm2 (were lower than those in the estrogen group, but the differences were not significant (P>0.05. Findings show that the required time for wound healing in the estrogen-treated group was lower than that in the control group, but the difference was not significant (P>0.05.   Conclusion:  Based on this study, topical estrogen has no effect on the rate of wound healing or the rate of wound area .

  12. Effect of Topical Estrogen in the Mangement of Traumatic Facial Wounds

    Science.gov (United States)

    Ghazizadeh Hashemi, Seyed Amirhosein; Barati, Behrooz; Mohammadi, Hosein; Saeidi, Masumeh; Bahreini, Abbas; Kiani, Mohammad Ali

    2016-01-01

    Introduction: Acute skin wound healing is a complicated process comprising various phases. Recent animal studies have shown that steroid sex hormones such as estrogen maybe helpful in the regulation of several pathophysiologic stages that are involved in wound healing. In this study we examined the effects of topical estrogen in the treatment of traumatic facial wounds. Materials and Methods: Patients referred to Luqman Hospital, Tehran with traumatic wounds were enrolled in this case-control study into two groups of equal size. From the second week of the study, topical estrogen (0.625 mg conjugated topical estrogen ointment) was administered in the case group, while the control group received a Eucerin dressing only. The two groups were then compared in terms of wound healing rate on Day 7,14, and 30. Results: Thirty patients with mean age of 16.02+36.23 years were compared in the control and estrogen-treated groups. After treatment, no scars or keloids were observed in either group. The wound area in the estrogen group was lower than that in the control group on Day 14 and 30, but the difference was not significant (P>0.05). Healing rates in the control group on Day 14 (7.1+42.3 vs.50.3+4.9 mm2) and Day 30 (1.9+93.5 vs. + 97.3+0.6 mm2) (were lower than those in the estrogen group, but the differences were not significant (P>0.05). Findings show that the required time for wound healing in the estrogen-treated group was lower than that in the control group, but the difference was not significant (P>0.05). Conclusion: Based on this study, topical estrogen has no effect on the rate of wound healing or the rate of wound area. PMID:26878003

  13. GPR30 mediates anorectic estrogen-induced STAT3 signaling in the hypothalamus.

    Science.gov (United States)

    Kwon, Obin; Kang, Eun Seok; Kim, Insook; Shin, Sora; Kim, Mijung; Kwon, Somin; Oh, So Ra; Ahn, Young Soo; Kim, Chul Hoon

    2014-11-01

    Estrogen plays an important role in the control of energy balance in the hypothalamus. Leptin-independent STAT3 activation (i.e., tyrosine(705)-phosphorylation of STAT3, pSTAT3) in the hypothalamus is hypothesized as the primary mechanism of the estrogen-induced anorexic response. However, the type of estrogen receptor that mediates this regulation is unknown. We investigated the role of the G protein-coupled receptor 30 (GPR30) in estradiol (E2)-induced STAT3 activation in the hypothalamus. Regulation of STAT3 activation by E2, G-1, a specific agonist of GPR30 and G-15, a specific antagonist of GPR30 was analyzed in vitro and in vivo. Effect of GPR30 activation on eating behavior was analyzed in vivo. E2 stimulated pSTAT3 in cells expressing GPR30, but not expressing estrogen receptor ERα and ERβ. G-1 induced pSTAT3, and G-15 inhibited E2-induced pSTAT3 in primary cultures of hypothalamic neurons. A cerebroventricular injection of G-1 increased pSTAT3 in the arcuate nucleus of mice, which was associated with a decrease in food intake and body weight gain. These results suggest that GPR30 is the estrogen receptor that mediates the anorectic effect of estrogen through the STAT3 pathway in the hypothalamus. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Expression of the estrogen receptors and steroidogenic enzymes involved in estradiol formation in the monkey vagina.

    Science.gov (United States)

    Bertin, Jonathan; Ouellet, Johanne; Dury, Alain Yves; Pelletier, Georges; Labrie, Fernand

    2014-11-01

    Estrogens are well recognized to have beneficial effects on vulvovaginal atrophy because of menopause. The distribution of estrogen receptors and enzymes responsible for estradiol (E2) formation within the vagina may provide insight into how dehydroepiandrosterone, a precursor of both estrogens and androgens, improves vulvovaginal atrophy. The purpose of the study was to determine where the steroidogenic enzymes responsible for E2 formation as well as estrogen receptors are localized in vaginal specimens collected from cynomolgus monkeys (Macaca fascicularis), the closest model to the human. HSD3B1, HSD17B1, HSD17B5, HSD17B12, aromatase (CYP19A1), estrogen receptor (ER)-α, and ER-β were measured or localized by quantitative real-time polymerase chain reaction, immunohistochemistry, and immunofluorescence. Estrogens were quantified by liquid chromatography/tandem mass spectrometry. All steroidogenic enzymes and estrogen receptors are localized mainly in the superficial layer of the stratified squamous epithelium, blood vessel walls, and muscle fibers of the vagina. Immunolabeling of HSD17B5 and HSD17B12 shows that these enzymes are uniformly distributed from the basal membrane to the superficial keratinized cells, whereas HSD3B1 and aromatase are particularly localized in the outer (external) portion of the epithelial layer. ER-α and ER-β are also distributed within the vaginal epithelium, with expression especially elevated at the basal membrane level. The enzymes responsible for E2 formation as well as ERs are expressed mainly in the superficial layer of the stratified epithelium as well as the muscle layer of the vagina. The present data provide morphologic and biochemical support for the role of local dehydroepiandrosterone transformation into estrogens in regulating epithelial cell maturation, pH, fluid secretion, smooth muscle activity, and blood flow regulation in the primate vagina. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. CERAPP: Collaborative Estrogen Receptor Activity Prediction Project

    Data.gov (United States)

    U.S. Environmental Protection Agency — Data from a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity Prediction Project) demonstrating using predictive computational...

  16. Estrogen receptor alpha: molecular mechanisms and emerging insights.

    Science.gov (United States)

    Candelaria, Nicholes R; Liu, Ka; Lin, Chin-Yo

    2013-10-01

    Estrogen receptor alpha (ERα) is a cellular receptor for the female sex hormone estrogen and other natural and synthetic ligands and play critical roles in normal development and physiology and in the etiology and treatment of endocrine-related diseases. ERα is a member of the nuclear receptor superfamily of transcription factors and regulates target gene expression in a ligand-dependent manner. It has also been shown to interact with G-protein coupled receptors and associated signaling molecules in the cytoplasm. Transcriptionally, ERα either binds DNA directly through conserved estrogen response element sequence motifs or indirectly by tethering to other interacting transcription factors and nucleate transcriptional regulatory complexes which include an array of co-regulator proteins. Genome-scale studies of ERα transcriptional activity and localization have revealed mechanistic complexity and insights including novel interactions with several transcription factors, including FOXA1, AP-2g, GATA3, and RUNX1, which function as pioneering, collaborative, or tethering factors. The major challenge and exciting prospect moving forward is the comprehensive definition and integration of ERα complexes and mechanisms and their tissue-specific roles in normal physiology and in human diseases. Copyright © 2013 Wiley Periodicals, Inc.

  17. DHEA metabolites activate estrogen receptors alpha and beta

    Science.gov (United States)

    Michael Miller, Kristy K.; Al-Rayyan, Numan; Ivanova, Margarita M.; Mattingly, Kathleen A.; Ripp, Sharon L.; Klinge, Carolyn M.; Prough, Russell A.

    2012-01-01

    Dehydroepiandrosterone (DHEA) levels were reported to associate with increased breast cancer risk in postmenopausal women, but some carcinogen-induced rat mammary tumor studies question this claim. The purpose of this study was to determine how DHEA and its metabolites affect estrogen receptors α or β (ERα or ERβ) -regulated gene transcription and cell proliferation. In transiently transfected HEK-293 cells, androstenediol, DHEA, and DHEA-S activated ERα. In ERβ transfected HepG2 cells, androstenedione, DHEA, androstenediol, and 7-oxo DHEA stimulated reporter activity. ER antagonists ICI 182,780 (fulvestrant) and 4-hydroxytamoxifen, general P450 inhibitor miconazole, and aromatase inhibitor exemestane inhibited activation by DHEA or metabolites in transfected cells. ERβ-selective antagonist R,R-THC (R,R-cis-diethyl tetrahydrochrysene) inhibited DHEA and DHEA metabolite transcriptional activity in ERβ-transfected cells. Expression of endogenous estrogen-regulated genes: pS2, progesterone receptor, cathepsin D1, and nuclear respiratory factor-1 was increased by DHEA and its metabolites in an ER-subtype, gene, and cell-specific manner. DHEA metabolites, but not DHEA, competed with 17β-estradiol for ERα and ERβ binding and stimulated MCF-7 cell proliferation, demonstrating that DHEA metabolites interact directly with ERα and ERβ in vitro, modulating estrogen target genes in vivo. PMID:23123738

  18. Estrogen-mediated hemangioma-derived stem cells through estrogen receptor-α for infantile hemangioma

    Directory of Open Access Journals (Sweden)

    Zhang L

    2017-07-01

    -week treatment of E2 promoted expression of VEGF-A and FGF2 in HemSCs culture. Morphological, histological and immunohistological improvements were observed in vivo using murine IH model in which HemSCs and HUVECs were implanted into BALB/c-nu mice that were post-injected with E2. In the grafts, mean MVD was markedly increased. Conclusion: The results suggested that E2 promotes angiogenesis via combination with ER-α to up-regulate the expression of VEGF-A in HemSCs, promoting proliferation of IHs. These findings provide critical insight into the potential mechanisms of E2 action on IHs. Keywords: hemangioma-derived stem cells, estrogen, vascular endothelial growth factor-A, estrogen receptor-α, infantile hemangioma

  19. Bisphenol AF as an Inducer of Estrogen Receptor β (ERβ): Evidence for Anti-estrogenic Effects at Higher Concentrations in Human Breast Cancer Cells.

    Science.gov (United States)

    Okazaki, Hiroyuki; Takeda, Shuso; Kakizoe, Kazuhiro; Taniguchi, Aya; Tokuyasu, Miki; Himeno, Taichi; Ishii, Hiroyuki; Kohro-Ikeda, Eriko; Haraguchi, Koichi; Watanabe, Kazuhito; Aramaki, Hironori

    2017-01-01

    Bisphenols are endocrine disruptors that are widely found in the environment. Accumulating experimental evidence suggests an adverse interaction between bisphenols and estrogen signaling. Most studies have performed experiments that focused on estrogen receptor (ER) engagement by bisphenols. Therefore, the effects of bisphenols on the expression of ERα (ESR1) and ERβ (ESR2) remain largely unknown. In the present study, we examined the effects of four bisphenols: bisphenol A (BPA), bisphenol B (BPB), bisphenol S (BPS), and bisphenol AF (BPAF), on estrogen signaling in two human breast cancer cell lines (MCF-7 and SK-BR-3). Among these bisphenols, BPAF up-regulated the expression of ERβ, and this was coupled with the abrogation of estrogen response element (ERE)-mediated transcriptional activities as well as the down-regulation of Cdc2 expression in MCF-7 cells, without influencing the expression of ERα. BPAF functioned as an agonist of ERα at lower concentrations (nanomolar order), but did not exhibit any modulatory action on ERα transiently expressed in SK-BR-3 cells in the presence or absence of 17β-estradiol (E2) at higher concentrations (micromolar order). The introduction of ERβ cDNA resulted in greater reductions in MCF-7 cell viability than with BPAF alone. Since ERβ is a suppressive molecule of ERα function, these results provide rational evidence for BPAF functioning as an anti-estrogenic compound via the induction of ERβ at higher concentrations.

  20. Activation of transgenic estrogen receptor-beta by selected phytoestrogens in a stably transduced rat serotonergic cell line.

    Science.gov (United States)

    Amer, Dena A M; Kretzschmar, Georg; Müller, Nicole; Stanke, Nicole; Lindemann, Dirk; Vollmer, Günter

    2010-06-01

    Many flavonoids, a major group of phenolic plant-derived secondary metabolites, are known to possess estrogen-like bioactivities. However, little is known about their estrogenic properties in the central nervous system due to the lack of suitable cellular models expressing sufficient amounts of functional estrogen receptor beta (ERbeta). To overcome this deficit, we have created a cellular model, which is serotonergic in origin, to study properties of estrogenic substances by stably transducing RN46A-B14 cells derived from raphe nuclei region of the rat brain with a lentiviral vector encoding a human ERbeta. We clearly showed that the transgenic human ERbeta is a spontaneously expressed and a functional receptor. We have further assessed the estrogenicity of three different isoflavones and four different naringenin-type flavanones in this cell line utilizing a luciferase reporter gene assay. Genistein (GEN), Daidzein (DAI), Equol (EQ), Naringenin (NAR) and 8-prenylnaringenin (8-PN) showed strong estrogenic activity in a concentration-dependent manner as compared to 7-(O-prenyl)naringenin-4'-acetate (7-O-PN) which was only slightly estrogenic and 6-(1,1-dimethylallyl)naringenin (6-DMAN) that neither showed estrogenic nor anti-estrogenic activity in our model. All observed effects could be antagonized by the anti-estrogen fulvestrant. Moreover, co-treatment of cells with 17beta-estradiol (E2) and either GEN or DAI showed a slight additive effect as compared to EQ. On the other hand, 8-PN in addition to 7-O-PN, but not NAR and 6-DMAN, were able to slightly antagonize the responses triggered by E2. Our newly established cellular model may prove to be a useful tool in explicating basic physiological properties of ERbeta in the brain and may help unravel molecular and cellular mechanisms involved in serotonergic mood regulation by estrogen or potential plant-derived secondary metabolites. Copyright 2010 Elsevier Ltd. All rights reserved.

  1. Estrogen and the brain: does estrogen treatment improve cognitive function?

    Science.gov (United States)

    Hogervorst, Eef

    2013-03-01

    In this paper we describe potential reasons for the discrepancies between data from basic sciences and observational studies and those of large treatment studies investigating the association between brain function and sex steroids. Observational studies which often showed positive associations between hormone use and cognition can be affected by 'recall bias' and 'healthy user bias', while outcomes of treatment studies were hypothesized to be modified by age at treatment, age at or type of menopause, health status, addition of a progestogen or type of estrogen treatment. However, meta-analyses of data from treatment studies negate many of these hypotheses showing at best mainly short-term (up to 6 months) positive effects of estrogen treatment on cognition regardless of age. This positive effect may reverse, particularly in older women with prolonged hormone treatment, which was predominantly seen after addition of progestogen. Medroxyprogesterone acetate seemed to have worse effects on cognition than other types of progestogen in these long-term studies. Estradiol with or without a progestogen was three times more likely to have positive effects on cognition than conjugated equine estrogens. However, two-thirds of studies showed no associations at all which may be an underestimate given the possibility of publication bias. We briefly review alternative treatments, such as testosterone and soy-derived supplements, but currently insufficient data are available for conclusive comments. Women who have undergone surgical menopause or who undergo natural menopause before age 47 may benefit most from hormone treatment and a special case may need to be made for this group. Long-term safety studies for this group are urgently needed. 2013 © The Author(s).

  2. Hispolon inhibits the growth of estrogen receptor positive human breast cancer cells through modulation of estrogen receptor alpha

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Eun Hyang; Jang, Soon Young; Cho, In-Hye [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Hong, Darong [Department of Life and Nanopharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Jung, Bom; Park, Min-Ju [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Kim, Jong-Ho, E-mail: jonghokim@khu.ac.kr [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of)

    2015-08-07

    Human estrogen receptor α (ERα) is a nuclear transcription factor that is a major therapeutic target in breast cancer. The transcriptional activity of ERα is regulated by certain estrogen-receptor modulators. Hispolon, isolated from Phellinus linteus, a traditional medicinal mushroom called Sanghwang in Korea, has been used to treat various pathologies, such as inflammation, gastroenteric disorders, lymphatic diseases, and cancers. In this latter context, Hispolon has been reported to exhibit therapeutic efficacy against various cancer cells, including melanoma, leukemia, hepatocarcinoma, bladder cancer, and gastric cancer cells. However, ERα regulation by Hispolon has not been reported. In this study, we investigated the effects of Hispolon on the growth of breast cancer cells. We found that Hispolon decreased expression of ERα at both mRNA and the protein levels in MCF7 and T47D human breast cancer cells. Luciferase reporter assays showed that Hispolon decreased the transcriptional activity of ERα. Hispolon treatment also inhibited expression of the ERα target gene pS2. We propose that Hispolon, an anticancer drug extracted from natural sources, inhibits cell growth through modulation of ERα in estrogen-positive breast cancer cells and is a candidate for use in human breast cancer chemotherapy. - Highlights: • Hispolon decreased ERα expression at both mRNA and protein levels. • Hispolon decreased ERα transcriptional activity. • Hispolon treatment inhibited expression of ERα target gene pS2. • Shikonin is a candidate chemotherapeutic target in the treatment of human breast cancer.

  3. Single CpG site methylation controls estrogen receptor gene transcription and correlates with hormone therapy resistance.

    Science.gov (United States)

    Tsuboi, Kouki; Nagatomo, Takamasa; Gohno, Tatsuyuki; Higuchi, Toru; Sasaki, Shunta; Fujiki, Natsu; Kurosumi, Masafumi; Takei, Hiroyuki; Yamaguchi, Yuri; Niwa, Toshifumi; Hayashi, Shin-Ichi

    2017-07-01

    Hormone therapy is the most effective treatment for patients with estrogen receptor α-positive breast cancers. However, although resistance occurs during treatment in some cases and often reflects changed estrogen receptor α status, the relationship between changes in estrogen receptor α expression and resistance to therapy are poorly understood. In this study, we identified a mechanism for altered estrogen receptor α expression during disease progression and acquired hormone therapy resistance in aromatase inhibitor-resistant breast cancer cell lines. Subsequently, we investigated promoter switching and DNA methylation status of the estrogen receptor α promoter, and found marked changes of methylation at a single CpG site (CpG4) in resistant cells. In addition, luciferase reporter assays showed reduced transcriptional activity from this methylated CpG site. This CpG region was also completely conserved among species, suggesting that it acts as a methylation-sensitive Ets-2 transcription factor binding site, as confirmed using chromatin immunoprecipitation assays. In estrogen receptor α-positive tumors, CpG4 methylation levels were inversely correlated with estrogen receptor α expression status, suggesting that single CpG site plays an important role in the regulation of estrogen receptor α transcription. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Dopaminergic activation of estrogen receptors induces fos expression within restricted regions of the neonatal female rat brain.

    Directory of Open Access Journals (Sweden)

    Kristin M Olesen

    2008-05-01

    Full Text Available Steroid receptor activation in the developing brain influences a variety of cellular processes that endure into adulthood, altering both behavior and physiology. Recent data suggests that dopamine can regulate expression of progestin receptors within restricted regions of the developing rat brain by activating estrogen receptors in a ligand-independent manner. It is unclear whether changes in neuronal activity induced by dopaminergic activation of estrogen receptors are also region specific. To investigate this question, we examined where the dopamine D1-like receptor agonist, SKF 38393, altered Fos expression via estrogen receptor activation. We report that dopamine D1-like receptor agonist treatment increased Fos protein expression within many regions of the developing female rat brain. More importantly, prior treatment with an estrogen receptor antagonist partially reduced D1-like receptor agonist-induced Fos expression only within the bed nucleus of the stria terminalis and the central amygdala. These data suggest that dopaminergic activation of estrogen receptors alters neuronal activity within restricted regions of the developing rat brain. This implies that ligand-independent activation of estrogen receptors by dopamine might organize a unique set of behaviors during brain development in contrast to the more wide spread ligand activation of estrogen receptors by estrogen.

  5. Dopaminergic Activation of Estrogen Receptors Induces Fos Expression within Restricted Regions of the Neonatal Female Rat Brain

    Science.gov (United States)

    Olesen, Kristin M.; Auger, Anthony P.

    2008-01-01

    Steroid receptor activation in the developing brain influences a variety of cellular processes that endure into adulthood, altering both behavior and physiology. Recent data suggests that dopamine can regulate expression of progestin receptors within restricted regions of the developing rat brain by activating estrogen receptors in a ligand-independent manner. It is unclear whether changes in neuronal activity induced by dopaminergic activation of estrogen receptors are also region specific. To investigate this question, we examined where the dopamine D1-like receptor agonist, SKF 38393, altered Fos expression via estrogen receptor activation. We report that dopamine D1-like receptor agonist treatment increased Fos protein expression within many regions of the developing female rat brain. More importantly, prior treatment with an estrogen receptor antagonist partially reduced D1-like receptor agonist-induced Fos expression only within the bed nucleus of the stria terminalis and the central amygdala. These data suggest that dopaminergic activation of estrogen receptors alters neuronal activity within restricted regions of the developing rat brain. This implies that ligand-independent activation of estrogen receptors by dopamine might organize a unique set of behaviors during brain development in contrast to the more wide spread ligand activation of estrogen receptors by estrogen. PMID:18478050

  6. Long-term effects of early life exposure to environmental estrogens on ovarian function: Role of epigenetics

    Science.gov (United States)

    Cruz, Gonzalo; Foster, Warren; Paredes, Alfonso; Yi, Kun Don; Uzumcu, Mehmet

    2014-01-01

    Estrogens play an important role in development and function of the brain and reproductive tract. Accordingly, it is thought that developmental exposure to environmental estrogens can disrupt neural and reproductive tract development potentially resulting in long-term alterations in neurobehavior and reproductive function. Many chemicals have been shown to have estrogenic activity whereas others affect estrogen production and turnover resulting in disruption of estrogen signaling pathways. However, these mechanisms and the concentrations required to induce these effects cannot account for the myriad adverse effects of environmental toxicants on estrogen sensitive target tissues. Hence, alternative mechanisms are thought to underlie the adverse effects documented in experimental animal models and thus could be important to human health. In this review, the epigenetic regulation of gene expression is explored as a potential target of environmental toxicants including estrogenic chemicals. We suggest that toxicant-induced changes in epigenetic signatures are important mechanisms underlying disruption of ovarian follicular development. In addition, we discuss how exposure to environmental estrogens during early life can alter gene expression through effects on epigenetic control potentially leading to permanent changes in ovarian physiology. PMID:25040227

  7. Estrogen responsiveness of the TFIID subunit TAF4B in the normal mouse ovary and in ovarian tumors.

    Science.gov (United States)

    Wardell, Jennifer R; Hodgkinson, Kendra M; Binder, April K; Seymour, Kimberly A; Korach, Kenneth S; Vanderhyden, Barbara C; Freiman, Richard N

    2013-11-01

    Estrogen signaling in the ovary is a fundamental component of normal ovarian function, and evidence also indicates that excessive estrogen is a risk factor for ovarian cancer. We have previously demonstrated that the gonadally enriched TFIID subunit TAF4B, a paralog of the general transcription factor TAF4A, is required for fertility in mice and for the proliferation of ovarian granulosa cells following hormonal stimulation. However, the relationship between TAF4B and estrogen signaling in the normal ovary or during ovarian tumor initiation and progression has yet to be defined. Herein, we show that Taf4b mRNA and TAF4B protein, but not Taf4a mRNA or TAF4A protein, are increased in whole ovaries and granulosa cells of the ovary after exposure to 17beta-estradiol or the synthetic estrogen diethylstilbestrol and that this response occurs within hours after stimulation. Furthermore, this increase occurs via nuclear estrogen receptors both in vivo and in a mouse granulosa cancer cell line, NT-1. We observe a significant increase in Taf4b mRNA in estrogen-supplemented mouse ovarian tumors, which correlates with diminished survival of these mice. These data highlight the novel response of the general transcription factor TAF4B to estrogen in the normal ovary and during ovarian tumor progression in the mouse, suggesting its potential role in regulating actions downstream of estrogen stimulation.

  8. Estrogen Modulates ubc9 Expression and Synaptic Redistribution in the Brain of APP/PS1 Mice and Cortical Neurons.

    Science.gov (United States)

    Lai, Yu-Jie; Liu, Lu; Hu, Xiao-Tong; He, Ling; Chen, Guo-Jun

    2017-03-01

    Estrogen exerts multiple actions in the brain and is an important neuroprotective factor in a number of neuronal disorders. However, the underlying mechanism remains unknown. Studies demonstrate that ubiquitin-conjugating enzyme 9 (ubc9) has an integral role in synaptic plasticity and may contribute to the pathology of neuronal disorders. We aimed to investigate the effects of estrogen on ubc9 and in the Alzheimer's disease brain. Ubc9 protein and mRNA were significantly increased in the cortex and hippocampus of APP/PS1 mice with enhanced SUMOylation. Systemic estrogen administration led to reduced ubc9 expression in ovariectomized APP/PS1 mice and reduced SUMOylation. The inhibition of ubc9 expression by estrogen was found to be dose-dependent in cultured neurons. However, estrogen receptor (ER) antagonist ICI182780 did not block the inhibition of ubc9 expression by estrogen. Furthermore, the reduced expression of ubc9 was not mediated by ERα or ERβ agonists alone or in combination, but by the membrane-impermeable ER agonist E2-bovine serum albumin. The activation of the G protein-coupled ER mediated the inhibition of ubc9 expression of estrogen. A phosphoinositide 3-kinase (PI3K) inhibitor, rather than an extracellular signal-regulated kinase inhibitor, blocked the inhibition of ubc9 by estrogen. Estrogen treatment significantly increased the phosphorylation of PI3K, which suggests that activation of the PI3K pathway by estrogen is required for ubc9 regulation. Further, ubc9 interacted with the synaptic proteins post-synaptic density protein 95 (PSD95) and synaptophysin. Estrogen decreased the interaction of ubc9 with post-synaptic PSD95, but increased the interaction of ubc9 with pre-synaptic synaptophysin. These results suggest that a membrane-bound ER might mediate the estrogen inhibition of ubc9 in cortical neurons, where PI3K plays an important role. We also show that ubc9 can interact with synaptic proteins, which are subject to estrogen regulation.

  9. Quantum chemical studies of estrogenic compounds

    Science.gov (United States)

    Quantum chemical methods are potent tools to provide information on the chemical structure and electronic properties of organic molecules. Modern computational chemistry methods have provided a great deal of insight into the binding of estrogenic compounds to estrogenic receptors (ER), an important ...

  10. Estrogen induces glomerulosclerosis in analbuminemic rats

    NARCIS (Netherlands)

    Joles, JA; van Goor, H; Koomans, HA

    Progression of chronic renal disease: is usually more rapid in males, both In humans and in experimental animals. Estrogen-replacement studies indicate that this may be related to the beneficial effects of estrogen on the lipoprotein profile. However, in hyperlipidemic analbuminemic rats (NAR),

  11. Shp2 controls female body weight and energy balance by integrating leptin and estrogen signals.

    Science.gov (United States)

    He, Zhao; Zhang, Sharon S; Meng, Qingyuan; Li, Shuangwei; Zhu, Helen H; Raquil, Marie-Astrid; Alderson, Nazilla; Zhang, Hai; Wu, Jiarui; Rui, Liangyou; Cai, Dongsheng; Feng, Gen-Sheng

    2012-05-01

    In mammals, leptin regulates food intake and energy balance mainly through the activation of LepRb in the hypothalamus, and estrogen has a leptin-like effect in the hypothalamic control of metabolism. However, it remains to be elucidated how estrogen signaling is intertwined with the leptin pathway. We show here that Shp2, a nonreceptor tyrosine phosphatase, acts to integrate leptin and estrogen signals. The expression of a dominant-active mutant (Shp2(D61A)) in forebrain neurons conferred female, but not male, transgenic mice resistance to high-fat diet (HFD)-induced obesity and liver steatosis, accompanied by improved insulin sensitivity and glucose homeostasis. Fed with either HFD or regular chow food, Shp2(D61A) female mice showed dramatically enhanced leptin sensitivity. Microinjection of Shp2(D61A)-expressing adeno-associated virus into mediobasal hypothalamus elicited a similar antiobese effect in female mice. Biochemical analyses showed a physical association of Shp2 with estrogen receptor alpha, which is necessary for the synergistic and persistent activation of Erk by leptin and estrogen. Together, these results elucidate a mechanism for the direct cross talk of leptin and estrogen signaling and offer one explanation for the propensity of postmenopausal women to develop obesity.

  12. Preliminary Molecular Dynamic Simulations of the Estrogen Receptor Alpha Ligand Binding Domain from Antagonist to Apo

    Directory of Open Access Journals (Sweden)

    Adrian E. Roitberg

    2008-06-01

    Full Text Available Estrogen receptors (ER are known as nuclear receptors. They exist in the cytoplasm of human cells and serves as a DNA binding transcription factor that regulates gene expression. However the estrogen receptor also has additional functions independent of DNA binding. The human estrogen receptor comes in two forms, alpha and beta. This work focuses on the alpha form of the estrogen receptor. The ERα is found in breast cancer cells, ovarian stroma cells, endometrium, and the hypothalamus. It has been suggested that exposure to DDE, a metabolite of DDT, and other pesticides causes conformational changes in the estrogen receptor. Before examining these factors, this work examines the protein unfolding from the antagonist form found in the 3ERT PDB crystal structure. The 3ERT PDB crystal structure has the estrogen receptor bound to the cancer drug 4-hydroxytamoxifen. The 4-hydroxytamoxifen ligand was extracted before the simulation, resulting in new conformational freedom due to absence of van der Waals contacts between the ligand and the receptor. The conformational changes that result expose the binding clef of the co peptide beside Helix 12 of the receptor forming an apo conformation. Two key conformations in the loops at either end of the H12 are produced resulting in the antagonist to apo conformation transformation. The results were produced over a 42ns Molecular Dynamics simulation using the AMBER FF99SB force field.

  13. Downregulation of beta-catenin and transdifferentiation of human osteoblasts to adipocytes under estrogen deficiency.

    Science.gov (United States)

    Foo, Clara; Frey, Soenke; Yang, Hong Hyun; Zellweger, Rene; Filgueira, Luis

    2007-09-01

    Postmenopausal osteoporosis, caused by estrogen deficiency, is characterized by the structural deterioration of bone accompanied by an increase in bone marrow adipocytes. Transgenic animal models have shown that there is a reciprocal relationship between osteoblastogenesis and adipogenesis in vivo. The present study investigated whether the estrogen and the canonical Wnt signaling pathways are linked together and regulate the phenotype and function, differentiation and proliferation of human osteoblasts using an in vitro estrogen-deficiency model. Human osteoblasts (hFOB 1.19) and fulvestrant, an estrogen receptor blocker, were used to mimic estrogen deficiency in vitro. Osteogenic and adipogenic differentiation was measured by using specific stains and microscopy, as well as by measuring the expression of bone cell-specific markers with reverse transcription polymerase chain reaction. Expression of estrogen receptor-alpha (ERalpha) and beta-catenin was detected in Western blots and by immunoprecipitation. The cells expressed the 46-kDa and the 77-kDa ERalpha isoforms and beta-catenin. Fulvestrant reduced expression of ERalpha and beta-catenin. beta-Catenin was co-immunoprecipitated with ERalpha, indicating that these two proteins form a new signaling complex and transcription factor. In addition, it induced intracellular lipid droplet accumulation and downregulation of bone cell markers, indicating adipocyte differentiation.

  14. Possibilities and potential roles of estrogen in the pathogenesis of proliferation hemangiomas formation.

    Science.gov (United States)

    Sun, Zhi-Yong; Yang, Li; Yi, Cheng-Gang; Zhao, Huan; Han, Da-Li; Yang, Tao; Wang, Lu; Nie, Chun-Lei; Zhang, Guo-You; Yin, Guo-Qian; Wang, Gang; Teng, Xiao-Pin; Fei, Dong-Mei; Wang, Jin; Zhou, Wen-Kai; Li, Yang; Liu, Bin; Liu, Yin; Zhang, Man-Jing; Wu, Shang-Min; Zhang, Xi; Pan, Hua; Xiao, Bo; Zhao, Ke-Feng; Liu, Dan; Guo, Shu-Zhong

    2008-08-01

    Hemangiomas, often categorized as angiogenic diseases, are the most common tumors of infancy, the life span of which is generally divided into proliferating phase, involuting phase, and involuted phase. Despite their high prevalence, the mechanism leading to proliferation hemangiomas formation is poorly understood and the best approach to their management remains controversial. None of the current therapeutic modalities is ideal, partly because the pathogenesis of hemangioma and the mechanism of its proliferation are far from clear. Many clues reveal that estrogen has an important role in developing the vascular system, experimental and clinical evidences accumulated in recent years also suggest the potential for estrogen to influence neovascularization. Based on those, we hypothesize that estrogen play a potential role in the development of hemangiomas, mainly by regulating some key angiogenic factors, including MMP-9, EPCs, VEGF, NO, etc. Accepting the hypothesis to be correct, a therapy that identify estrogen as a potential target for the design of new, more specific treatments can be used to prevent the proliferation hemangiomas formation. The hypothesis may lead a new direction in the study of mechanisms for proliferation hemangiomas formation, and further study of the precise mechanisms for estrogen-induced hemangiomas will produce effective antiestrogens and estrogen receptor antagonists as new medication for the very difficult problem.

  15. Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer.

    Science.gov (United States)

    Singhal, Hari; Greene, Marianne E; Tarulli, Gerard; Zarnke, Allison L; Bourgo, Ryan J; Laine, Muriel; Chang, Ya-Fang; Ma, Shihong; Dembo, Anna G; Raj, Ganesh V; Hickey, Theresa E; Tilley, Wayne D; Greene, Geoffrey L

    2016-06-01

    The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER(+) (estrogen receptor-positive)/PR(+) human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER(+)/PR(+) breast cancers should be explored.

  16. The role of estrogen in bone growth and formation: changes at puberty

    Directory of Open Access Journals (Sweden)

    Divya Singh

    2010-12-01

    Full Text Available Divya Singh1, Sabyasachi Sanyal2, Naibedya Chattopadhyay11Division of Endocrinology, 2Division of Drug Target Discovery and Development, Central Drug Research Institute (Council of Scientific and Industrial Research, Lucknow, Uttar Pradesh, IndiaAbstract: A high peak bone mass (PBM at skeletal maturity is a good predictor for lower rate of fracture risks in later life. Growth during puberty contributes significantly to PBM achievement in women and men. The growth hormone (GH/insulin-like growth factor 1 (IGF-1 axis has a critical role in pubertal bone growth. There is an increase in GH and IGF-1 levels during puberty; thus, it is assumed that sex steroids contribute to higher GH/IGF-1 action during growth. Recent studies indicate that estrogen increases GH secretion in boys and girls, and the major effect of testosterone on GH secretion is via aromatization to estrogen. Estrogen is pivotal for epiphyseal fusion in young men and women. From studies of individuals with a mutated aromatase gene and a case study of male patient with defective estrogen receptor-alpha (ER-α, it is clear that estrogen is indispensable for normal pubertal growth and growth plate fusion. ER-α and estrogen receptor-beta (ER-β have been localized in growth plate and bone. ER knockout studies have shown that ER-α-/- female mice have reduced linear appendicular growth, while ER-β-/- mice have increased appendicular growth. No such effect is seen in ER-β-/- males; however, repressed growth is seen in ER-α-/- males, resulting in shorter long bones. Thus, ER-β represses longitudinal bone growth in female mice, while it has no function in the regulation of longitudinal bone growth in male mice. These findings indicate that estrogen plays a critical role in skeletal physiology of males as well as females.Keywords: peak bone mass, puberty, estrogen, growth plate

  17. Glutamic acid ameliorates estrogen deficiency-induced menopausal-like symptoms in ovariectomized mice.

    Science.gov (United States)

    Han, Na-Ra; Kim, Hee-Yun; Yang, Woong Mo; Jeong, Hyun-Ja; Kim, Hyung-Min

    2015-09-01

    Some amino acids are considered alternative therapies for improving menopausal symptoms. Glutamic acid (GA), which is abundant in meats, fish, and protein-rich plant foods, is known to be a neurotransmitter or precursor of γ-aminobutyric acid. Although it is unclear if GA functions in menopausal symptoms, we hypothesized that GA would attenuate estrogen deficiency-induced menopausal symptoms. The objective to test our hypothesis was to examine an estrogenic effect of GA in ovariectomized (OVX) mice, estrogen receptor (ER)-positive human osteoblast-like MG-63 cells, and ER-positive human breast cancer MCF-7 cells. The results demonstrated that administration with GA to mice suppressed body weight gain and vaginal atrophy when compared with the OVX mice. A microcomputed tomographic analysis of the trabecular bone showed increases in bone mineral density, trabecular number, and connectivity density as well as a significant decrease in total porosity of the OVX mice treated with GA. In addition, GA increased serum levels of alkaline phosphatase and estrogen compared with the OVX mice. Furthermore, GA induced proliferation and increased ER-β messenger RNA (mRNA) expression, estrogen response element (ERE) activity, extracellular signal-regulated kinase phosphorylation, and alkaline phosphatase activity in MG-63 cells. In MCF-7 cells, GA also increased proliferation, Ki-67 mRNA expression, ER-β mRNA expression, and ERE activity. Estrogen response element activity increased by GA was inhibited by an estrogen antagonist. Taken together, our data demonstrated that GA has estrogenic and osteogenic activities in OVX mice, MG-63 cells, and MCF-7 cells. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Common soil of smoking-associated and hormone-related cancers: estrogen deficiency

    Directory of Open Access Journals (Sweden)

    Zsuzsanna Suba

    2011-12-01

    Full Text Available Accumulation of non-smoker, non-drinker elderly postmenopausal female patients among smokingassociated oral cancer cases raised the plausible idea: estrogen deficiency maybe a cancer risk factor. On the other hand, the extremely rare cases of young women with oral cancer regularly exhibited hormonal disorders, such as irregular menstrual cycles and infertility. Furthermore, in the history of middle-aged female, oral cancer cases a primary ovarian failure or complete hysterectomy was a conspicuously frequent finding suggestive of an estrogen deficient milieu. There were many striking contradictions concerning the associations of female sexual steroids and cancer risk as well. Until now, breast and endometrial cancers were regarded as typically estrogen-induced tumors, particularly in postmenopausal cases. However, unexplained beneficial anti-cancer effects of hormonereplacement therapy were reported against cancers at several sites, even tumors of the highly hormone-responsive organs. Re-evaluation of results of the experimental and epidemiological studies, which endeavored to justify the carcinogenic capacity of estrogen, exhibited many shortcomings and controversies. The new findings both on smoking associated and on hormone related cancers added up to the same conversion; not estrogen but rather its deficiency might provoke cancer initiation. Thorough review of the literary data justified that the exquisite regulatory capacity of estrogen and its surveillance on growth, development, differentiation, and metabolism are indispensable, whereas an estrogen-deficient milieu may induce a breakdown in gene-regulation. Recognition of the anticancer capacity of estrogen may provide new insights into the etiology of malignancies and leads to new strategies for cancer prevention and cure.

  19. Estrogen and progesterone receptors in gynecomastia.

    Science.gov (United States)

    Pensler, J M; Silverman, B L; Sanghavi, J; Goolsby, C; Speck, G; Brizio-Molteni, L; Molteni, A

    2000-10-01

    The etiology of gynecomastia is unknown. There seems to be no increased incidence of malignancies in patients with idiopathic gynecomastia; however, patients with Klinefelter syndrome exhibit an increased incidence of malignancy. The authors reviewed the results of 34 patients with gynecomastia diagnosed in adolescence who, following initial evaluation, had a mastectomy. The estrogen and progesterone receptors were analyzed in these patients. Three of the patients were diagnosed with Klinefelter syndrome. These three patients exhibited elevated amounts of estrogen and progesterone receptors. None of the patients who were not diagnosed with this syndrome demonstrated significant elevation of their estrogen or progesterone receptors. The presence of elevated estrogen and progesterone receptors in patients with Klinefelter syndrome provides a potential mechanism by which these patients may develop breast neoplasms. The absence of elevated estrogen and progesterone receptors in patients with idiopathic gynecomastia may serve to clarify why these patients' disease rarely degenerates into malignancy.

  20. Estrogen-dependent expression of sine oculis homeobox 1 in the mouse uterus during the estrous cycle

    Energy Technology Data Exchange (ETDEWEB)

    Bae, Sijeong [Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do 13488 (Korea, Republic of); Kwon, Hwang [Fertility Center of CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do 13496 (Korea, Republic of); Yoon, Hyemin [Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do 13488 (Korea, Republic of); Park, Miseon [Fertility Center of CHA Gangnam Medical Center, Seoul 06135 (Korea, Republic of); Kim, Hye-Ryun; Song, Haengseok [Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do 13488 (Korea, Republic of); Hong, Kwonho, E-mail: kwonho.hong@dankook.ac.kr [Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan-si, Chungcheongnam-do 31116 (Korea, Republic of); Choi, Youngsok, E-mail: youngsokchoi@cha.ac.kr [Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do 13488 (Korea, Republic of); Fertility Center of CHA Gangnam Medical Center, Seoul 06135 (Korea, Republic of)

    2016-04-08

    The sine oculis homeobox 1 (SIX1) is a member of the Six gene family. SIX1 is involved in tissue development by regulating proliferation, apoptosis, and differentiation. However, function of SIX1 in the uterus remains unknown. Here, we found that Six1 expression is regulated along the estrous cycle in mouse uterus. Six1 expression was significantly increased at estrus stage and decreased at the rest of stages. SIX1 is detected in the luminal and glandular epithelium of uterine endometrium at the estrus stage. Estrogen injection increased Six1 expression in the ovariectomized mouse uterus, whereas progesterone had no effect on its expression. Estrogen receptor antagonist inhibited estrogen-induced Six1 expression. Our findings imply that SIX1 may play a role as an important regulator to orchestrate the dynamic of uterine endometrium in response to estrogen level during the estrous cycle. These results will give us a better understanding of uterine biology. - Highlights: • Six1 expression is regulated during the estrous cycle in mouse uterus. • Six1 is highly expressed at the estrus stage of estrous cycle. • SIX1 is detected in luminal/glandular epithelium of the uterus at the estrus stage. • Estrogen stimulates Six1 expression in an estrogen receptor-dependent manner.

  1. Correlation between insulin-induced estrogen receptor methylation and atherosclerosis.

    Science.gov (United States)

    Min, Jia; Weitian, Zhong; Peng, Cai; Yan, Peng; Bo, Zhang; Yan, Wang; Yun, Bai; Xukai, Wang

    2016-11-10

    Hyperinsulinemia and insulin resistance have been recently recognized as an important cause of atherosclerosis. Clinical studies have also found that expression of the estrogen receptor is closely related to the incidence of atherosclerosis. This study investigate the effects of insulin and estrogen receptor α (ER-α) in atherosclerosis. Double knockout ApoE/Lepr mice were given intraperitoneal injections of insulin, and their aortae were harvested for hematoxylin-eosin staining and immunohistochemical analysis. In addition, vascular smooth muscle cells (VSMCs) were treated with insulin or infected with a lentivirus encoding exogenous ER-α, and changes in gene expression were detected by real-time polymerase chain reaction and western blotting. The methylation levels of the ER-α gene were tested using bisulfite sequencing PCR, and flow cytometry and EdU assay were used to measure VSMCs proliferation. Our results showed that insulin can induce the formation of atherosclerosis. Gene expression analysis revealed that insulin promotes the expression of DNA methyltransferases and inhibits ER-α expression, while 5-aza-2'-deoxycytidine can inhibit this effect of insulin. Bisulfite sequencing PCR analysis showed that methylation of the ER-α second exon region increased in VSMCs treated with insulin. The results also showed that ER-α can inhibit VSMCs proliferation. Our data suggest that insulin promotes the expression of DNA methyltransferases, induces methylation of ER-α second exon region and decreases the expression of ER-α, thereby interfering with estrogen regulation of VSMCs proliferation, resulting in atherosclerosis.

  2. Expression of aromatase and estrogen receptor alpha in chondrosarcoma, but no beneficial effect of inhibiting estrogen signaling both in vitro and in vivo

    Science.gov (United States)

    2011-01-01

    Background Chondrosarcomas are malignant cartilage-forming tumors which are highly resistant to conventional chemotherapy and radiotherapy. Estrogen signaling is known to play an important role in proliferation and differentiation of chondrocytes and in growth plate regulation at puberty. Our experiments focus on unraveling the role of estrogen signaling in the regulation of neoplastic cartilage growth and on interference with estrogen signaling in chondrosarcomas in vitro and in vivo. Methods We investigated the protein expression of estrogen receptor alpha (ESR1), androgen receptor (AR), and aromatase in tumor specimens of various chondrosarcoma subtypes, and (primary) chondrosarcoma cultures. Dose-response curves were generated of conventional central chondrosarcoma cell lines cultured in the presence of 17β-estradiol, dihydrotestosterone, 4-androstene-3,17 dione, 4-hydroxytamoxifen, fulvestrant and aromatase inhibitors. In a pilot series, the effect of anastrozole (n = 4) or exemestane (n = 2) treatment in 6 chondrosarcoma patients with progressive disease was explored. Results We showed protein expression of ESR1 and aromatase in a large majority of all subtypes. Only a minority of the tumors showed few AR positive cells. The dose-response assays showed no effect of any of the compounds on proliferation of conventional chondrosarcoma in vitro. The median progression-free survival of the patients treated with aromatase inhibitors did not significantly deviate from untreated patients. Conclusions The presence of ESR1 and aromatase in chondrosarcoma tumors and primary cultures supports a possible role of estrogen signaling in chondrosarcoma proliferation. However, our in vitro and pilot in vivo studies have shown no effect of estrogen-signaling inhibition on tumor growth. PMID:22613849

  3. Bisphenol A and estrogen induce proliferation of human thyroid tumor cells via an estrogen-receptor-dependent pathway.

    Science.gov (United States)

    Zhang, YongHong; Wei, Feng; Zhang, Jing; Hao, Lanxiang; Jiang, Jie; Dang, Liansheng; Mei, Dan; Fan, ShanShan; Yu, Yajin; Jiang, Ling

    2017-11-01

    To determine the relationship between papillary thyroid carcinoma and environmental exposure to bisphenol A (BPA) or 17-β estrogen (E2) by assessing the effects of these compounds on estrogen receptor expression and AKT/mTOR signaling. The effects of low levels of BPA (1mM-10nM) and 17β-estradiol (E2, 0.1mM-1nM) on ER expression and cellular proliferation were determined in human thyroid papillary cancer BHP10-3 cells. Protein and mRNA levels of estrogen nuclear receptors (ERα/ERβ) and membrane receptors (GPR30) were determined by immunofluorescence assay, Western blotting, and RT-PCR, respectively, and proliferation was assessed by CCK-8 assay. The proliferative effects of BPA and E2 were both concentration- and time-dependent. Expression of ERα/ERβ and GPR30 were enhanced by BPA and E2. BPA and E2 could quickly phosphorylate AKT/mTOR. Moreover, ICI suppressed ERα expression and activated GPR30 as did G-1. G-15 reversed the effects of E2 on GPR30 and AKT/mTOR, but did not alter the effect of BPA. BPA influences thyroid cancer proliferation by regulating expression of ERs and GPR30, a mechanism that differs from E2. In addition, ICI and G-15 may have the potential to be used as anti-thyroid cancer agents. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Ozonation of estrogenic chemicals in biologically treated sewage

    DEFF Research Database (Denmark)

    Hansen, Kamilla Marie Speht; Andersen, Henrik Rasmus; Ledin, Anna

    2010-01-01

    for removal of 17 estrogenic chemicals. The estrogenic compounds included parabens, industrial phenols, sunscreen chemicals, and steroid estrogens. The obtained values of Electrical Energy per Order (EEOs) for the treatment of the estrogens were in the range 0.14–1.1 kWh/m3 corresponding to 1.7–14 g O3/m3...

  5. Estrogen Receptor β Activation Rapidly Modulates Male Sexual Motivation through the Transactivation of Metabotropic Glutamate Receptor 1a

    Science.gov (United States)

    Seredynski, Aurore L.; Balthazart, Jacques; Ball, Gregory F.

    2015-01-01

    In addition to the transcriptional activity of their liganded nuclear receptors, estrogens, such as estradiol (E2), modulate cell functions, and consequently physiology and behavior, within minutes through membrane-initiated events. The membrane-associated receptors (mERs) underlying the acute effects of estrogens on behavior have mostly been documented in females where active estrogens are thought to be of ovarian origin. We determined here, by acute intracerebroventricular injections of specific agonists and antagonists, the type(s) of mERs that modulate rapid effects of brain-derived estrogens on sexual motivation in male Japanese quail. Brain aromatase blockade acutely inhibited sexual motivation. Diarylpropionitrile (DPN), an estrogen receptor β (ERβ)-specific agonist, and to a lesser extent 17α-estradiol, possibly acting through ER-X, prevented this effect. In contrast, drugs targeting ERα (PPT and MPP), GPR30 (G1 and G15), and the Gq-mER (STX) did not affect sexual motivation. The mGluR1a antagonist LY367385 significantly inhibited sexual motivation but mGluR2/3 and mGluR5 antagonists were ineffective. LY367385 also blocked the behavioral restoration induced by E2 or DPN, providing functional evidence that ERβ interacts with metabotropic glutamate receptor 1a (mGluR1a) signaling to acutely regulate male sexual motivation. Together these results show that ERβ plays a key role in sexual behavior regulation and the recently uncovered cooperation between mERs and mGluRs is functional in males where it mediates the acute effects of estrogens produced centrally in response to social stimuli. The presence of an ER–mGluR interaction in birds suggests that this mechanism emerged relatively early in vertebrate history and is well conserved. SIGNIFICANCE STATEMENT The membrane-associated receptors underlying the acute effects of estrogens on behavior have mostly been documented in females, where active estrogens are thought to be of ovarian origin. Using acute

  6. Pushing estrogen receptor around in breast cancer.

    Science.gov (United States)

    Lim, Elgene; Tarulli, Gerard; Portman, Neil; Hickey, Theresa E; Tilley, Wayne D; Palmieri, Carlo

    2016-12-01

    The estrogen receptor-α (herein called ER) is a nuclear sex steroid receptor (SSR) that is expressed in approximately 75% of breast cancers. Therapies that modulate ER action have substantially improved the survival of patients with ER-positive breast cancer, but resistance to treatment still remains a major clinical problem. Treating resistant breast cancer requires co-targeting of ER and alternate signalling pathways that contribute to resistance to improve the efficacy and benefit of currently available treatments. Emerging data have shown that other SSRs may regulate the sites at which ER binds to DNA in ways that can powerfully suppress the oncogenic activity of ER in breast cancer. This includes the progesterone receptor (PR) that was recently shown to reprogram the ER DNA binding landscape towards genes associated with a favourable outcome. Another attractive candidate is the androgen receptor (AR), which is expressed in the majority of breast cancers and inhibits growth of the normal breast and ER-positive tumours when activated by ligand. These findings have led to the initiation of breast cancer clinical trials evaluating therapies that selectively harness the ability of SSRs to 'push' ER towards anti-tumorigenic activity. Our review will focus on the established and emerging clinical evidence for activating PR or AR in ER-positive breast cancer to inhibit the tumour growth-promoting functions of ER. © 2016 Society for Endocrinology.

  7. Progesterone antagonizes the positive influence of estrogen on Chlamydia trachomatis serovar E in an Ishikawa/SHT-290 co-culture model.

    Science.gov (United States)

    Kintner, Jennifer; Schoborg, Robert V; Wyrick, Priscilla B; Hall, Jennifer V

    2015-06-01

    Studies indicate that estrogen enhances Chlamydia trachomatis serovar E infection in genital epithelial cells. Hormones have direct and indirect effects on endometrial epithelial cells. Estrogen and progesterone exposure induces endometrial stromal cells to release effectors that subsequently regulate growth and maturation of uterine epithelial cells. Estrogen enhances C. trachomatis infection by aiding entry and intracellular development in endometrial epithelial cell (Ishikawa, IK)/SHT-290 stromal cell co-culture. Enhanced chlamydial infection was mediated by direct estrogen-stimulated signaling events in epithelial cells and indirectly via estrogen-induced stromal cell effectors. The current study investigates the effects of hormones on chlamydial development using culture conditions representative of the menstrual cycle. Chlamydia trachomatis-infected IK or IK/SHT-290 cultures were exposed to 10(-8) M estrogen (E2), 10(-7) M progesterone (P4) or a combination of both hormones (10(-8) M E2 followed by 10(-9) M E2/10(-7) M P4). Chlamydial infectivity and progeny production were significantly decreased (30-66%) in cultures exposed to progesterone or estrogen/progesterone combination compared to estrogen alone. Thus, progesterone antagonized the positive effects of estrogen on chlamydial infection. These data indicate the susceptibility of endometrial epithelial cells to C. trachomatis infection during the menstrual cycle is altered by phase specific actions of sex hormones in the genital tract. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  8. Estrogen stimulates osteoprotegerin expression via the suppression of miR-145 expression in MG-63 cells.

    Science.gov (United States)

    Jia, Jun; Zhou, Hengxing; Zeng, Xiantie; Feng, Shiqing

    2017-04-01

    Osteoprotegerin (OPG) is implicated in the pathogenesis of postmenopausal osteoporosis, and other metabolic bone diseases caused by estrogen deficiency. Previous studies have demonstrated that estrogen may stimulate OPG expression in osteoblast cells at the transcriptional level; however, whether estrogen can regulate OPG expression at a post-transcriptional level remains elusive. The present study aimed to investigate the role of microRNA (miRNA) in estrogen‑mediated OPG production in human osteoblast‑like MG‑63 cells. The results from ELISA, western blotting and reverse transcription-quantitative polymerase chain reaction (RT‑qPCR) confirmed that estrogen may upregulate OPG expression. Mechanistic studies indicated that estrogen increased the activity of a luciferase reporter harboring the OPG 3'‑untranslated region (3'‑UTR). Bioinformatics analysis demonstrated that there is a potential targeting site in the OPG 3'‑UTR for miRNA (miR)‑145, which is associated with osteoblast differentiation. The results of an RT‑qPCR suggested that estrogen suppressed miR‑145 expression. In addition, dual‑luciferase assay, RT‑qPCR and western blot analysis indicated that miR‑145 directly targets and negatively regulates OPG expression. Furthermore, transfection of cells with miR‑145 mimics was able to partially inhibit the induction of OPG expression by estrogen, thus confirming the role of miR‑145 in estrogen‑mediated OPG induction. Taken together, the results of the present study demonstrated that estrogen may post-transcriptionally regulate OPG expression through suppression of miR-145 expression.

  9. The Effects of Synthetic Estrogen Exposure on the Sexually Dimorphic Liver Transcriptome of the Sex-Role-Reversed Gulf Pipefish: e0139401

    National Research Council Canada - National Science Library

    Emily Rose; Sarah P Flanagan; Adam G Jones

    2015-01-01

    .... Here, we investigate gene expression patterns in the liver of the sex-role-reversed Gulf pipefish, because the liver is known to be sexually dimorphic and estrogen-regulated in species with conventional sex roles...

  10. Estrogen Levels in the three Trimesters

    African Journals Online (AJOL)

    into three trimester periods , as a means to simplify reference to ... In the normal non-pregnant female, estrogens are secreted in ... Department of Physiology, School of Basic Medical Sciences, College of Medical Sciences, University of Benin ...

  11. Sulfation of thyroid hormone by estrogen sulfotransferase

    NARCIS (Netherlands)

    M.H.A. Kester (Monique); T.J. Visser (Theo); C.H. van Dijk (Caren); D. Tibboel (Dick); A.M. Hood (Margaret); N.J. Rose; W. Meinl; U. Pabel; H. Glatt; C.N. Falany; M.W. Coughtrie

    1999-01-01

    textabstractSulfation is one of the pathways by which thyroid hormone is inactivated. Iodothyronine sulfate concentrations are very high in human fetal blood and amniotic fluid, suggesting important production of these conjugates in utero. Human estrogen

  12. Breast Cancer and Estrogen-Alone Update

    Science.gov (United States)

    ... Current Issue Past Issues Research News From NIH Breast Cancer and Estrogen-Alone Update Past Issues / Summer 2006 ... hormone therapy does not increase the risk of breast cancer in postmenopausal women, according to an updated analysis ...

  13. Urinary estrogen metabolites and breast cancer

    DEFF Research Database (Denmark)

    Dallal, Cher M; Stone, Roslyn A; Cauley, Jane A

    2013-01-01

    ), and their ratio (2:16a-OHE1) in relation to breast cancer risk. ¿Methods: Primary data on 726 premenopausal women (183 invasive breast cancer cases and 543 controls) and 1,108 postmenopausal women (385 invasive breast cancer cases and 723 controls) were analyzed. Urinary estrogen metabolites were measured using...... enzyme linked immunosorbent assays. Study-specific and combined multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated based on tertiles of estrogen metabolites. Multinomial logistic regression models were fit according to hormone receptor status.¿Results: Higher......Background: Circulating estrogens are associated with increased breast cancer risk, yet the role of estrogen metabolites in breast carcinogenesis remains unclear. This combined analysis of 5 published studies evaluates urinary 2-hydroxyestrone (2-OHE1), 16a-hydroxyestrone (16a-OHE1...

  14. Estrogens, Genetic Polymorphisms and Breast Cancer Risk

    National Research Council Canada - National Science Library

    Okobia, Michael N; Bunker, Clareann H; Kuller, Lewis; Ferrell, Robert E; Anyanwu, Stanley N; Ezeome, Emmanuel R; Uche, Emmanuel E

    2004-01-01

    ... cancer in Nigerian women. A case-control study is being undertaken to investigate the exposure level to estrogen and its metabolites in these women by examining the genotype frequencies of the genes encoding aromatase...

  15. Estrogen May Influence Women's Depression Risk

    Science.gov (United States)

    ... news/fullstory_167353.html Estrogen May Influence Women's Depression Risk Early menstruation, more frequent periods seem to ... reproductive years may have a lower risk of depression, a new study finds. Previous research has suggested ...

  16. Calmodulin-like protein 3 is an estrogen receptor alpha coregulator for gene expression and drug response in a SNP, estrogen, and SERM-dependent fashion.

    Science.gov (United States)

    Qin, Sisi; Ingle, James N; Liu, Mohan; Yu, Jia; Wickerham, D Lawrence; Kubo, Michiaki; Weinshilboum, Richard M; Wang, Liewei

    2017-08-18

    We previously performed a case-control genome-wide association study in women treated with selective estrogen receptor modulators (SERMs) for breast cancer prevention and identified single nucleotide polymorphisms (SNPs) in ZNF423 as potential biomarkers for response to SERM therapy. The ZNF423rs9940645 SNP, which is approximately 200 bp away from the estrogen response elements, resulted in the SNP, estrogen, and SERM-dependent regulation of ZNF423 expression and, "downstream", that of BRCA1. Electrophoretic mobility shift assay-mass spectrometry was performed to identify proteins binding to the ZNF423 SNP and coordinating with estrogen receptor alpha (ERα). Clustered, regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing was applied to generate ZR75-1 breast cancer cells with different ZNF423 SNP genotypes. Both cultured cells and mouse xenograft models with different ZNF423 SNP genotypes were used to study the cellular responses to SERMs and poly(ADP-ribose) polymerase (PARP) inhibitors. We identified calmodulin-like protein 3 (CALML3) as a key sensor of this SNP and a coregulator of ERα, which contributes to differential gene transcription regulation in an estrogen and SERM-dependent fashion. Furthermore, using CRISPR/Cas9-engineered ZR75-1 breast cancer cells with different ZNF423 SNP genotypes, striking differences in cellular responses to SERMs and PARP inhibitors, alone or in combination, were observed not only in cells but also in a mouse xenograft model. Our results have demonstrated the mechanism by which the ZNF423 rs9940645 SNP might regulate gene expression and drug response as well as its potential role in achieving more highly individualized breast cancer therapy.

  17. Estrogen Stimulates Proliferation and Differentiation of Neural Stem/Progenitor Cells through Different Signal Transduction Pathways

    Directory of Open Access Journals (Sweden)

    Makiko Okada

    2010-10-01

    Full Text Available Our previous study indicated that both 17β-estradiol (E2, known to be an endogenous estrogen, and bisphenol A (BPA, known to be a xenoestrogen, could positively influence the proliferation or differentiation of neural stem/progenitor cells (NS/PCs. The aim of the present study was to identify the signal transduction pathways for estrogenic activities promoting proliferation and differentiation of NS/PCs via well known nuclear estrogen receptors (ERs or putative membrane-associated ERs. NS/PCs were cultured from the telencephalon of 15-day-old rat embryos. In order to confirm the involvement of nuclear ERs for estrogenic activities, their specific antagonist, ICI-182,780, was used. The presence of putative membrane-associated ER was functionally examined as to whether E2 can activate rapid intracellular signaling mechanism. In order to confirm the involvement of membrane-associated ERs for estrogenic activities, a cell-impermeable E2, bovine serum albumin-conjugated E2 (E2-BSA was used. We showed that E2 could rapidly activate extracellular signal-regulated kinases 1/2 (ERK 1/2, which was not inhibited by ICI-182,780. ICI-182,780 abrogated the stimulatory effect of these estrogens (E2 and BPA on the proliferation of NS/PCs, but not their effect on the differentiation of the NS/PCs into oligodendroglia. Furthermore, E2-BSA mimicked the activity of differentiation from NS/PCs into oligodendroglia, but not the activity of proliferation. Our study suggests that (1 the estrogen induced proliferation of NS/PCs is mediated via nuclear ERs; (2 the oligodendroglial generation from NS/PCs is likely to be stimulated via putative membrane‑associated ERs.

  18. Immunosuppression Following Exposure to Exogenous Estrogens

    Science.gov (United States)

    1983-08-01

    and laboratory animals aad has been associated with endo- metrial cancer , breast cancer , and vaginal adenocarcinoma (McLachlan, 1980). In mice, DES...demonstrate binding affinity for the estrogen receptor are the flavones genistin, mirestrol, and the fluorescent coumestrol. The mycotoxin zearalanone (P...inhibition assay, Cancer Treatment Rep., 62:1807-1816. Eroschenko, V. P. and R. D. Palmiter (19?0), Estrogenicity of kepone in birds and mammals. In

  19. Sex differences in opioid analgesia and addiction: interactions among opioid receptors and estrogen receptors

    Science.gov (United States)

    2013-01-01

    Opioids are widely used as the pain reliever and also notorious for being addictive drugs. Sex differences in the opioid analgesia and addiction have been reported and investigated in human subjects and animal models. Yet, the molecular mechanism underlying the differences between males and females is still unclear. Here, we reviewed the literature describing the sex differences in analgesic responses and addiction liabilities to clinically relevant opioids. The reported interactions among opioids, estrogens, opioid receptors, and estrogen receptors are also evaluated. We postulate that the sex differences partly originated from the crosstalk among the estrogen and opioid receptors when stimulated by the exogenous opioids, possibly through common secondary messengers and the downstream gene transcriptional regulators. PMID:24010861

  20. Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland.

    Science.gov (United States)

    Johnson, Michael D; Kenney, Nicholas; Stoica, Adriana; Hilakivi-Clarke, Leena; Singh, Baljit; Chepko, Gloria; Clarke, Robert; Sholler, Peter F; Lirio, Apolonio A; Foss, Colby; Reiter, Ronald; Trock, Bruce; Paik, Soonmyoung; Martin, Mary Beth

    2003-08-01

    It has been suggested that environmental contaminants that mimic the effects of estrogen contribute to disruption of the reproductive systems of animals in the wild, and to the high incidence of hormone-related cancers and diseases in Western populations. Previous studies have shown that functionally, cadmium acts like steroidal estrogens in breast cancer cells as a result of its ability to form a high-affinity complex with the hormone binding domain of the estrogen receptor. The results of the present study show that cadmium also has potent estrogen-like activity in vivo. Exposure to cadmium increased uterine wet weight, promoted growth and development of the mammary glands and induced hormone-regulated genes in ovariectomized animals. In the uterus, the increase in wet weight was accompanied by proliferation of the endometrium and induction of progesterone receptor (PgR) and complement component C3. In the mammary gland, cadmium promoted an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PgR and C3. In utero exposure to the metal also mimicked the effects of estrogens. Female offspring experienced an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary gland.

  1. Hippocampal learning, memory, and neurogenesis: Effects of sex and estrogens across the lifespan in adults.

    Science.gov (United States)

    Duarte-Guterman, Paula; Yagi, Shunya; Chow, Carmen; Galea, Liisa A M

    2015-08-01

    This article is part of a Special Issue "Estradiol and Cognition". There are sex differences in hippocampus-dependent cognition and neurogenesis suggesting that sex hormones are involved. Estrogens modulate certain forms of spatial and contextual memory and neurogenesis in the adult female rodent, and to a lesser extent male, hippocampus. This review focuses on the effects of sex and estrogens on hippocampal learning, memory, and neurogenesis in the young and aged adult rodent. We discuss how factors such as the type of estrogen, duration and dose of treatment, timing of treatment, and type of memory influence the effects of estrogens on cognition and neurogenesis. We also address how reproductive experience (pregnancy and mothering) and aging interact with estrogens to modulate hippocampal cognition and neurogenesis in females. Given the evidence that adult hippocampal neurogenesis plays a role in long-term spatial memory and pattern separation, we also discuss the functional implications of regulating neurogenesis in the hippocampus. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Keya De Mukhopadhyay

    Full Text Available In postmenopausal women, local estrogen produced by adipose stromal cells in the breast is believed to support estrogen receptor alpha (ERα positive breast cancer cell survival and growth. This raises the question of how the ERα positive metastatic breast cancer cells survive after they enter blood and lymph circulation, where estrogen level is very low in postmenopausal women. In this study, we show that the aromatase expression increased when ERα positive breast cancer cells were cultured in suspension. Furthermore, treatment with the aromatase substrate, testosterone, inhibited suspension culture-induced apoptosis whereas an aromatase inhibitor attenuated the effect of testosterone suggesting that suspended circulating ERα positive breast cancer cells may up-regulate intracrine estrogen activity for survival. Consistent with this notion, a moderate level of ectopic aromatase expression rendered a non-tumorigenic ERα positive breast cancer cell line not only tumorigenic but also metastatic in female nude mice without exogenous estrogen supplementation. The increased malignant phenotype was confirmed to be due to aromatase expression as the growth of orthotopic tumors regressed with systemic administration of an aromatase inhibitor. Thus, our study provides experimental evidence that aromatase plays an important role in the survival of metastatic ERα breast cancer cells by suppressing anoikis.

  3. Estrogenic effects of several BPA analogs in the developing zebrafish brain

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    Joel eCano-Nicolau

    2016-03-01

    Full Text Available Important set of studies have demonstrated the endocrine disrupting activity of Bisphenol A (BPA. The present work aimed at defining estrogenic-like activity of several BPA structural analogs, including BPS, BPF, BPAF, and BPAP, on 4-day or 7-day post-fertilization (dpf zebrafish larva as an in vivo model. We measured the induction level of the estrogen-sensitive marker cyp19a1b gene (Aromatase B, expressed in the brain, using three different in situ/in vivo strategies: 1 Quantification of cyp19a1b transcripts using RT-qPCR in wild type 7-dpf larva brains exposed to bisphenols ; 2 Detection and distribution of cyp19a1b transcripts using in situ hybridization on 7-dpf brain sections (hypothalamus; and 3 Quantification of the cyp19a1b promoter activity in live cyp19a1b-GFP transgenic zebrafish (EASZY assay at 4-dpf larval stage. These three different experimental approaches demonstrated that BPS, BPF or BPAF exposure, similarly to BPA, significantly activates the expression of the estrogenic marker in the brain of developing zebrafish. In vitro experiments using both reporter gene assay in a glial cell context and competitive ligand binding assays strongly suggested that up-regulation of cyp19a1b is largely mediated by the zebrafish estrogen nuclear receptor alpha (zfERα. Importantly, and in contrast to other tested bisphenol A analogs, the bisphenol AP (BPAP did not show estrogenic activity in our model.

  4. Evidence of an estrogen receptor form devoid of estrogen binding ability in MCF-7 cells.

    Science.gov (United States)

    El Khissiin, A; Journé, F; Laïos, I; Seo, H S; Leclercq, G

    2000-12-01

    In MCF-7 breast cancer cells, hydroxytamoxifen (OH-Tam) up-regulates the estrogen receptor (ER) in a form unable to bind [(3)H]estradiol (E(2)). We show here that this property is not restricted to this antiestrogen. [(3)H]E(2) binding assays (whole cell assays, DCC assays on cell extracts) and enzyme immunoassays (Abbott) performed in parallel, establish the permanent presence of such unusual ERs in the absence of any exposure of the cells to a ligand. E(2) and the pure antiestrogen RU 58 668, which down-regulate ER, also decrease [(3)H]E(2) binding. In control cells, these ERs represent about the half of the whole receptor population; they also display a tendency to stabilize within the cell nucleus. Loss of E(2) binding ability appears irreversible, since we failed to label receptor accumulated under OH-Tam with [(3)H]E(2) or [(3)H]tamoxifen aziridine (TAZ). Cycloheximide (CHX), which blocks E(2)-induced down regulation of ER, failed to stabilize [(3)H]E(2) binding (whole cell assay) after an [(3)H]E(2) pulse (1 h), confirming that regulation of E(2) binding and peptide level are related to different regulatory mechanisms. Loss of binding ability could not be ascribed to any ER cleavage as demonstrated by Western blotting with a panel of ER antibodies raised against its various domains (67 kDa ER solely detected). We propose that loss of E(2) binding ability is related to the aging process of the receptor, i.e. it is progressively converted to a form devoted to degradation after it has accomplished its physiological role. Ligands may favor (E(2), RU 58 668) or impede (OH-Tam) this elimination process.

  5. The relationship between estrogen, estrogen receptors and periodontal disease in adult women.

    Science.gov (United States)

    Shapiro, Laurence F; Freeman, Katherine

    2014-11-01

    The literature supports the fact that estrogen plays an important role in skeletal maintenance and remodeling. Estrogen, acting through estrogen receptors in the cells of the periodontal ligament, has a regulatory interaction on bone dynamics through a complex set of basic multicellular units (BMUs). Deficiency of estrogen results in an increased number of BMUs and enhanced bone turnover. The impact of the changes in estrogen deficiency on bone dynamics is primarily mediated through osteoclasts, with greater interdiction of estrogen's actions on trabecular bone than on cortical bone. The purpose of this manuscript is to review the literature for evidence to support an association between estrogen and periodontal disease in adult women, as well as bone mineral density, and to help clarify the mechanism of action. We found in our review of all pertinent databases, including Cochrane, that there are few peer-reviewed clinical studies that examine the relationship between estrogen deficiency and periodontal disease, and bone mineral density (BMD) and periodontal disease. Thus, future research is needed to investigate these associations so that at-risk patients can be identified earlier to avoid functional and esthetic sequellae of periodontal disease.

  6. Conservation of estrogen receptor function in invertebrate reproduction.

    Science.gov (United States)

    Jones, Brande L; Walker, Chris; Azizi, Bahareh; Tolbert, Laren; Williams, Loren Dean; Snell, Terry W

    2017-03-04

    Rotifers are microscopic aquatic invertebrates that reproduce both sexually and asexually. Though rotifers are phylogenetically distant from humans, and have specialized reproductive physiology, this work identifies a surprising conservation in the control of reproduction between humans and rotifers through the estrogen receptor. Until recently, steroid signaling has been observed in only a few invertebrate taxa and its role in regulating invertebrate reproduction has not been clearly demonstrated. Insights into the evolution of sex signaling pathways can be gained by clarifying how receptors function in invertebrate reproduction. In this paper, we show that a ligand-activated estrogen-like receptor in rotifers binds human estradiol and regulates reproductive output in females. In other invertebrates characterized thus far, ER ligand binding domains have occluded ligand-binding sites and the ERs are not ligand activated. We have used a suite of computational, biochemical and biological techniques to determine that the rotifer ER binding site is not occluded and can bind human estradiol. Our results demonstrate that this mammalian hormone receptor plays a key role in reproduction of the ancient microinvertebrate Brachinous manjavacas. The presence and activity of the ER within the phylum Rotifera indicates that the ER structure and function is highly conserved throughout animal evolution.

  7. aP2-Cre-mediated inactivation of estrogen receptor alpha causes hydrometra.

    Science.gov (United States)

    Antonson, Per; Matic, Marko; Portwood, Neil; Kuiper, Raoul V; Bryzgalova, Galyna; Gao, Hui; Windahl, Sara H; Humire, Patricia; Ohlsson, Claes; Berggren, Per-Olof; Gustafsson, Jan-Åke; Dahlman-Wright, Karin

    2014-01-01

    In this study we describe the reproductive phenotypes of a novel mouse model in which Cre-mediated deletion of ERα is regulated by the aP2 (fatty acid binding protein 4) promoter. ERα-floxed mice were crossed with transgenic mice expressing Cre-recombinase under the control of the aP2 promoter to generate aP2-Cre/ERα(flox/flox) mice. As expected, ERα mRNA levels were reduced in adipose tissue, but in addition we also detected an 80% reduction of ERα levels in the hypothalamus of aP2-Cre/ERα(flox/flox) mice. Phenotypic analysis revealed that aP2-Cre/ERα(flox/flox) female mice were infertile. In line with this, aP2-Cre/ERα(flox/flox) female mice did not cycle and presented 3.8-fold elevated estrogen levels. That elevated estrogen levels were associated with increased estrogen signaling was evidenced by increased mRNA levels of the estrogen-regulated genes lactoferrin and aquaporin 5 in the uterus. Furthermore, aP2-Cre/ERα(flox/flox) female mice showed an accumulation of intra-uterine fluid, hydrometra, without overt indications for causative anatomical anomalies. However, the vagina and cervix displayed advanced keratosis with abnormal quantities of accumulating squamous epithelial cells suggesting functional obstruction by keratin plugs. Importantly, treatment of aP2-Cre/ERα(flox/flox) mice with the aromatase inhibitor Letrozole caused regression of the hydrometra phenotype linking increased estrogen levels to the observed phenotype. We propose that in aP2-Cre/ERα(flox/flox) mice, increased serum estrogen levels cause over-stimulation in the uterus and genital tracts resulting in hydrometra and vaginal obstruction.

  8. Gene expression responses in male fathead minnows exposed to binary mixtures of an estrogen and antiestrogen

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    Perkins Edward J

    2009-07-01

    Full Text Available Abstract Background Aquatic organisms are continuously exposed to complex mixtures of chemicals, many of which can interfere with their endocrine system, resulting in impaired reproduction, development or survival, among others. In order to analyze the effects and mechanisms of action of estrogen/anti-estrogen mixtures, we exposed male fathead minnows (Pimephales promelas for 48 hours via the water to 2, 5, 10, and 50 ng 17α-ethinylestradiol (EE2/L, 100 ng ZM 189,154/L (a potent antiestrogen known to block activity of estrogen receptors or mixtures of 5 or 50 ng EE2/L with 100 ng ZM 189,154/L. We analyzed gene expression changes in the gonad, as well as hormone and vitellogenin plasma levels. Results Steroidogenesis was down-regulated by EE2 as reflected by the reduced plasma levels of testosterone in the exposed fish and down-regulation of genes in the steroidogenic pathway. Microarray analysis of testis of fathead minnows treated with 5 ng EE2/L or with the mixture of 5 ng EE2/L and 100 ng ZM 189,154/L indicated that some of the genes whose expression was changed by EE2 were blocked by ZM 189,154, while others were either not blocked or enhanced by the mixture, generating two distinct expression patterns. Gene ontology and pathway analysis programs were used to determine categories of genes for each expression pattern. Conclusion Our results suggest that response to estrogens occurs via multiple mechanisms, including canonical binding to soluble estrogen receptors, membrane estrogen receptors, and other mechanisms that are not blocked by pure antiestrogens.

  9. Estrogen receptor-mediated neuroprotection: The role of the Alzheimer’s disease-related gene seladin-1

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    Alessandro Peri

    2008-09-01

    Full Text Available Alessandro Peri, Mario SerioDepartment of Clinical Physiopathology, Endocrine Unit, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies (DENOThe, University of Florence, Florence, ItalyAbstract: Experimental evidence supports a protective role of estrogen in the brain. According to the fact that Alzheimer’s disease (AD is more common in postmenopausal women, estrogen treatment has been proposed. However, there is no general consensus on the beneficial effect of estrogen or selective estrogen receptor modulators in preventing or treating AD. It has to be said that several factors may markedly affect the efficacy of the treatment. A few years ago, the seladin-1 gene (for selective Alzheimer’s disease indicator-1 has been isolated and found to be down-regulated in brain regions affected by AD. Seladin-1 has been found to be identical to the gene encoding the enzyme 3-beta-hydroxysterol delta-24-reductase, involved in the cholesterol biosynthetic pathway, which confers protection against β-amyloid-mediated toxicity and from oxidative stress, and is an effective inhibitor of caspase-3 activity, a key mediator of apoptosis. Interestingly, we found earlier that the expression of this gene is up-regulated by estrogen. Furthermore, our very recent data support the hypothesis that seladin-1 is a mediator of the neuroprotective effects of estrogen. This review will summarize the current knowledge regarding the neuroprotective effects of seladin-1 and the relationship between this protein and estrogen.Keywords: seladin-1, DHCR24, estrogen, brain, Alzheimer’s disease

  10. Vaginal estrogens for the treatment of dyspareunia.

    Science.gov (United States)

    Krychman, Michael L

    2011-03-01

    Vaginal atrophy, which is associated with vaginal itching, burning, dryness, irritation, and pain, is estimated to affect up to 40% of postmenopausal women. Estrogens play a key role in maintaining vaginal health; women with low serum estradiol are more likely to experience vaginal dryness, dyspareunia, and reduced sexual activity compared with women who have higher estradiol levels. The purpose of this review is to assess the prevalence and impact of dyspareunia, a symptom of vaginal atrophy, on the health of postmenopausal women and to evaluate treatment options using vaginal estrogens (U.S. Food and Drug Administration [FDA] approved). Relevant published literature was identified by searching Index Medicus using the PubMed online database. The search terms dyspareunia, vaginal estrogen, vaginal hormone therapy, vaginal atrophy, and atrophic vaginitis were the focus of the literature review. Current treatment guidelines for vaginal atrophy recommend the use of minimally absorbed local vaginal estrogens, along with non-hormonal lubricants or moisturizers, coupled with maintenance of sexual activity. Vaginal estrogen therapy has been shown to provide improvement in the signs and symptoms of vaginal or vulvar atrophy. Vaginal tablets, rings, and creams are indicated for the treatment of vaginal atrophy, and the FDA has recently approved a low-dose regimen of conjugated estrogens cream to treat moderate-to-severe postmenopausal dyspareunia. The use of low-dose vaginal estrogens has been shown to be effective in treating symptoms of vaginal atrophy without causing significant proliferation of the endometrial lining, and no significant differences have been seen among vaginal preparations in terms of endometrial safety. Women should be informed of the potential benefits and risks of the treatment options available, and with the help of their healthcare provider, choose an intervention that is most suitable to their individual needs and circumstances. © 2010

  11. Ligands specify estrogen receptor alpha nuclear localization and degradation

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    Caze-Subra Stéphanie

    2010-12-01

    Full Text Available Abstract Background The estrogen receptor alpha (ERα is found predominately in the nucleus, both in hormone stimulated and untreated cells. Intracellular distribution of the ERα changes in the presence of agonists but the impact of different antiestrogens on the fate of ERα is a matter of debate. Results A MCF-7 cell line stably expressing GFP-tagged human ERα (SK19 cell line was created to examine the localization of ligand-bound GFP-ERα. We combined digitonin-based cell fractionation analyses with fluorescence and immuno-electron microscopy to determine the intracellular distribution of ligand-bound ERα and/or GFP-ERα. Using fluorescence- and electron microscopy we demonstrate that both endogenous ERα and GFP-ERα form numerous nuclear focal accumulations upon addition of agonist, 17β-estradiol (E2, and pure antagonists (selective estrogen regulator disruptor; SERD, ICI 182,780 or RU58,668, while in the presence of partial antagonists (selective estrogen regulator modulator; SERM, 4-hydroxytamoxifen (OHT or RU39,411, diffuse nuclear staining persisted. Digitonin based cell fractionation analyses confirmed that endogenous ERα and GFP-ERα predominantly reside in the nuclear fraction. Overall ERα protein levels were reduced after estradiol treatment. In the presence of SERMs ERα was stabilized in the nuclear soluble fraction, while in the presence of SERDs protein levels decreased drastically and the remaining ERα was largely found in a nuclear insoluble fraction. mRNA levels of ESR1 were reduced compared to untreated cells in the presence of all ligands tested, including E2. E2 and SERDs induced ERα degradation occurred in distinct nuclear foci composed of ERα and the proteasome providing a simple explanation for ERα sequestration in the nucleus. Conclusions Our results indicate that chemical structure of ligands directly affect the nuclear fate and protein turnover of the estrogen receptor alpha independently of their impact on

  12. Distinct roles for aryl hydrocarbon receptor nuclear translocator and ah receptor in estrogen-mediated signaling in human cancer cell lines.

    Directory of Open Access Journals (Sweden)

    Mark P Labrecque

    Full Text Available The activated AHR/ARNT complex (AHRC regulates the expression of target genes upon exposure to environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD. Importantly, evidence has shown that TCDD represses estrogen receptor (ER target gene activation through the AHRC. Our data indicates that AHR and ARNT act independently from each other at non-dioxin response element sites. Therefore, we sought to determine the specific functions of AHR and ARNT in estrogen-dependent signaling in human MCF7 breast cancer and human ECC-1 endometrial carcinoma cells. Knockdown of AHR with siRNA abrogates dioxin-inducible repression of estrogen-dependent gene transcription. Intriguingly, knockdown of ARNT does not effect TCDD-mediated repression of estrogen-regulated transcription, suggesting that AHR represses ER function independently of ARNT. This theory is supported by the ability of the selective AHR modulator 3',4'-dimethoxy-α-naphthoflavone (DiMNF to repress estrogen-inducible transcription. Furthermore, basal and estrogen-activated transcription of the genes encoding cathepsin-D and pS2 are down-regulated in MCF7 cells but up-regulated in ECC-1 cells in response to loss of ARNT. These responses are mirrored at the protein level with cathepsin-D. Furthermore, knock-down of ARNT led to opposite but corresponding changes in estrogen-stimulated proliferation in both MCF7 and ECC-1 cells. We have obtained experimental evidence demonstrating a dioxin-dependent repressor function for AHR and a dioxin-independent co-activator/co-repressor function for ARNT in estrogen signalling. These results provide us with further insight into the mechanisms of transcription factor crosstalk and putative therapeutic targets in estrogen-positive cancers.

  13. Transcriptional regulators transforming growth factor-β1 and estrogen-related receptor-α identified as putative mediators of calf rumen epithelial tissue development and function during weaning.

    Science.gov (United States)

    Connor, E E; Baldwin, R L; Walker, M P; Ellis, S E; Li, C; Kahl, S; Chung, H; Li, R W

    2014-07-01

    Molecular mechanisms regulating rumen epithelial development remain largely unknown. To identify gene networks and regulatory factors controlling rumen development, Holstein bull calves (n=18) were fed milk replacer only (MRO) until 42 d of age. Three calves each were euthanized at 14 and 42 d of age for tissue collection to represent preweaning, and the remaining calves were provided diets of either milk replacer + orchard grass hay (MH; n=6) to initiate weaning without development of rumen papillae, or milk replacer + calf starter (MG; n=6) to initiate weaning and development of rumen papillae. At 56 and 70 d of age, 3 calves from the MH and MG groups were euthanized for collection of rumen epithelium. Total RNA and protein were extracted for microarray analysis and to validate detected changes in selected protein expression, respectively. As expected, calves fed MRO had no rumen papillae and development of papillae was greater in MG versus MH calves. Differentially expressed genes between the MRO diet at d 42 (preweaning) versus the MG or MH diets at d 56 (during weaning) were identified using permutation analysis of differential expression. Expression of 345 and 519 transcripts was uniquely responsive to MG and MH feeding, respectively. Ingenuity Pathway Analysis (Qiagen, Redwood City, CA) indicated that the top-ranked biological function affected by the MG diet was the cell cycle, and TFGB1, FBOX01, and PPARA were identified as key transcriptional regulators of genes responsive to the MG diet and associated with development of rumen papillae. Increased expressions of TGFB1 mRNA and protein in response to the MG diet were confirmed by subsequent analyses. The top-ranking biological function affected by the MH diet was energy production. Receptors for IGF-1 and insulin, ESRRA, and PPARD were identified by ingenuity pathway analysis as transcriptional regulators of genes responsive to the MH diet. Further analysis of TGFB1 and ESRRA mRNA expression in rumen

  14. Sequential changes in the expression of Wnt- and Notch-related genes in the vagina and uterus of ovariectomized mice after estrogen exposure.

    Science.gov (United States)

    Nakamura, Takeshi; Miyagawa, Shinichi; Katsu, Yoshinao; Sato, Tomomi; Iguchi, Taisen; Ohta, Yasuhiko

    2012-01-01

    Estrogen regulates morphological changes in reproductive organs, such as the vagina and uterus, during the estrous cycles in mice. Estrogen depletion by ovariectomy in adults results in atrophy accompanied by apoptosis in vaginal and uterine cells, while estrogen treatment following ovariectomy elicits cell proliferation in both organs. Sequential changes in mRNA expression of wingless-related MMTV integration site (Wnt) and Notch signaling genes were analyzed in the vagina and uterus of ovariectomized adult mice after a single injection of 17β-estradiol to provide understanding over the molecular basis of differences in response to estrogen in these organs. We found estrogen-dependent up-regulation of Wnt4, Wnt5a and p21 and down-regulation of Wnt11, hairy/enhancer-of-split related with YRPW motif-1 (Hey1) and delta-like 4 (Dll4) in the vagina, and up-regulation of Wnt4, Wnt5a, Hey1, Heyl, Dll1, p21 and p53 and down-regulation of Wnt11, Hey2 and Dll4 in the uterus. The expression of Wnt4, Hey1, Hey2, Heyl, Dll1 and p53 showed different patterns after the estrogen injection. Expression patterns for Wnt5a, Wnt11, Dll4 and p21 in the vagina and uterus were similar, suggesting that these genes are involved in the proliferation of cells in both those organs in mice.

  15. Intratumoral levels of estrogens in breast cancer.

    Science.gov (United States)

    Blankenstein, M A; van de Ven, J; Maitimu-Smeele, I; Donker, G H; de Jong, P C; Daroszewski, J; Szymczak, J; Milewicz, A; Thijssen, J H

    1999-01-01

    Breast cancer tissue is an endocrine organ and particularly the estrogen biosynthetic properties of this tissue have been well studied. The concentration of estradiol in breast cancer tissue from postmenopausal patients is considerably higher than that in the circulation and appears to depend largely on local production. Androgenic precursor steroids are abundantly present, but estrogen storage pools like fatty acid derivatives appear to be less important than initially thought. New, potent and highly specific aromatase inhibitors effectively inhibit peripheral conversion of androgens to estrogens (Cancer Res. 53: 4563, 1993) as well as intratumour aromatase, median aromatase activity being 89% lower in the tissue from patients pretreated with aromatase inhibitor 7 days prior to surgery (P < 0.001). Also the intratissue concentrations of estrogens were decreased (64% and 80% reduction, respectively for estrone and estradiol; P = 0.001 and <0.05; Cancer Res. 57: 2109, 1997). These results illustrate that intratissue estrogen biosynthesis is effectively inhibited by the new generation of aromatase inhibitors. The pathophysiological consequences of this finding are currently under study.

  16. Estrogenicity of glabridin in Ishikawa cells.

    Directory of Open Access Journals (Sweden)

    Melissa Su Wei Poh

    Full Text Available Glabridin is an isoflavan from licorice root, which is a common component of herbal remedies used for treatment of menopausal symptoms. Past studies have shown that glabridin resulted in favorable outcome similar to 17β-estradiol (17β-E2, suggesting a possible role as an estrogen replacement therapy (ERT. This study aims to evaluate the estrogenic effect of glabridin in an in-vitro endometrial cell line -Ishikawa cells via alkaline phosphatase (ALP assay and ER-α-SRC-1-co-activator assay. Its effect on cell proliferation was also evaluated using Thiazoyl blue tetrazolium bromide (MTT assay. The results showed that glabridin activated the ER-α-SRC-1-co-activator complex and displayed a dose-dependent increase in estrogenic activity supporting its use as an ERT. However, glabridin also induced an increase in cell proliferation. When glabridin was treated together with 17β-E2, synergistic estrogenic effect was observed with a slight decrease in cell proliferation as compared to treatment by 17β-E2 alone. This suggest that the combination might be better suited for providing high estrogenic effects with lower incidences of endometrial cancer that is associated with 17β-E2.

  17. Brain aromatase (Cyp19A2) and estrogen receptors, in larvae and adult pejerrey fish Odontesthes bonariensis: Neuroanatomical and functional relations

    Science.gov (United States)

    Strobl-Mazzulla, P. H.; Lethimonier, C.; Gueguen, M.M.; Karube, M.; Fernandino, J.I.; Yoshizaki, G.; Patino, R.; Strussmann, C.A.; Kah, O.; Somoza, G.M.

    2008-01-01

    Although estrogens exert many functions on vertebrate brains, there is little information on the relationship between brain aromatase and estrogen receptors. Here, we report the cloning and characterization of two estrogen receptors, ?? and ??, in pejerrey. Both receptors' mRNAs largely overlap and were predominantly expressed in the brain, pituitary, liver, and gonads. Also brain aromatase and estrogen receptors were up-regulated in the brain of estradiol-treated males. In situ hybridization was performed to study in more detail, the distribution of the two receptors in comparison with brain aromatase mRNA in the brain of adult pejerrey. The estrogen receptors' mRNAs exhibited distinct but partially overlapping patterns of expression in the preoptic area and the mediobasal hypothalamus, as well as in the pituitary gland. Moreover, the estrogen receptor ??, but not ??, were found to be expressed in cells lining the preoptic recess, similarly as observed for brain aromatase. Finally, it was shown that the onset expression of brain aromatase and both estrogen receptors in the head of larvae preceded the morphological differentiation of the gonads. Because pejerrey sex differentiation is strongly influenced by temperature, brain aromatase expression was measured during the temperature-sensitive window and was found to be significantly higher at male-promoting temperature. Taken together these results suggest close neuroanatomical and functional relationships between brain aromatase and estrogen receptors, probably involved in the sexual differentiation of the brain and raising interesting questions on the origin (central or peripheral) of the brain aromatase substrate. ?? 2008 Elsevier Inc.

  18. Unliganded estrogen receptor α stimulates bone sialoprotein gene expression.

    Science.gov (United States)

    Takai, Hideki; Matsumura, Hiroyoshi; Matsui, Sari; Kim, Kyung Mi; Mezawa, Masaru; Nakayama, Yohei; Ogata, Yorimasa

    2014-04-10

    Estrogen is one of the steroid hormones essential for skeletal development. The estrogen receptor (ER) is a transcription factor and a member of the steroid receptor superfamily. There are two different forms of the ER, usually referred to as α and β, each encoded by a separate gene. Hormone-activated ERs form dimers, since the two forms are coexpressed in many cell types. Bone sialoprotein (BSP) is a tissue-specific acidic glycoprotein that is expressed by differentiated osteoblasts, odontoblasts and cementoblasts during the initial formation of mineralized tissue. To determine the molecular basis of the tissue-specific expression of BSP and its regulation by estrogen and the ER, we have analyzed the effects of β-estradiol and ERα on BSP gene transcription. ERα protein levels were increased after ERα overexpression in ROS17/2.8 cells. While BSP mRNA levels were increased by ERα overexpression, the endogenous and overexpressed BSP mRNA levels were not changed by β-estradiol (10(-8)M, 24 h). Luciferase activities of different sized BSP promoter constructs (pLUC3~6) were increased by ERα overexpression, whereas basal and induced luciferase activities by ERα overexpression were not influenced by β-estradiol. Effects of ERα overexpression were abrogated by 2 bp mutations in either the cAMP response element (CRE) or activator protein 1 (AP1)/glucocorticoid response element (GRE). Gel shift analyses showed that ERα overexpression increased binding to the CRE and AP1/GRE elements. Notably, the CRE-protein complexes were disrupted by ERα, CREB and phospho-CREB antibodies. The AP1/GRE-protein complexes were supershifted by the c-Fos antibody. These studies demonstrate that ERα stimulates BSP gene transcription in a ligand-independent manner by targeting the CRE and AP1/GRE elements in the rat BSP gene promoter. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Non-feminizing estrogens: a novel neuroprotective therapy.

    Science.gov (United States)

    Petrone, Ashley B; Gatson, Joshua W; Simpkins, James W; Reed, Miranda N

    2014-05-25

    While the conflict between basic science evidence for estrogen neuroprotection and the lack of effectiveness in clinical trials is only now being resolved, it is clear that strategies for estrogen neuroprotection that avoid activation of ERs have the potential for clinical application. Herein we review the evidence from both in vitro and in vivo studies that describe high potency neuroprotection with non-feminizing estrogens. We have characterized many of the essential chemical features of non-feminizing estrogens that eliminate or reduce ER binding while maintaining or enhancing neuroprotection. Additionally, we provide evidence that these non-feminizing estrogens have efficacy in protecting the brain from AD neuropathology and traumatic brain injury. In conclusion, it appears that the non-feminizing estrogen strategy for neuroprotection is a viable option to achieve the beneficial neuroprotective effects of estrogens while eliminating the toxic off-target effects of chronic estrogen administration. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. Conditional expression of constitutively active estrogen receptor {alpha} in chondrocytes impairs longitudinal bone growth in mice

    Energy Technology Data Exchange (ETDEWEB)

    Ikeda, Kazuhiro [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Tsukui, Tohru [Experimental Animal Laboratory, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Imazawa, Yukiko; Horie-Inoue, Kuniko [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Inoue, Satoshi, E-mail: INOUE-GER@h.u-tokyo.ac.jp [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer Conditional transgenic mice expressing constitutively active estrogen receptor {alpha} (caER{alpha}) in chondrocytes were developed. Black-Right-Pointing-Pointer Expression of caER{alpha} in chondrocytes impaired longitudinal bone growth in mice. Black-Right-Pointing-Pointer caER{alpha} affects chondrocyte proliferation and differentiation. Black-Right-Pointing-Pointer This mouse model is useful for understanding the physiological role of ER{alpha}in vivo. -- Abstract: Estrogen plays important roles in the regulation of chondrocyte proliferation and differentiation, which are essential steps for longitudinal bone growth; however, the mechanisms of estrogen action on chondrocytes have not been fully elucidated. In the present study, we generated conditional transgenic mice, designated as caER{alpha}{sup ColII}, expressing constitutively active mutant estrogen receptor (ER) {alpha} in chondrocytes, using the chondrocyte-specific type II collagen promoter-driven Cre transgenic mice. caER{alpha}{sup ColII} mice showed retardation in longitudinal growth, with short bone lengths. BrdU labeling showed reduced proliferation of hypertrophic chondrocytes in the proliferating layer of the growth plate of tibia in caER{alpha}{sup ColII} mice. In situ hybridization analysis of type X collagen revealed that the maturation of hypertrophic chondrocytes was impaired in caER{alpha}{sup ColII} mice. These results suggest that ER{alpha} is a critical regulator of chondrocyte proliferation and maturation during skeletal development, mediating longitudinal bone growth in vivo.

  1. Estrogen receptor affinity chromatography: a new method for characterization of novel estrogenic disinfection by-products.

    Science.gov (United States)

    Shang, Guodong; Xue, Jinling; Li, Man; Hu, Hong-Ying; Lu, Yun

    2014-06-01

    To identify the unknown estrogenic disinfection by-products (DBPs) from the chlorination extract, an effective method based on affinity chromatography with immobilized human recombinant estrogen receptor α (ERα) was developed, which has an advantage in targeting different potential estrogenic compounds from mixed sample simultaneously by comparing their relative binding activities to ER. The new method worked well for six known environmental estrogens. To further test the validity of this method for unknown chemicals, six DBPs of diethylstilbestrol (DES) with relatively strong ER binding affinity after chlorination were isolated and identified. It was found that except for 2-chloro-DES which showed 1.36 times stronger binding affinity than DES, most of the by-products bound to ER much more weakly than DES. All these seven by-products induced a dose-dependent transcriptional activation in two-hybrid-yeast assays. Z,Z-dienestrol (DE) and 2-chloro-DES, which exhibiting the weakest and the strongest binding affinity, were further tested for their transcriptional potential as 0.00243 and 0.014 compared to DES, respectively. However, they were still potential harmful environmental estrogenic disruptors as their estrogenic activities were much stronger than that of bisphenol A (BPA). These results demonstrated that the new method can help to screen unknown estrogenic compounds from mixture more efficiently. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Estrogen-associated severe hypertriglyceridemia with pancreatitis.

    Science.gov (United States)

    Aljenedil, Sumayah; Hegele, Robert A; Genest, Jacques; Awan, Zuhier

    Estrogen, whether therapeutic or physiologic, can cause hypertriglyceridemia. Hypertriglyceridemia-induced pancreatitis is a rare complication. We report 2 women who developed estrogen-associated severe hypertriglyceridemia with pancreatitis. The first patient developed pancreatitis secondary to hypertriglyceridemia associated with in vitro fertilization cycles. Marked reduction in her triglyceride was achieved with dietary restrictions and fibrate. The second patient developed pancreatitis secondary to hypertriglyceridemia during her pregnancies. She was noncompliant with the treatment; therefore, her triglyceride remained high after delivery. In both patients, no hypertriglyceridemia-associated genes mutations were identified, although the second patient had strong polygenic susceptibility to hypertriglyceridemia. Estrogen-induced severe hypertriglyceridemia with pancreatitis can be a life-threatening condition. Screening in high-risk patients is crucial to prevent subsequent complications. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  3. Use of vaginal estrogen in Danish women

    DEFF Research Database (Denmark)

    Meaidi, Amani; Goukasian, Irina; Lidegaard, Oejvind

    2016-01-01

    INTRODUCTION: We know little about the use of vaginal estrogen in perimenopausal and postmenopausal women. We aimed to assess the prevalence of vaginal estrogen use in Denmark. MATERIAL AND METHODS: The study was designed as a nationwide cross-sectional study of all Danish women aged 40-79 years......, living in Denmark during the period 2007-2013. The Danish Prescription Register delivered data permitting us to assess the prevalence, age and regional geographical belonging of women purchasing prescribed vaginal estradiol. The number of women using over-the-counter vaginal estriol products...... was estimated from sale statistics from the same register. RESULTS: In 2013, 10.2% of all Danish women between 40 and 79 years of age used vaginal estradiol. The prevalence of women using this type of vaginal estrogen increased from 8.5% in year 2007 to 10.2% in 2013. The use peaked at 16.5% in women aged 60...

  4. Estrogenic and anti-estrogenic activity of 23 commercial textile dyes.

    Science.gov (United States)

    Bazin, Ingrid; Ibn Hadj Hassine, Aziza; Haj Hamouda, Yosra; Mnif, Wissem; Bartegi, Ahgleb; Lopez-Ferber, Miguel; De Waard, Michel; Gonzalez, Catherine

    2012-11-01

    The presence of dyes in wastewater effluent of textile industry is well documented. In contrast, the endocrine disrupting effects of these dyes and wastewater effluent have been poorly investigated. Herein, we studied twenty-three commercial dyes, usually used in the textile industry, and extracts of blue jean textile wastewater samples were evaluated for their agonistic and antagonistic estrogen activity. Total estrogenic and anti-estrogenic activities were measured using the Yeast Estrogen Screen bioassay (YES) that evaluates estrogen receptor binding-dependent transcriptional and translational activities. The estrogenic potencies of the dyes and wastewater samples were evaluated by dose-response curves and compared to the dose-response curve of 17β-estradiol (E2), the reference compound. The dose-dependent anti-estrogenic activities of the dyes and wastewater samples were normalized to the known antagonistic effect of 4-hydroxytamoxifen (4-OHT) on the induction of the lac Z reporter gene by E2. About half azo textile dyes have anti-estrogenic activity with the most active being Blue HFRL. Most azo dyes however have no or weak estrogenic activity. E2/dye or E2/waste water ER competitive binding assays show activity of Blue HFRL, benzopurpurine 4B, Everzol Navy Blue FBN, direct red 89 BNL 200% and waste water samples indicating a mechanism of action common to E2. Our results indicate that several textile dyes are potential endocrine disrupting agents. The presence of some of these dyes in textile industry wastewater may thus impact the aquatic ecosystem. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. DEHP exposure impairs mouse oocyte cyst breakdown and primordial follicle assembly through estrogen receptor-dependent and independent mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Mu, Xinyi [Laboratory of Reproductive Biology, Chongqing Medical University, Chongqing 400016 (China); Department of Histology and Embryology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016 (China); Liao, Xinggui; Chen, Xuemei; Li, Yanli; Wang, Meirong; Shen, Cha; Zhang, Xue; Wang, Yingxiong; Liu, Xueqing [Laboratory of Reproductive Biology, Chongqing Medical University, Chongqing 400016 (China); He, Junlin, E-mail: hejunlin_11@aliyun.com [Laboratory of Reproductive Biology, Chongqing Medical University, Chongqing 400016 (China)

    2015-11-15

    Highlights: • DEHP inhibits primordial folliculogenesis in vivo and in vitro. • Estrogen receptors participate in the effect of DEHP on early ovarian development. • DEHP exposure impairs the expression of Notch2 signaling components. • DEHP exposure disrupts the proliferation of pregranulosa precursor cells. - Abstract: Estrogen plays an essential role in the development of mammalian oocytes, and recent studies suggest that it also regulates primordial follicle assembly in the neonatal ovaries. During the last decade, potential exposure of humans and animals to estrogen-like endocrine disrupting chemicals has become a growing concern. In the present study, we focused on the effect of diethylhexyl phthalate (DEHP), a widespread plasticizer with estrogen-like activity, on germ-cell cyst breakdown and primordial follicle assembly in the early ovarian development of mouse. Neonatal mice injected with DEHP displayed impaired cyst breakdown. Using ovary organ cultures, we revealed that impairment was mediated through estrogen receptors (ERs), as ICI 182,780, an efficient antagonist of ER, reversed this DEHP-mediated effect. DEHP exposure reduced the expression of ERβ, progesterone receptor (PR), and Notch2 signaling components. Finally, DEHP reduced proliferation of pregranulosa precursor cells during the process of primordial folliculogenesis. Together, our results indicate that DEHP influences oocyte cyst breakdown and primordial follicle formation through several mechanisms. Therefore, exposure to estrogen-like chemicals during fetal or neonatal development may adversely influence early ovarian development.

  6. WISP-2 is a secreted protein and can be a marker of estrogen exposure in MCF-7 cells.

    Science.gov (United States)

    Inadera, Hidekuni; Dong, Hong-Yan; Matsushima, Kouji

    2002-06-14

    As many structurally diverse chemicals have been reported to function as estrogens, evaluations for estrogenicity of compounds are of widespread concern. Recently, we identified WISP-2 (Wnt-1 inducible signaling pathway protein 2) as a novel estrogen-inducible gene in human breast cancer cells. In this study, we examined whether WISP-2 could be utilized as a marker for screening environmentally relevant compounds for estrogenicity. In MCF-7 cells, progesterone, dexamethasone, tri-iodothyronine, and 2,3,7,8-tetrachlorodibenzo-p-dioxin did not regulate the expression of WISP-2, indicating that its induction is highly specific for hormones that interact with the estrogen receptor. Western blot analysis detected WISP-2 protein induced by 17-beta-estradiol (E2), not only in the cell lysates but also in the culture supernatant of exposed cells, indicating that WISP-2 was a secreted protein. The induction of WISP-2 protein by E2 in the culture supernatant was dose-dependent with estimated EC(50) levels between 10 and 100 pM. Our results demonstrated the capacity to screen environmental compounds for estrogenicity via WISP-2 induction.

  7. Estrogenic activity of flavonoids in mice. The importance of estrogen receptor distribution, metabolism and bioavailability

    DEFF Research Database (Denmark)

    Breinholt, Vibeke; Hossaini, A.; Svendsen, Gitte W.

    2000-01-01

    The in vivo estrogenic potential of the flavonoids apigenin, kaempferol, genistein and equol was investigated in immature female mice. Genistein and equol, administered by gavage for 4 consecutive days [post-natal day (PND) 17-20, 100 mg/kg body weight], was found to significantly increase uterine...... or lower potency. Bioavailability, metabolism, the ability to alter ER alpha distribution in the uterus and the estrogenic potential of parent compound and metabolites may thus contribute to the differences in in vivo estrogenicity of dietary flavonoids....

  8. The Tissue-Selective Estrogen Complex (Bazedoxifene/Conjugated Estrogens for the Treatment of Menopause

    Directory of Open Access Journals (Sweden)

    Stefano Lello

    2017-01-01

    Full Text Available The tissue-selective estrogen complex (TSEC pairs conjugated estrogens (CE with a selective estrogen receptor modulator (SERM, bazedoxifene acetate (BZA. A 2-year treatment with the TSEC improved vasomotor symptoms, quality of life, and vaginal atrophy in healthy postmenopausal women. In addition, the TSEC prevented vertebral and hip bone loss without increasing mammographic density, breast tenderness, the risk of myocardial infarction, stroke, or venous thromboembolism. Finally, the BZA 20 mg/CE 0.45 mg dose did not increase the risk of endometrial hyperplasia. Based on these findings, the TSEC can be considered as a first-line treatment for symptomatic postmenopausal women.

  9. Antiapoptotic effects of estrogen in normal and cancer human cervical epithelial cells.

    Science.gov (United States)

    Wang, Qifang; Li, Xin; Wang, Liqin; Feng, Ying-Hong; Zeng, Robin; Gorodeski, George

    2004-12-01

    The present study investigated the antiapoptotic effects of estrogen in normal and cancer human cervical cells and the mechanisms involved. Baseline apoptosis in human cervical epithelial cells is mediated predominantly by P2X7-receptor-induced, Ca(2+)-dependent activation of the mitochondrial (caspase-9) pathway. Treatment with 10 nM 17beta-estradiol blocked apoptosis induced by the P2X7-receptor ligands ATP and 2',3'-0-(4-benzoylbenzoyl)-ATP in normal human cervical epithelial cells (hECEs) and attenuated the effect in hECEs immortalized with human papillomavirus-16 (ECE16-1) and the cancer cervical cells HT3 and CaSki. Diethylstilbestrol and to a lesser degree estrone could mimic the effects of 17beta-estradiol, whereas actinomycin-D and cycloheximide attenuated the response. The antiapoptotic effect of estrogen did not depend on cell cycle phase, and in both normal and cancer cervical cells, it involved attenuation of activation of caspase-9 and the terminal caspase-3. However, involvement of cascades upstream to the caspase-9 differed in normal vs. cancer cervical cells. In the normal hECEs estrogen blocked P2X7-receptor-induced calcium influx. In contrast, in the cancer CaSki cells, estrogen up-regulated expression of Bcl-2 and attenuated Ca(2+)-induced mitochondrial swelling (i.e. formation of mitochondrial permeability transition pores). Estrogen had no effect on P2X7-receptor-induced apoptosis in the anaplastic SiHa and Hela cells. These results point to a novel antiapoptotic effect of estrogen in the cervix that is independent of its mitogenic function. The results also suggest that cancer cervical cells evolved antiapoptotic mechanisms that enable the cells to evade apoptosis and could therefore promote tumor progression.

  10. Molecular analysis of the vaginal response to estrogens in the ovariectomized rat and postmenopausal woman

    Directory of Open Access Journals (Sweden)

    Peano Bryan J

    2008-06-01

    Full Text Available Abstract Background Vaginal atrophy (VA is the thinning of the vaginal epithelial lining, typically the result of lowered estrogen levels during menopause. Some of the consequences of VA include increased susceptibility to bacterial infection, pain during sexual intercourse, and vaginal burning or itching. Although estrogen treatment is highly effective, alternative therapies are also desired for women who are not candidates for post-menopausal hormone therapy (HT. The ovariectomized (OVX rat is widely accepted as an appropriate animal model for many estrogen-dependent responses in humans; however, since reproductive biology can vary significantly between mammalian systems, this study examined how well the OVX rat recapitulates human biology. Methods We analyzed 19 vaginal biopsies from human subjects pre and post 3-month 17β-estradiol treated by expression profiling. Data were compared to transcriptional profiling generated from vaginal samples obtained from ovariectomized rats treated with 17β-estradiol for 6 hrs, 3 days or 5 days. The level of differential expression between pre- vs. post- estrogen treatment was calculated for each of the human and OVX rat datasets. Probe sets corresponding to orthologous rat and human genes were mapped to each other using NCBI Homologene. Results A positive correlation was observed between the rat and human responses to estrogen. Genes belonging to several biological pathways and GO categories were similarly differentially expressed in rat and human. A large number of the coordinately regulated biological processes are already known to be involved in human VA, such as inflammation, epithelial development, and EGF pathway activation. Conclusion At the transcriptional level, there is evidence of significant overlap of the effects of estrogen treatment between the OVX rat and human VA samples.

  11. Predicting response to the anti-estrogen fulvestrant in recurrent ovarian cancer.

    Science.gov (United States)

    Argenta, Peter A; Um, Inhwa; Kay, Charlene; Harrison, David; Faratian, Dana; Sueblinvong, Thanasak; Geller, Melissa A; Langdon, Simon P

    2013-11-01

    Anti-estrogen therapy appears to have efficacy in a subset of ovarian cancers, as demonstrated in multiple phase II studies. Identifying sensitive patients early in treatment may allow for targeted, low-toxicity primary therapy or prevention of recurrence. We have previously demonstrated that the likelihood of response to letrozole could be improved by patient selection based on estrogen-pathway marker expression. We sought to identify ovarian cancer biomarkers that might indicate sensitivity to fulvestrant, an estrogen receptor antagonist. Tissue samples from the primary tumors of patients enrolled in a phase II study of fulvestrant for the treatment of multiply-recurrent ovarian cancer were embedded randomly in a tissue microarray (TMA). Estrogen receptor alpha (ERα) expression was assessed by both conventional immunohistochemistry (IHC) and quantitative immunofluorescence (IF) (AQUA) while expression of 14 other estrogen-regulated markers was assessed by quantitative IF and correlated with clinical outcomes. Almost half of patients experienced clinical benefit (CR+PR+SD) at 90 days despite a median of 5 previous treatment regimens. 24 of 26 patient samples were available and included in the TMA. ERα expression, measured either by conventional IHC or by AQUA analysis, was associated with clinical benefit, while TFF1 and vimentin expression (measured by IF AQUA score) was predictive of progression-free survival. These results confirm our previous observation that clinical ovarian cancer includes a subset of tumors with sensitivity to estrogen pathway blockade. Expression profile of sensitive tumors appears to be detectably different from insensitive tumors, suggesting that further improvements in treatment efficacy can be obtained through appropriate patient selection. © 2013.

  12. Ritonavir binds to and downregulates estrogen receptors: Molecular mechanism of promoting early atherosclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Xiang, Jin [Ministry of Education Laboratory of Combinatorial Biosynthesis and Drug Discovery, School of Pharmaceutical Science, Wuhan University, Wuhan 430071 (China); Wang, Ying [Department of Pathophysiology, School of Medicine, Wuhan University, Wuhan 430071 (China); Su, Ke [Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Liu, Min [Ministry of Education Laboratory of Combinatorial Biosynthesis and Drug Discovery, School of Pharmaceutical Science, Wuhan University, Wuhan 430071 (China); Hu, Peng-Chao [Department of Pathophysiology, School of Medicine, Wuhan University, Wuhan 430071 (China); Ma, Tian; Li, Jia-Xi [Ministry of Education Laboratory of Combinatorial Biosynthesis and Drug Discovery, School of Pharmaceutical Science, Wuhan University, Wuhan 430071 (China); Wei, Lei [Department of Pathophysiology, School of Medicine, Wuhan University, Wuhan 430071 (China); Zheng, Zhongliang, E-mail: biochem@whu.edu.cn [State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072 (China); Yang, Fang, E-mail: fang-yang@whu.edu.cn [Department of Physiology, School of Medicine, Wuhan University, Wuhan 430071 (China)

    2014-10-01

    Estrogenic actions are closely related to cardiovascular disease. Ritonavir (RTV), a human immunodeficiency virus (HIV) protease inhibitor, induces atherosclerosis in an estrogen-related manner. However, how RTV induce pathological phenotypes through estrogen pathway remains unclear. In this study, we found that RTV increases thickness of coronary artery walls of Sprague Dawley rats and plasma free fatty acids (FFA) levels. In addition, RTV could induce foam cell formation, downregulate both estrogen receptor α (ERα) and ERβ expression, upregulate G protein-coupled estrogen receptor (GPER) expression, and all of them could be partially blocked by 17β-estradiol (E2), suggesting RTV acts as an antagonist for E2. Computational modeling shows a similar interaction with ERα between RTV and 2-aryl indoles, which are highly subtype-selective ligands for ERα. We also found that RTV directly bound to ERα and selectively inhibited the nuclear localization of ERα, and residue Leu536 in the hydrophobic core of ligand binding domain (LBD) was essential for the interaction with RTV. In addition, RTV did not change the secondary structure of ERα-LBD like E2, which explained how ERα lost the capacity of nuclear translocation under the treatment of RTV. All of the evidences suggest that ritonavir acts as an antagonist for 17β-estradiol in regulating α subtype estrogen receptor function and early events of atherosclerosis. - Graphical abstract: RTV directly binds to ERα and Leu536 in the hydrophobic core of ligand binding domain is essential for the interaction. - Highlights: • RTV increases the thickness of rat coronary artery wall and foam cell formation. • RTV downregulates the expression of ERα and ERβ. • RTV inhibits ERα promoter activity. • RTV directly binds to ERα and the key amino acid is Leu536. • RTV inhibits the nuclear translocation of ERα and GPER.

  13. Selective estrogen receptor modulators (SERMs): Mechanisms of anticarcinogenesis and drug resistance

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, Joan S. [Fox Chase Cancer Center, Alfred G. Knudson Chair of Cancer Research, 333 Cottman Avenue, Philadelphia, PA 19111 (United States); Jordan, V. Craig [Fox Chase Cancer Center, Alfred G. Knudson Chair of Cancer Research, 333 Cottman Avenue, Philadelphia, PA 19111 (United States)]. E-mail: v.craig.jordan@fccc.edu

    2005-12-11

    Despite the beneficial effects of estrogens in women's health, there is a plethora of evidence that suggest an important role for these hormones, particularly 17{beta}-estradiol (E{sub 2}), in the development and progression of breast cancer. Most estrogenic responses are mediated by estrogen receptors (ERs), either ER{alpha} or ER{beta}, which are members of the nuclear receptor superfamily of ligand-dependent transcription factors. Selective estrogen receptor modulators (SERMs) are ER ligands that in some tissues (i.e. bone and cardiovascular system) act like estrogens but block estrogen action in others. Tamoxifen is the first SERM that has been successfully tested for the prevention of breast cancer in high-risk women and is currently approved for the endocrine treatment of all stages of ER-positive breast cancer. Raloxifene, a newer SERM originally developed for osteoporosis, also appears to have preventive effect on breast cancer incidence. Numerous studies have examined the molecular mechanisms for the tissue selective action of SERMs, and collectively they indicate that different ER ligands induce distinct conformational changes in the receptor that influence its ability to interact with coregulatory proteins (i.e. coactivators and corepressors) critical for the regulation of target gene transcription. The relative expression of coactivators and corepressors, and the nature of the ER and its target gene promoter also affect SERM biocharacter. This review summarizes the therapeutic application of SERMs in medicine; particularly breast cancer, and highlights the emerging understanding of the mechanism of action of SERMs in select target tissues, and the inevitable development of resistance.

  14. Estrogen and colorectal cancer incidence and mortality.

    Science.gov (United States)

    Lavasani, Sayeh; Chlebowski, Rowan T; Prentice, Ross L; Kato, Ikuko; Wactawski-Wende, Jean; Johnson, Karen C; Young, Alicia; Rodabough, Rebecca; Hubbell, F Allan; Mahinbakht, Ali; Simon, Michael S

    2015-09-15

    The preponderance of observational studies describe an association between the use of estrogen alone and a lower incidence of colorectal cancer. In contrast, no difference in the incidence of colorectal cancer was seen in the Women's Health Initiative (WHI) randomized, placebo-controlled trial with estrogen alone after a mean intervention of 7.1 years and cumulative follow-up of 13.2 years. This study extends these findings by providing detailed analyses of the effects of estrogen alone on the histology, grade, and stage of colorectal cancer, relevant subgroups, and deaths from and after colorectal cancer. The WHI study was a randomized, double-blind, placebo-controlled trial involving 10,739 postmenopausal women with prior hysterectomy. Participants were assigned to conjugated equine estrogen at 0.625 mg/d (n = 5279) or a matching placebo (n = 5409). Rates of colorectal cancer diagnoses and deaths from and after colorectal cancer were assessed throughout the study. Colorectal cancer rates in the estrogen-alone and placebo groups were comparable: 0.14% and 0.12% per year, respectively (hazard ratio [HR], 1.13; 95% confidence interval [CI], 0.83-1.58; P = .43). Bowel screening examinations were comparable between the 2 groups throughout the study. The grade, stage, and location of colorectal cancer did not differ between the randomization groups. There were more colorectal cancer deaths in the estrogen-alone group (34 [0.05%] vs 24 [0.03%]; HR, 1.46, 95% CI, 0.86-2.46; P = .16), but the difference was not statistically significant. The colorectal cancer incidence was higher for participants with a history of colon polyp removal in the estrogen-alone group (0.23% vs 0.02%; HR, 13.47; nominal 95% CI, 1.76-103.0; P colorectal cancer or deaths from or after colorectal cancer. A possibly higher risk of colorectal cancer in women with prior colon polyp removal who use estrogen alone requires confirmation. © 2015 American Cancer Society.

  15. Neuroprotection from Brain Injury by Novel Estrogens

    Science.gov (United States)

    2001-08-01

    Cholst I, McEwen B, Amador R, Zabriskie J. Observations in a preliminary open trial of estradiol therapy for senile dementia -Alzheimer’s type...system- senile dementia (Alzheimer’s type). J Steroid Biochem 1989;34:521-25. 6. Ohkura T, Isse K, Akazawa K, Hamamoto M, Yaoi Y, Hagino N. Low-dose estro...Postmenopausal estrogen use and Parkinson’s disease with Neuronal effects of estrogens with weak ER agonist ac- and without dementia . Neurology 50:1141-1143

  16. CERAPP: Collaborative estrogen receptor activity prediction project

    DEFF Research Database (Denmark)

    Mansouri, Kamel; Abdelaziz, Ahmed; Rybacka, Aleksandra

    2016-01-01

    Background: Humans are exposed to thousands of man-made chemicals in the environment. Some chemicals mimic natural endocrine hormones and, thus, have the potential to be endocrine disruptors. Most of these chemicals have never been tested for their ability to interact with the estrogen receptor (ER......). Risk assessors need tools to prioritize chemicals for evaluation in costly in vivo tests, for instance, within the U.S. EPA Endocrine Disruptor Screening Program. oBjectives: We describe a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity Prediction Project...

  17. Estrogen and cigarette sidestream smoke particulate matter exhibit ERα-dependent tumor-promoting effects in lung adenocarcinoma cells.

    Science.gov (United States)

    Kuo, Lun-Cheng; Cheng, Li-Chuan; Lee, Chia-Huei; Lin, Chun-Ju; Chen, Pei-Yu; Li, Lih-Ann

    2017-09-01

    Estrogen and secondhand smoke are key risk factors for nonsmoking female lung cancer patients who frequently have lung adenocarcinoma and show tumor estrogen receptor α (ERα) expression. We speculated that estrogen and secondhand smoke might cause harmful effects via ERα signaling. Our results showed that 17β-estradiol (E2), the primary form of endogenous estrogen, exacerbated proliferation, migration, and granzyme B resistance of lung adenocarcinoma cells in an ERα-dependent manner. Cigarette sidestream smoke particulate matter (CSSP), the major component of secondhand smoke, could activate ERα activity dose dependently in human lung adenocarcinoma cells. The estrogenic activity of CSSP was abolished by an ERα-selective antagonist. CSSP regulated the nuclear entry, phosphorylation, and turnover of ERα similarly to E2. Furthermore, CSSP enhanced E2-stimulated ERα activity and Ser118 phosphorylation even when ERα became saturated with E2. Activation of ERα by CSSP required GSK3β activity, but not involving polycyclic aromatic hydrocarbons, reactive oxygen species, calcium, epidermal growth factor receptor, and PI3K/Akt. Although CSSP possessed cytotoxicity, ERα-expressing cells grew and migrated faster than nonexpressing cells on recovery from CSSP exposure as observed in E2-pretreated cells. Knockdown of ERα by siRNA diminished E2- and CSSP-stimulated cell migration. Twenty-one genes, including SERPINB9, were identified to be upregulated by both E2 and CSSP via ERα. Increased SERPINB9 expression was accompanied with increased resistance to granzyme B-mediated apoptosis. This study demonstrates that estrogen has ERα-dependent tumor-promoting activity. CSSP acts like estrogen and shows a potential to enhance estrogen-induced ERα action. Copyright © 2017 the American Physiological Society.

  18. 21 CFR 310.515 - Patient package inserts for estrogens.

    Science.gov (United States)

    2010-04-01

    ... package inserts for estrogens. (a) Requirement for a patient package insert. FDA concludes that the safe... the Federal Food, Drug, and Cosmetic Act. (b) Distribution requirements. (1) For estrogen drug...) Exemptions. This section does not apply to estrogen-progestogen oral contraceptives. Labeling requirements...

  19. Cumulative Estrogen Exposure and Prospective Memory in Older Women

    Science.gov (United States)

    Hesson, Jacqueline

    2012-01-01

    This study looked at cumulative lifetime estrogen exposure, as estimated with a mathematical index (Index of Cumulative Estrogen Exposure (ICEE)) that included variables (length of time on estrogen therapy, age at menarche and menopause, postmenopausal body mass index, time since menopause, nulliparity and duration of breastfeeding) known to…

  20. Oxytocin and Estrogen Receptor β in the Brain: An Overview

    Directory of Open Access Journals (Sweden)

    Alexandra eAcevedo-Rodriguez

    2015-10-01

    Full Text Available Oxytocin is a neuropeptide synthesized primarily by neurons of the paraventricular and supraoptic nuclei of the hypothalamus. These neurons have axons that project into the posterior pituitary and release oxytocin into the bloodstream to promote labor and lactation; however, oxytocin neurons also project to other brain areas where it plays a role in numerous brain functions. Oxytocin binds to the widely expressed oxytocin receptor, and, in doing so, it regulates homeostatic processes, social recognition and fear conditioning. In addition to these functions, oxytocin decreases neuroendocrine stress signaling and anxiety-related and depression-like behaviors. Steroid hormones differentially modulate stress responses and alter oxytocin receptor expression. In particular, estrogen receptor β activation has been found to both reduce anxiety-related behaviors and increase oxytocin peptide transcription, suggesting a role for oxytocin in this estrogen receptor β mediated anxiolytic effect. Further research is needed to identify modulators of oxytocin signaling and the pathways utilized and to elucidate molecular mechanisms controlling oxytocin expression to allow better therapeutic manipulations of this system in patient populations.

  1. Estrogen activates rapid signaling in the brain: role of estrogen receptor alpha and estrogen receptor beta in neurons and glia.

    Science.gov (United States)

    Mhyre, A J; Dorsa, D M

    2006-01-01

    The aging process is known to coincide with a decline in circulating sex hormone levels in both men and women. Due to an increase in the average lifespan, a growing number of post-menopausal women are now receiving hormone therapy for extended periods of time. Recent findings of the Women's Health Initiative, however, have called into question the benefits of long-term hormone therapy for treating symptoms of menopause. The results of this study are still being evaluated, but it is clear that a better understanding of the molecular effects of estradiol is needed in order to develop new estrogenic compounds that activate specific mechanisms but lack adverse side effects. Traditionally, the effects of estradiol treatment have been ascribed to changes in gene expression, namely transcription at estrogen response elements. This review focuses on emerging information that estradiol can also activate a repertoire of membrane-initiated signaling pathways and that these rapid signaling events lead to functional changes at the cellular level. The various types of cells in the brain can respond differently to estradiol treatment based on the signaling properties of the cell, as well as which receptor, estrogen receptor alpha and/or estrogen receptor beta, is expressed. Taken together, these findings suggest that the estradiol-induced activation of membrane-initiated signaling pathways occurs in a cell-type specific manner and can differentially influence how the cells respond to various insults.

  2. Estrogen increases the transcription of human α2-Heremans-Schmid-glycoprotein by an interplay of estrogen receptor α and activator protein-1.

    Science.gov (United States)

    Qiu, C; Liu, X; Wang, J; Zhao, Y; Fu, Q

    2014-04-01

    The expression of α2-Heremans-Schmid-glycoprotein (AHSG) was estrogen responsive in oophorectomized (OVX) osteopenic rats and HepG2 cells. Estrogen receptor α (ERα) interacted with the c-Jun/c-Fos heterodimer and indirectly associated with the -1488/-1482 activator protein-1 (AP-1) motif of the AHSG promoter. Estrogen increased c-Jun/c-Fos expression via the mitogen-activated protein kinase (MAPK) pathway. AHSG is a hepatic secretory protein implicated in the regulation of bone homeostasis. Serum AHSG in women has been reported to decrease after menopause and increase with estrogen therapy. The detailed regulatory mechanism of estrogen on AHSG is unclear. A postmenopausal osteoporosis model was generated in OVX rats. Skeletal parameters were determined by automatic biochemical analysis and dual X-ray absorptiometry. The expression of AHSG was evaluated by ELISA, real-time PCR, and Western blot. The 1.5-kb 5'-promoter region of AHSG was analyzed by serial truncation and luciferase assays. The putative -1488/-1482 AP-1 responsive element was identified by electrophoresis mobility shift assay (EMSA). Chromatin immunoprecipitation (ChIP), re-ChIP, and co-immunoprecipitation (Co-IP) were used to characterize the interaction of ERα and AP-1 at the -1488/-1482 AP-1 binding site. The MAPK pathway was evaluated using a specific inhibitor and active transfection. The expression of AHSG was estrogen responsive in both OVX rats and estradiol (E2)/ERα-treated HepG2 cells. E2/ERα most prominently increased luciferase activity of a construct with a putative -1488/-1482 AP-1 binding element. ERα interacted with the c-Jun/c-Fos heterodimer and indirectly associated with the -1488/-1482 AP-1 motif of the AHSG promoter. c-Jun/c-Fos expression was increased via the MAPK pathway by E2/ERα. Estrogen activated the transcription of AHSG through an indirect binding of ERα to the -1488/-1482 AP-1 binding element, with the c-Jun/c-Fos heterodimers.

  3. Regulation of Catechol-O-Methyltransferase Expression in Human Myometrial Cells

    Science.gov (United States)

    Wentz, Melissa J.; Jamaluddin, Mohammad; Garfield, Robert E.; Al-Hendy, Ayman

    2014-01-01

    OBJECTIVE The catechol-O-methyltransferase enzyme catalyzes the methylation of the catechol estrogens, 2- or 4-hydroxyestrogen, to 2- or 4-methoxyestrogen. Both the hydroxy estrogens and methoxy estrogens were shown to modulate the effects of estrogen. Because catechol-O-methyltransferase activity controls levels of these metabolites, it may help regulate the cellular estrogenic milieu. In this study, we examined the regulation of catechol-O-methyltransferase expression in human myometrial cells. METHODS Catechol-O-methyltransferase expression was assessed by reverse transcription–polymerase chain reaction, Western blot, and luciferase assays in human myometrial cells after treatment with estrogen or progesterone. Catechol-O-methyltransferase expression was measured in cells after treatment with tumor necrosis factor alpha (TNFα) alone or with lactacystin, a protea-some inhibitor. Luciferase assays were also conducted using human myometrial cells containing an estrogen response element–luciferase reporter gene to measure levels of estrogen-mediated transactivation after treatment with estrogen and increasing concentrations of 2-hydroxestrogen. RESULTS Catechol-O-methyltransferase expression was down-regulated by progesterone or estrogen. Tumor necrosis factor alpha upregulated catechol-O-methyltransferase expression, whereas cotreatment with lactacystin attenuated this response, suggesting that TNFα activated nuclear factor kappa B to induce catechol-O-methyltransferase expression. Increased concentrations of 2-hydroxyestrogen attenuated estrogen-mediated transcription in the myometrial cells. CONCLUSION Catechol-O-methyltransferase expression may be regulated in the myometrium to control the local action of estrogen. Low levels of catechol-O-methyltransferase in the myometrium would result in an accumulation of 2-hydroxyestrogen and may antagonize the local effect of estrogen. High levels of catechol-O-methyltransferase in the myometrium would result in

  4. Determination of the Role of Estrogen Receptors and Estrogen Regulated Genes in B Cell Autoreactivity

    Science.gov (United States)

    2011-07-01

    coated overnight at 37°C. Plates were washed with water and blocked for 1 h at 37°C with 100 μl 2% BSA/PBS. Plates were washed twice with PBS/Tween...31. Lee YJ, et al. (2004) Association of the oestrogen receptor alpha gene polymorphisms with disease onset in systemic lupus erythematosus. Ann...Islander U, et al. (2003) Influence of oestrogen re- ceptor alpha and beta on the immune system in aged female mice. Immunology 110:149–57. 47. Lesley R

  5. Determination of the Role of Estrogen Receptors and Estrogen Regulated Genes in B cell Autoreactivity. Addendum

    Science.gov (United States)

    2012-07-01

    coated overnight at 37°C. Plates were washed with water and blocked for 1 h at 37°C with 100 μl 2% BSA/PBS. Plates were washed twice with PBS/Tween. Sera...Lee YJ, et al. (2004) Association of the oestrogen receptor alpha gene polymorphisms with disease onset in systemic lupus erythematosus. Ann. Rheum...Islander U, et al. (2003) Influence of oestrogen re- ceptor alpha and beta on the immune system in aged female mice. Immunology 110:149–57. 47. Lesley R

  6. Effect of combining in vitro estrogenicity data with kinetic characteristics of estrogenic compounds on the invivo predictive value

    NARCIS (Netherlands)

    Punt, A.; Brand, W.; Murk, A.J.; Wezel, van A.P.; Schriks, M.; Heringa, M.B.

    2013-01-01

    With the ultimate aim of increasing the utility of in vitro assays for toxicological risk assessment, a method was developed to calculate in vivo estrogenic potencies from in vitro estrogenic potencies of compounds by taking into account systemic availability. In vitro estrogenic potencies of three

  7. Food-associated estrogenic compounds induce estrogen receptor-mediated luciferase gene expression in transgenic male mice

    NARCIS (Netherlands)

    Veld, ter M.G.R.; Zawadzka, E.; Berg, van den J.H.J.; Saag, van der P.T.; Rietjens, I.M.C.M.; Murk, A.J.

    2008-01-01

    The present paper aims at clarifying to what extent seven food-associated compounds, shown before to be estrogenic in vitro, can induce estrogenic effects in male mice with an estrogen receptor (ER)-mediated luciferase (luc) reporter gene system. The luc induction was determined in different tissues

  8. Estrogenicity of food-associated estrogenic compounds in the fetuses of female transgenic mice upon oral and IP maternal exposure

    NARCIS (Netherlands)

    Veld, ter M.G.R.; Zawadzka, E.; Rietjens, I.M.C.M.; Murk, A.J.

    2009-01-01

    The present study investigated to what extent seven food-associated in vitro estrogenic compounds can induce estrogenic effects in the fetuses of pregnant female mice with an estrogen receptor (ER)-mediated luciferase (luc) reporter gene system. The luc-induction was determined either 8 h after

  9. Food-associated estrogenic compounds induce estrogen receptor-mediated luciferase gene expression in transgenic male mice.

    NARCIS (Netherlands)

    ter Veld, M.G.R.; Zawadzka, E.; van den Berg, J.H.J.; van der Saag, P.T.; Rietjens, I.M.C.M.; Murk, A.J.

    2008-01-01

    The present paper aims at clarifying to what extent seven food-associated compounds, shown before to be estrogenic in vitro, can induce estrogenic effects in male mice with an estrogen receptor (ER)-mediated luciferase (luc) reporter gene system. The luc induction was determined in different tissues

  10. Validation and application of a robust yeast estrogen bioassay for the screening of estrogenic activity in animal feed

    NARCIS (Netherlands)

    Bovee, T.F.H.; Bor, G.; Heskamp, H.H.; Hoogenboom, L.A.P.; Nielen, M.W.F.

    2006-01-01

    Previously we described the construction and properties of a rapid yeast bioassay stably expressing human estrogen receptor ¿ (hER¿) and yeast enhanced green fluorescent protein (yEGFP), the latter in response to estrogens. In the present study this yeast estrogen assay was validated as a

  11. Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17.

    Science.gov (United States)

    Hu, Dong G; Selth, Luke A; Tarulli, Gerard A; Meech, Robyn; Wijayakumara, Dhilushi; Chanawong, Apichaya; Russell, Roslin; Caldas, Carlos; Robinson, Jessica L L; Carroll, Jason S; Tilley, Wayne D; Mackenzie, Peter I; Hickey, Theresa E

    2016-10-01

    Glucuronidation is an enzymatic process that terminally inactivates steroid hormones, including estrogens and androgens, thereby influencing carcinogenesis in hormone-dependent cancers. While estrogens drive breast carcinogenesis via the estrogen receptor alpha (ERα), androgens play a critical role as prohormones for estrogen biosynthesis and ligands for the androgen receptor (AR). In this study, the expression and regulation of two androgen-inactivating enzymes, the UDP-glucuronosyltransferases UGT2B15 and UGT2B17, was assessed in breast cancer. In large clinical cohorts, high UGT2B15 and UGT2B17 levels positively influenced disease-specific survival in distinct molecular subgroups. Expression of these genes was highest in cases positive for ERα. In cell line models, ERα, AR, and the transcription factor FOXA1 cooperated to increase transcription via tandem binding events at their proximal promoters. ERα activity was dependent on FOXA1, facilitated by AR activation, and potently stimulated by estradiol as well as estrogenic metabolites of 5α-dihydrotestosterone. AR activity was mediated via binding to an estrogen receptor half-site 3' to the FOXA1 and ERα-binding sites. Although AR and FOXA1 bound the UGT promoters in AR-positive/ERα-negative breast cancer cell lines, androgen treatment did not influence basal transcription levels. Ex vivo culture of human breast tissue and ERα(+) tumors provided evidence for upregulation of UGT2B15 and UGT2B17 by estrogen or androgen treatment. ERα binding was evident at the promoters of these genes in a small cohort of primary tumors and distant metastases. Collectively, these data provide insight into sex steroid receptor-mediated regulation of androgen-inactivating enzymes in ERα(+) breast cancer, which may have subtype-specific consequences for disease progression and outcomes. Cancer Res; 76(19); 5881-93. ©2016 AACR. ©2016 American Association for Cancer Research.

  12. Estrogen receptor beta-selective agonists stimulate calcium oscillations in human and mouse embryonic stem cell-derived neurons.

    Directory of Open Access Journals (Sweden)

    Lili Zhang

    2010-07-01

    Full Text Available Estrogens are used extensively to treat hot flashes in menopausal women. Some of the beneficial effects of estrogens in hormone therapy on the brain might be due to nongenomic effects in neurons such as the rapid stimulation of calcium oscillations. Most studies have examined the nongenomic effects of estrogen receptors (ER in primary neurons or brain slices from the rodent brain. However, these cells can not be maintained continuously in culture because neurons are post-mitotic. Neurons derived from embryonic stem cells could be a potential continuous, cell-based model to study nongenomic actions of estrogens in neurons if they are responsive to estrogens after differentiation. In this study ER-subtype specific estrogens were used to examine the role of ERalpha and ERbeta on calcium oscillations in neurons derived from human (hES and mouse embryonic stem cells. Unlike the undifferentiated hES cells the differentiated cells expressed neuronal markers, ERbeta, but not ERalpha. The non-selective ER agonist 17beta-estradiol (E(2 rapidly increased [Ca2+]i oscillations and synchronizations within a few minutes. No change in calcium oscillations was observed with the selective ERalpha agonist 4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyltrisphenol (PPT. In contrast, the selective ERbeta agonists, 2,3-bis(4-Hydroxyphenyl-propionitrile (DPN, MF101, and 2-(3-fluoro-4-hydroxyphenyl-7-vinyl-1,3 benzoxazol-5-ol (ERB-041; WAY-202041 stimulated calcium oscillations similar to E(2. The ERbeta agonists also increased calcium oscillations and phosphorylated PKC, AKT and ERK1/2 in neurons derived from mouse ES cells, which was inhibited by nifedipine demonstrating that ERbeta activates L-type voltage gated calcium channels to regulate neuronal activity. Our results demonstrate that ERbeta signaling regulates nongenomic pathways in neurons derived from ES cells, and suggest that these cells might be useful to study the nongenomic mechanisms of estrogenic compounds.

  13. Genomic priming of the antisecretory response to estrogen in rat distal colon throughout the estrous cycle.

    LENUS (Irish Health Repository)

    O'Mahony, Fiona

    2009-11-01

    The secretion of Cl(-) across distal colonic crypt cells provides the driving force for the movement of fluid into the luminal space. 17beta-Estradiol (E2) produces a rapid and sustained reduction in secretion in females, which is dependent on the novel protein kinase C delta (PKC delta) isozyme and PKA isoform I targeting of KCNQ1 channels. This sexual dimorphism in the E2 response is associated with a higher expression level of PKC delta in female compared with the male tissue. The present study revealed the antisecretory response is regulated throughout the female reproductive (estrous) cycle and is primed by genomic regulation of the kinases. E2 (1-10 nm) decreased cAMP-dependent secretion in colonic epithelia during the estrus, metestrus, and diestrus stages. A weak inhibition of secretion was demonstrated in the proestrus stage. The expression levels of PKC delta and PKA fluctuated throughout the estrous cycle and correlated with the potency of the antisecretory effect of E2. The expression of PKC delta and PKA were up-regulated by estrogen at a transcriptional level via a PKC delta-MAPK-cAMP response element-binding protein-regulated pathway indicating a genomic priming of the antisecretory response. PK Cdelta was activated by the membrane-impermeant E2-BSA, and this response was inhibited by the estrogen receptor antagonist ICI 182,780. The 66-kDa estrogen receptor-alpha isoform was present at the plasma membrane of female colonic crypt cells with a lower abundance found in male colonic crypts. The study demonstrates estrogen regulation of intestinal secretion both at a rapid and transcriptional level, demonstrating an interdependent relationship between both nongenomic and genomic hormone responses.

  14. Photoperiod affects estrogen receptor α, estrogen receptor β and aggressive behavior

    OpenAIRE

    Trainor, Brian C.; Rowland, Michael R.; Nelson, Randy J.

    2007-01-01

    Estrogens have important effects on male and female social behavior. Despite growing knowledge of the anatomy and behavioral effects of the two predominant estrogen receptor subtypes in mammals (ERα and ERβ), relatively little is known about how these receptors respond to salient environmental stimuli. Many seasonally breeding species respond to changing photoperiods that predict seasonal changes in resource availability. We characterized the effects of photoperiod on aggressive behavior in t...

  15. The androgen receptor and estrogen receptor

    NARCIS (Netherlands)

    Oosterkamp, H.M.; Bernards, R.A.

    2002-01-01

    The androgen receptor (AR) and the estrogen receptors (ER) are members of the nuclear receptor (NR) family. These NRs are distinguished from the other transcription factors by their ability to control gene expression upon ligand binding (steroids, retinoids, thyroid hormone, vitamin D, fatty

  16. Estrogen Metabolism and Prostate Cancer Risk

    Science.gov (United States)

    1999-10-01

    hormones. Panico and colleagues (27) reported more elevated levels of estrogen and progesterones in the morning hours. The good correlation between...16 27 Panico S, Pisani P, Muti P, Recchione C, Covelleri A, Totis A, Berrino F. Diurinal variation of testosterone and estradiol: a source of bias in

  17. Aging, estrogen loss and epoxyeicosatrienoic acids (EETs.

    Directory of Open Access Journals (Sweden)

    Alison R Lee

    Full Text Available Inflammation is a key element in many cardiovascular diseases. Both estrogen loss, caused by menopause, and aging have inflammatory consequences. Epoxyeicosatrienoic acids (EETs are anti-inflammatory molecules synthesized by various cytochrome P450 (Cyp enzymes from arachidonic acid. EETs are in the third (Cytochrome P450 pathway of arachindonic acid metabolism, others being cyclooxygenases and lipoxygenases. We hypothesized that aging and estrogen loss would reduce levels of anti-inflammatory EETs. Adult (6 mo and aged (22 mo ovariectomized rats with (OP and without (Ovx 17-∃-estradiol replacement were used in this study. Mass spectrometry was used to measure levels of EETs and their metabolites, dihydroxyeicosatrienoic acids (DHETs. Levels of Cyp2C2, Cyp2C6, and Cyp2J2, the principal Cyps responsible for EETs synthesis, as well as soluble epoxide hydrolase (sEH, which metabolizes EETS to DHETs, were determined via western blot. Overall Cyp levels decreased with age, though Cyp2C6 increased in the liver. sEH was increased in the kidney with estrogen replacement. Despite protein changes, no differences were measured in plasma or aortic tissue levels of EETs. However, plasma 14,15 DHET was increased in aged Ovx, and 5,6 DHET in adult OP. In conclusion neither aging nor estrogen loss decreased the anti-inflammatory EETs in the cardiovascular system.

  18. Estrogen receptor, progesterone receptor, and human epidermal ...

    African Journals Online (AJOL)

    Current clinical practice employs the use of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), as biomarkers to appropriately select patients that would benefit from targeted therapy against these major molecular pathways of the disease. This study aims at ...

  19. Targeted estrogen delivery reverses the metabolic syndrome

    NARCIS (Netherlands)

    Finan, Brian; Yang, Bin; Ottaway, Nickki; Stemmer, Kerstin; Müller, Timo D.; Yi, Chun-Xia; Habegger, Kirk; Schriever, Sonja C.; García-Cáceres, Cristina; Kabra, Dhiraj G.; Hembree, Jazzminn; Holland, Jenna; Raver, Christine; Seeley, Randy J.; Hans, Wolfgang; Irmler, Martin; Beckers, Johannes; de Angelis, Martin Hrabě; Tiano, Joseph P.; Mauvais-Jarvis, Franck; Perez-Tilve, Diego; Pfluger, Paul; Zhang, Lianshan; Gelfanov, Vasily; DiMarchi, Richard D.; Tschöp, Matthias H.

    2012-01-01

    We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate

  20. Cyclin G2 suppresses estrogen-mediated osteogenesis through inhibition of Wnt/β-catenin signaling.

    Directory of Open Access Journals (Sweden)

    Jinlan Gao

    Full Text Available Estrogen plays an important role in the maintenance of bone formation, and deficiency in the production of estrogen is directly linked to postmenopausal osteoporosis. To date, the underlying mechanisms of estrogen-mediated osteogenic differentiation are not well understood. In this study, a pluripotent mesenchymal precursor cell line C2C12 was used to induce osteogenic differentiation and subjected to detection of gene expressions or to manipulation of cyclin G2 expressions. C57BL/6 mice were used to generate bilateral ovariectomized and sham-operated mice for analysis of bone mineral density and protein expression. We identified cyclin G2, an unconventional member of cyclin, is involved in osteoblast differentiation regulated by estrogen in vivo and in vitro. In addition, the data showed that ectopic expression of cyclin G2 suppressed expression of osteoblast transcription factor Runx2 and osteogenic differentiation marker genes, as well as ALP activity and in vitro extracellular matrix mineralization. Mechanistically, Wnt/β-catenin signaling pathway is essential for cyclin G2 to inhibit osteogenic differentiation. To the best of our knowledge, the current study presents the first evidence that cyclin G2 serves as a negative regulator of both osteogenesis and Wnt/β-catenin signaling. Most importantly, the basal and 17β-estradiol-induced osteogenic differentiation was restored by overexpression of cyclin G2. These results taken together suggest that cyclin G2 may function as an endogenous suppressor of estrogen-induced osteogenic differentiation through inhibition of Wnt/β-catenin signaling.

  1. Different effects of bisphenol-A on memory behavior and synaptic modification in intact and estrogen-deprived female mice.

    Science.gov (United States)

    Xu, Xiaohong; Gu, Ting; Shen, Qiaoqiao

    2015-03-01

    Bisphenol-A (BPA) has the capability of interfering with the effects of estrogens on modulating brain function. The purpose of this study was to investigate the effects of BPA on memory and synaptic modification in the hippocampus of female mice under different levels of cycling estrogen. BPA exposure (40, 400 μg/kg/day) for 8 weeks did not affect spatial memory and passive avoidance task of gonadally intact mice but improved ovariectomy (Ovx)-induced memory impairment, whereas co-exposure of BPA with estradiol benzoate (EB) diminished the rescue effect of EB on memory behavior of Ovx mice. The results of morphometric measurement showed that BPA positively modified the synaptic interface structure and increased the synaptic density of CA1 pyramidal cell in the hippocampus of Ovx females, but inhibited the enhancement of EB on synaptic modification and synaptogenesis of Ovx mice. Furthermore, BPA up-regulated synaptic proteins synapsin I and PSD-95 and NMDA receptor NR2B but inhibited EB-induced increase in PSD-95 and NR2B in the hippocampus of Ovx mice. These results suggest that BPA interfered with normal hormonal regulation in synaptic plasticity and memory of female mice as a potent estrogen mimetic and as a disruptor of estrogen under various concentrations of cycling estrogen. © 2014 International Society for Neurochemistry.

  2. Epidermal Growth Factor and Estrogen Act by Independent Pathways to Additively Promote the Release of the Angiogenic Chemokine CXCL8 by Breast Tumor Cells

    Directory of Open Access Journals (Sweden)

    Karin Haim

    2011-03-01

    Full Text Available The tumor microenvironment contains multiple cancer-supporting factors, whose joint activities promote malignancy. Here, we show that epidermal growth factor (EGF and estrogen upregulate in an additive manner the transcription and the secretion of the angiogenic chemokine CXCL8 (interleukin 8 [IL-8] in breast tumor cells. In view of published findings on cross-regulatory interactions between EGF receptors and estrogen receptors in breast tumor cells, we asked whether the additive effects of EGF and estrogen were due to their ability to (1 induce intracellular cross talk and amplify shared regulatory pathways or (2 act in independent mechanisms, which complement each other. We found that stimulation by EGF alone induced the release of CXCL8 through signaling pathways involving ErbB2, ErbB1, Erk, and phosphoinositide 3-kinase (PI3K. ErbB2 and Erk were also involved in estrogen activities on CXCL8 but to a lower extent than with EGF. However, in the joint stimulatory setup, the addition of estrogen to EGF has led to partial (ErbB2, ErbB1, Erk or complete (PI3K shutoff of the involvement of these activation pathways in CXCL8 up-regulation. Furthermore, when costimulation by EGF + estrogen was applied, the effects of estrogen were channeled to regulation of CXCL8 at the transcription level, acting through the transcription factor estrogen receptor α (ERα. In parallel, in the joint stimulation, EGF acted independently at the transcription level through AP-1, to upregulate CXCL8 expression. The independent activities of EGF and estrogen on CXCL8 transcription reinforce the need to introduce simultaneous targeting of ErbBs and ERα to achieve effective therapy in breast cancer.

  3. Estrogen and its role in gastrointestinal health and disease.

    LENUS (Irish Health Repository)

    Hogan, Aisling M

    2012-02-01

    INTRODUCTION: While the concept of a role of estrogen in gastrointestinal (in particular, colonic) malignancy has generated excitement in recent years, no review has examined the role of this potent and omnipresent steroid hormone in physiological states or its contribution to the development of benign pathological processes. Understanding these effects (and mechanisms therein) may provide a platform for a deeper understanding of more complex disease processes. METHODS: A literature search was conducted using the PubMed database and the search terms were "estrogen," "estrogen AND gastrointestinal tract," "estrogen AND colon," "estrogen AND esophagus," "estrogen AND small intestine," "estrogen AND stomach," "estrogen AND gallbladder," and "estrogen AND motility." Bibliographies of extracted studies were further cross-referenced. In all, 136 full-text articles were selected for review. A logical organ-based approach was taken to enable extraction of data of clinical relevance and meaningful interpretation thereof. Insight is provided into the hypotheses, theories, controversies, and contradictions generated over the last five decades by extensive investigation of estrogen in human, animal, and cell models using techniques as diverse as autoradiographic studies of baboons to human population analysis. CONCLUSIONS: Effects from esophagus through to the colon and rectum are summarized in this first concise collection of data pertaining to estrogenic actions in gastrointestinal health and disease. Mechanisms of these actions are discussed where possible. Undoubtedly, this hormone exerts many actions yet to be elucidated, and its potential therapeutic applications remain, as yet, largely unexplored.

  4. ESTROGEN RECEPTORS OF HAIRS BLACKS AND WHITES

    Directory of Open Access Journals (Sweden)

    H. Laswati

    2014-12-01

    Full Text Available Background: Aging is termed as same as degenerative process, in which all part of tissue organs retarted the microstructure either macrostructure, forming and function even the colour, including black hair change to white hair. Several researchers have been recommended that estrogen hormone be able ease black to white hair, but hormone without any presenting of receptor won’t be work properly. The main aim of this study were to determine amount of estrogen receptor contents in famales and males black and white hairs included the microscopically structure. Method: Twelve females and males there were 50 -56 years old each pairs black and white head hairs were plucked along with follicles. This estrogen receptors analyzed using radioreceptor binding assay there were 5mm eah hair follices including the root cutted and each pair put its in 2 ml glass tube already filled in with 500 µl 125I-estradiol and incubated in 37oC for 3 hrs. Following times were over the tube flushed twice carefully the hair won’t be flushed. Then count by putting in the gamma counter chamber for 1 minute each. The values that shown in the monitor as CPM (count per minute, recorded as receptor of estradiol. Results: Mean (±SD sum estrogen receptor in females black and white hairs were 479.3 ± 37.5 and 387.7 ± 33.0, but significantly decreased in male black hair was 316.9±17.8 and 274.0 ± 19.8. All those pairs significantly different either female black and white hairs or male black and white hair and also significantly different among groups. Conclusion: The lowest estrogen receptors recorded in male white hairs and microstructure decreasing of melanin contents.

  5. Estrogen Receptor α Is Required for Maintaining Baseline Renin Expression.

    Science.gov (United States)

    Lu, Ko-Ting; Keen, Henry L; Weatherford, Eric T; Sequeira-Lopez, Maria Luisa S; Gomez, R Ariel; Sigmund, Curt D

    2016-05-01

    Enzymatic cleavage of angiotensinogen by renin represents the critical rate-limiting step in the production of angiotensin II, but the mechanisms regulating the initial expression of the renin gene remain incomplete. The purpose of this study is to unravel the molecular mechanism controlling renin expression. We identified a subset of nuclear receptors that exhibited an expression pattern similar to renin by reanalyzing a publicly available microarray data set. Expression of some of these nuclear receptors was similarly regulated as renin in response to physiological cues, which are known to regulate renin. Among these, only estrogen receptor α (ERα) and hepatic nuclear factor α have no known function in regulating renin expression. We determined that ERα is essential for the maintenance of renin expression by transfection of small interfering RNAs targeting Esr1, the gene encoding ERα, in renin-expressing As4.1 cells. We also observed that previously characterized negative regulators of renin expression, Nr2f2 and vitamin D receptor, exhibited elevated expression in response to ERα inhibition. Therefore, we tested whether ERα regulates renin expression through an interaction with Nr2f2 and vitamin D receptor. Renin expression did not return to baseline when we concurrently suppressed both Esr1 and Nr2f2 or Esr1 and vitamin D receptor mRNAs, strongly suggesting that Esr1 regulates renin expression independent of Nr2f2 and vitamin D receptor. ERα directly binds to the hormone response element within the renin enhancer region. We conclude that ERα is a previously unknown regulator of renin that directly binds to the renin enhancer hormone response element sequence and is critical in maintaining renin expression in renin-expressing As4.1 cells. © 2016 American Heart Association, Inc.

  6. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases.

    Science.gov (United States)

    Dragin, Nadine; Bismuth, Jacky; Cizeron-Clairac, Géraldine; Biferi, Maria Grazia; Berthault, Claire; Serraf, Alain; Nottin, Rémi; Klatzmann, David; Cumano, Ana; Barkats, Martine; Le Panse, Rozen; Berrih-Aknin, Sonia

    2016-04-01

    Autoimmune diseases affect 5% to 8% of the population, and females are more susceptible to these diseases than males. Here, we analyzed human thymic transcriptome and revealed sex-associated differences in the expression of tissue-specific antigens that are controlled by the autoimmune regulator (AIRE), a key factor in central tolerance. We hypothesized that the level of AIRE is linked to sexual dimorphism susceptibility to autoimmune diseases. In human and mouse thymus, females expressed less AIRE (mRNA and protein) than males after puberty. These results were confirmed in purified murine thymic epithelial cells (TECs). We also demonstrated that AIRE expression is related to sexual hormones, as male castration decreased AIRE thymic expression and estrogen receptor α-deficient mice did not show a sex disparity for AIRE expression. Moreover, estrogen treatment resulted in downregulation of AIRE expression in cultured human TECs, human thymic tissue grafted to immunodeficient mice, and murine fetal thymus organ cultures. AIRE levels in human thymus grafted in immunodeficient mice depended upon the sex of the recipient. Estrogen also upregulated the number of methylated CpG sites in the AIRE promoter. Together, our results indicate that in females, estrogen induces epigenetic changes in the AIRE gene, leading to reduced AIRE expression under a threshold that increases female susceptibility to autoimmune diseases.

  7. Membrane-initiated estrogen signaling via Gq-coupled GPCR in the central nervous system.

    Science.gov (United States)

    Vail, Gwyndolin; Roepke, Troy A

    2018-01-29

    The last few decades have revealed increasing complexity and depth to our knowledge of receptor-mediated estrogen signaling. Nuclear estrogen receptors (ERs) ERα and ERβ remain the fundamental dogma, but recent research targeting membrane-bound ERs urges for a more expanded view on ER signaling. ERα and ERβ are also involved in membrane-delineated signaling alongside membrane-specific G protein-coupled estrogen receptor 1 (GPER1), ER-X, and the Gq-coupled membrane ER (Gq-mER). Membrane ERs are responsible for eliciting rapid responses to estrogen signaling, and their importance has been increasingly indicated in central nervous system (CNS) regulation of such functions as reproduction, energy homeostasis, and stress. While the Gq-mER signaling pathway is well characterized, the receptor structure and gene remains uncharacterized, although it is not similar to the nuclear ERα/β. This review will describe the current knowledge of this putative membrane ER and its selective ligand, STX, from its initial characterization in hypothalamic melanocortin circuitry to recent research exploring its role in the CNS outside of the hypothalamus. Copyright © 2018 Elsevier Inc. All rights reserved.

  8. Estrogen receptors (ERα versus ERβ): friends or foes in human biology?

    Science.gov (United States)

    Planey, Sonia Lobo; Kumar, Raj; Arnott, John A

    2014-02-01

    Most of the biological effects of estrogens are mediated via the estrogen receptors (ERs) at the level of gene regulation. Recently, new information regarding the role of ERs in physiology, pathology and the mechanisms through which estrogens bring about these functions has emerged. The physiological effects of estrogen are manifested through two ER isoforms - ERα and ERβ - which display distinct regions of sequence homology. The crystal structures of these receptors bound to their specific ligands (e.g. agonists or antagonists) have revealed much about how ligand binding alters receptor structure/conformation and the interaction with coactivators or corepressors as well as how it determines the cellular response to a ligand. ERs are involved in the variety of physiological and pathological activities and different cells and tissues have shown divergent responses to these two receptor isoforms. The discovery of sub-isoforms of ER alpha and beta has further complicated our understanding of how the interaction between ERs and its ligands contribute to the development of disease. Nevertheless, continuing efforts in the study of ERs have helped us to more clearly define their role in disease and to develop novel, ER-targeted therapeutics.

  9. Suppression of estrogen receptor transcriptional activity by connective tissue growth factor.

    Directory of Open Access Journals (Sweden)

    Long Cheng

    Full Text Available Secreted growth factors have been shown to stimulate the transcriptional activity of estrogen receptors (ER that are responsible for many biological processes. However, whether these growth factors physically interact with ER remains unclear. Here, we show for the first time that connective tissue growth factor (CTGF physically and functionally associates with ER. CTGF interacted with ER both in vitro and in vivo. CTGF interacted with ER DNA-binding domain. ER interaction region in CTGF was mapped to the thrombospondin type I repeat, a cell attachment motif. Overexpression of CTGF inhibited ER transcriptional activity as well as the expression of estrogen-responsive genes, including pS2 and cathepsin D. Reduction of endogenous CTGF with CTGF small interfering RNA enhanced ER transcriptional activity. The interaction between CTGF and ER is required for the repression of estrogen-responsive transcription by CTGF. Moreover, CTGF reduced ER protein expression, whereas the CTGF mutant that did not repress ER transcriptional activity also did not alter ER protein levels. The results suggested the transcriptional regulation of estrogen signaling through interaction between CTGF and ER, and thus may provide a novel mechanism by which cross-talk between secreted growth factor and ER signaling pathways occurs.

  10. In silico screening of estrogen-like chemicals based on different nonlinear classification models.

    Science.gov (United States)

    Liu, Huanxiang; Papa, Ester; Walker, John D; Gramatica, Paola

    2007-07-01

    Increasing concern is being shown by the scientific community, government regulators, and the public about endocrine-disrupting chemicals that are adversely affecting human and wildlife health through a variety of mechanisms. There is a great need for an effective means of rapidly assessing endocrine-disrupting activity, especially estrogen-simulating activity, because of the large number of such chemicals in the environment. In this study, quantitative structure activity relationship (QSAR) models were developed to quickly and effectively identify possible estrogen-like chemicals based on 232 structurally-diverse chemicals (training set) by using several nonlinear classification methodologies (least-square support vector machine (LS-SVM), counter-propagation artificial neural network (CP-ANN), and k nearest neighbour (kNN)) based on molecular structural descriptors. The models were externally validated by 87 chemicals (prediction set) not included in the training set. All three methods can give satisfactory prediction results both for training and prediction sets, and the most accurate model was obtained by the LS-SVM approach through the comparison of performance. In addition, our model was also applied to about 58,000 discrete organic chemicals; about 76% were predicted not to bind to Estrogen Receptor. The obtained results indicate that the proposed QSAR models are robust, widely applicable and could provide a feasible and practical tool for the rapid screening of potential estrogens.

  11. Efficacy of a Low Dose of Estrogen on Antioxidant Defenses and Heart Rate Variability

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    Cristina Campos

    2014-01-01

    Full Text Available This study tested whether a low dose (40% less than the pharmacological dose of 17-β estradiol would be as effective as the pharmacological dose to improve cardiovascular parameters and decrease cardiac oxidative stress. Female Wistar rats (n=9/group were divided in three groups: (1 ovariectomized (Ovx, (2 ovariectomized animals treated for 21 days with low dose (LE; 0.2 mg, and (3 high dose (HE; 0.5 mg 17-β estradiol subcutaneously. Hemodynamic assessment and spectral analysis for evaluation of autonomic nervous system regulation were performed. Myocardial superoxide dismutase (SOD and catalase (CAT activities, redox ratio (GSH/GSSG, total radical-trapping antioxidant potential (TRAP, hydrogen peroxide, and superoxide anion concentrations were measured. HE and LE groups exhibited an improvement in hemodynamic function and heart rate variability. These changes were associated with an increase in the TRAP, GSH/GSSG, SOD, and CAT. A decrease in hydrogen peroxide and superoxide anion was also observed in the treated estrogen groups as compared to the Ovx group. Our results indicate that a low dose of estrogen is just as effective as a high dose into promoting cardiovascular function and reducing oxidative stress, thereby supporting the approach of using low dose of estrogen in clinical settings to minimize the risks associated with estrogen therapy.

  12. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases

    Science.gov (United States)

    Dragin, Nadine; Bismuth, Jacky; Cizeron-Clairac, Géraldine; Biferi, Maria Grazia; Berthault, Claire; Serraf, Alain; Nottin, Rémi; Klatzmann, David; Cumano, Ana; Barkats, Martine; Le Panse, Rozen

    2016-01-01

    Autoimmune diseases affect 5% to 8% of the population, and females are more susceptible to these diseases than males. Here, we analyzed human thymic transcriptome and revealed sex-associated differences in the expression of tissue-specific antigens that are controlled by the autoimmune regulator (AIRE), a key factor in central tolerance. We hypothesized that the level of AIRE is linked to sexual dimorphism susceptibility to autoimmune diseases. In human and mouse thymus, females expressed less AIRE (mRNA and protein) than males after puberty. These results were confirmed in purified murine thymic epithelial cells (TECs). We also demonstrated that AIRE expression is related to sexual hormones, as male castration decreased AIRE thymic expression and estrogen receptor α–deficient mice did not show a sex disparity for AIRE expression. Moreover, estrogen treatment resulted in downregulation of AIRE expression in cultured human TECs, human thymic tissue grafted to immunodeficient mice, and murine fetal thymus organ cultures. AIRE levels in human thymus grafted in immunodeficient mice depended upon the sex of the recipient. Estrogen also upregulated the number of methylated CpG sites in the AIRE promoter. Together, our results indicate that in females, estrogen induces epigenetic changes in the AIRE gene, leading to reduced AIRE expression under a threshold that increases female susceptibility to autoimmune diseases. PMID:26999605

  13. Urethral dysfunction in female mice with estrogen receptor β deficiency.

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    Yung-Hsiang Chen

    Full Text Available Estrogen has various regulatory functions in the growth, development, and differentiation of the female urogenital system. This study investigated the roles of ERβ in stress urinary incontinence (SUI. Wild-type (ERβ(+/+ and knockout (ERβ(-/- female mice were generated (aged 6-8 weeks, n = 6 and urethral function and protein expression were measured. Leak point pressures (LPP and maximum urethral closure pressure (MUCP were assessed in mice under urethane anesthesia. After the measurements, the urethras were removed for proteomic analysis using label-free quantitative proteomics by nano-liquid chromatography-mass spectrometry (LC-MS/MS analysis. The interaction between these proteins was further analysed using MetaCore. Lastly, Western blot was used to confirm the candidate proteins. Compared with the ERβ(+/+ group, the LPP and MUCP values of the ERβ(-/- group were significantly decreased. Additionally, we identified 85 differentially expressed proteins in the urethra of ERβ(-/- female mice; 57 proteins were up-regulated and 28 were down-regulated. The majority of the ERβ knockout-modified proteins were involved in cell-matrix adhesion, metabolism, immune response, signal transduction, nuclear receptor translational regelation, and muscle contraction and development. Western blot confirmed the up-regulation of myosin and collagen in urethra. By contrast, elastin was down-regulated in the ERβ(-/- mice. This study is the first study to estimate protein expression changes in urethras from ERβ(-/- female mice. These changes could be related to the molecular mechanism of ERβ in SUI.

  14. WNT4 mediates estrogen receptor signaling and endocrine resistance in invasive lobular carcinoma cell lines.

    Science.gov (United States)

    Sikora, Matthew J; Jacobsen, Britta M; Levine, Kevin; Chen, Jian; Davidson, Nancy E; Lee, Adrian V; Alexander, Caroline M; Oesterreich, Steffi

    2016-09-20

    Invasive lobular carcinoma (ILC) of the breast typically presents with clinical biomarkers consistent with a favorable response to endocrine therapies, and over 90 % of ILC cases express the estrogen receptor (ER). However, a subset of ILC cases may be resistant to endocrine therapies, suggesting that ER biology is unique in ILC. Using ILC cell lines, we previously demonstrated that ER regulates a distinct gene expression program in ILC cells, and we hypothesized that these ER-driven pathways modulate the endocrine response in ILC. One potential novel pathway is via the Wnt ligand WNT4, a critical signaling molecule in mammary gland development regulated by the progesterone receptor. The ILC cell lines MDA-MB-134-VI, SUM44PE, and BCK4 were used to assess WNT4 gene expression and regulation, as well as the role of WNT4 in estrogen-regulated proliferation. To assess these mechanisms in the context of endocrine resistance, we developed novel ILC endocrine-resistant long-term estrogen-deprived (ILC-LTED) models. ILC and ILC-LTED cell lines were used to identify upstream regulators and downstream signaling effectors of WNT4 signaling. ILC cells co-opted WNT4 signaling by placing it under direct ER control. We observed that ER regulation of WNT4 correlated with use of an ER binding site at the WNT4 locus, specifically in ILC cells. Further, WNT4 was required for endocrine response in ILC cells, as WNT4 knockdown blocked estrogen-induced proliferation. ILC-LTED cells remained dependent on WNT4 for proliferation, by either maintaining ER function and WNT4 regulation or uncoupling WNT4 from ER and upregulating WNT4 expression. In the latter case, WNT4 expression was driven by activated nuclear factor kappa-B signaling in ILC-LTED cells. In ILC and ILC-LTED cells, WNT4 led to suppression of CDKN1A/p21, which is critical for ILC cell proliferation. CDKN1A knockdown partially reversed the effects of WNT4 knockdown. WNT4 drives a novel signaling pathway in ILC cells, with a

  15. Molecular Modeling of Estrogen Receptor Alpha Mutated Breast Cancer to Guide New Therapeutic Strategies

    Science.gov (United States)

    2017-10-01

    ER in 10-40% of metastatic hormone therapy resistant breast tumors suggests that these mutations may be a common mechanism leading to resistance...LBD) of ER in approximately 20% of metastatic hormone therapy resistant breast tumors suggests that these mutations are a common mechanism leading...mutations. 2. KEYWORDS Breast cancer, Estrogen receptor alpha, hormone therapy resistance, gene regulation, genomics, CRSIPR/Cas9, epigenetic

  16. Letrozole induced low estrogen levels affected the expressions of duodenal and renal calcium-processing gene in laying hens.

    Science.gov (United States)

    Li, Qiao; Zhao, Xingkai; Wang, Shujie; Zhou, Zhenlei

    2017-10-14

    Estrogen regulates the calcium homeostasis in hens, but the mechanisms involved are still unclear fully. In this study, we investigated whether letrozole (LZ) induced low estrogen levels affected the calcium absorption and transport in layers. In the duodenum, we observed a significant decrease of mRNA expressions of Calbindin-28k (CaBP-28k) and plasma membrane Ca(2+)-ATPase (PMCA 1b) while CaBP-28k protein expression was declined in birds with LZ treatment, and the mRNA levels of duodenal transient receptor potential vanilloid 6 (TRPV6) and Na(+)/Ca(2+) exchanger 1 (NCX1) were not affected. Interestingly, we observed the different changes in the kidney. The renal mRNA expressions of TRPV6 and NCX1 were unregulated while the PMCA1b was down-regulated in low estrogen layers, however, the CaBP-28k gene and protein expressions were no changed in the kidney. Furthermore, it showed that the duodenal estradiol receptor 2 (ESR2) transcripts rather than parathyroid hormone 1 receptor (PTH1R) and calcitonin receptor (CALCR) played key roles to down-regulate calcium transport in LZ-treated birds. In conclusion, CaBP-28k, PMCA 1b and ESR2 genes in the duodenum may be primary targets for estrogen regulation in order to control calcium homeostasis in hens. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Selective Estrogen Receptor Modulator (SERM)-like Activities of Diarylheptanoid, a Phytoestrogen from Curcuma comosa, in Breast Cancer Cells, Pre-osteoblast Cells, and Rat Uterine Tissues.

    Science.gov (United States)

    Thongon, Natthakan; Boonmuen, Nittaya; Suksen, Kanoknetr; Wichit, Patsorn; Chairoungdua, Arthit; Tuchinda, Patoomratana; Suksamrarn, Apichart; Winuthayanon, Wipawee; Piyachaturawat, Pawinee

    2017-05-03

    Diarylheptanoids from Curcuma comosa, of the Zingiberaceae family, exhibit diverse estrogenic activities. In this study we investigated the estrogenic activity of a major hydroxyl diarylheptanoid, 7-(3,4 -dihydroxyphenyl)-5-hydroxy-1-phenyl-(1E)-1-heptene (compound 092) isolated from C. comosa. The compound elicited different transcriptional activities of estrogen agonist at low concentrations (0.1-1 μM) and antagonist at high concentrations (10-50 μM) using luciferase reporter gene assay in HEK-293T cells. In human breast cancer (MCF-7) cells, compound 092 showed an anti-estrogenic activity by down-regulating ERα-signaling and suppressing estrogen-responsive genes, whereas it attenuated the uterotrophic effect of estrogen in immature ovariectomized rats. Of note, compound 092 promoted mouse pre-osteoblastic (MC3T3-E1) cell differentiation and the related bone markers, indicating its positive osteogenic effect. Our findings highlight a new, nonsteroidal, estrogen agonist/antagonist of catechol diarylheptanoid from C. comosa, which is scientific evidence supporting its potential as a dietary supplement to prevent bone loss with low risk of breast and uterine cancers in postmenopausal women.

  18. Role of progesterone and estrogen in the preparation of the uterus and induction of implantation in the mouse

    Energy Technology Data Exchange (ETDEWEB)

    Huet-Hudson, Y.M.

    1989-01-01

    The implantation of the embryo into the uterine wall and subsequent decidualization of the uterine endometrium requires ovarian progesterone and estrogen. Prerequisites for implantation include (1) the preparation of the uterus for embryo implantation and (2) increase stromal capillary permeability at the site of embryo attachment. During the first three days of pregnancy, epithelial cells undergo proliferation, death and differentiation, in response to preovaluatory estrogen. These events occur in stromal cells in response to progesterone on days 4 and 5. The mechanism by which the steroid hormones modulate their functions and how estrogen initiates implantation in a progesterone-primed (P{sub 4}) uterus in not clearly understood. The author shows that 24h of P{sub 4}-priming is adequate for induction of implantation in the mouse. In addition, following this initial exposure of the uterus to P{sub 4} a long lasting effect is induced i.e. 24h of priming is no longer required for the induction of implantation. The uterine cell proliferation and differentiation that occurs in response to steroid hormones could be through their modulation of the expression of proto-oncogenes and growth factors. Results show that the proto-oncogene, c-myc and the growth factor, EGF are expressed in a cell-type specific manner in the uterus and are regulated by P{sub 4} and estrogen in a spatial and temporal manner during early pregnancy. It is apparent that c-myc protein in epithelia is primarily regulated by estrogen, while in the stroma by P{sub 4}. {sup 3}H-thymidine incorporation in specific uterine cell-types correlated with expression of the c-myc protein. On the other hand, EGF is always localized to the epithelia and is primarily regulated by estrogen.

  19. Yeast Estrogen Screen Assay as a Tool for Detecting Estrogenic Activity in Water Bodies

    Directory of Open Access Journals (Sweden)

    Mirjana Bistan

    2012-01-01

    Full Text Available The presence of endocrine-disrupting compounds in wastewater, surface water, groundwater and even drinking water has become a major concern worldwide, since they negatively affect wildlife and humans. Therefore, these substances should be effectively removed from effluents before they are discharged into surface water to prevent pollution of groundwater, which can be a source of drinking water. Furthermore, an efficient control of endocrine-disrupting compounds in wastewater based on biological and analytical techniques is required. In this study, a yeast estrogen screen (YES bioassay has been introduced and optimized with the aim to assess potential estrogenic activity of waters. First, assay duration, concentration of added substrate to the assay medium and wavelength used to measure the absorbance of the substrate were estimated. Several compounds, such as 17-β-estradiol, 17-α-ethinylestradiol, bisphenol A, nonylphenol, genisteine, hydrocortisone, dieldrin, atrazine, methoxychlor, testosterone and progesterone were used to verify its specificity and sensitivity. The optimized YES assay was sensitive and responded specifically to the selected estrogenic and nonestrogenic compounds in aqueous samples. Potential estrogenicity of influent and effluent samples of two wastewater treatment plants was assessed after the samples had been concentrated by solid-phase extraction (SPE procedure using Oasis® HLB cartridges and methanol as eluting solvent. Up to 90 % of relative estrogenic activity was detected in concentrated samples of influents to wastewater treatment plants and estrogenic activity was still present in the concentrated effluent samples. We found that the introduced YES assay is a suitable screening tool for monitoring the potential estrogenicity of effluents that are discharged into surface water.

  20. Trichostatin A enhances estrogen receptor-alpha repression in MCF-7 breast cancer cells under hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Noh, Hyunggyun; Park, Joonwoo; Shim, Myeongguk; Lee, YoungJoo, E-mail: yjlee@sejong.ac.kr

    2016-02-12

    Estrogen receptor (ER) is a crucial determinant of resistance to endocrine therapy, which may change during the progression of breast cancer. We previously showed that hypoxia induces ESR1 gene repression and ERα protein degradation via proteasome-mediated pathway in breast cancer cells. HDAC plays important roles in the regulation of histone and non-histone protein post-translational modification. HDAC inhibitors can induce epigenetic changes and have therapeutic potential for targeting various cancers. Trichostatin A exerts potent antitumor activities against breast cancer cells in vitro and in vivo. In this report, we show that TSA augments ESR1 gene repression at the transcriptional level and downregulates ERα protein expression under hypoxic conditions through a proteasome-mediated pathway. TSA-induced estrogen response element-driven reporter activity in the absence of estrogen was synergistically enhanced under hypoxia; however, TSA inhibited cell proliferation under both normoxia and hypoxia. Our data show that the hypoxia-induced repression of ESR1 and degradation of ERα are enhanced by concomitant treatment with TSA. These findings expand our understanding of hormone responsiveness in the tumor microenvironment; however, additional in-depth studies are required to elucidate the detailed mechanisms of TSA-induced ERα regulation under hypoxia. - Highlights: • TSA augments ESR1 gene repression at the transcriptional level under hypoxia. • TSA downregulates ERα protein expression under hypoxia. • TSA-induced ERα regulation under hypoxia is essential for understanding the behavior and progression of breast cancer.

  1. Estrogen modulates xanthine dehydrogenase/xanthine oxidase activity by a receptor-independent mechanism.

    Science.gov (United States)

    Budhiraja, Rohit; Kayyali, Usamah S; Karamsetty, Mallik; Fogel, Michael; Hill, Nicholas S; Chalkley, Roger; Finlay, Geraldine A; Hassoun, Paul M

    2003-12-01

    Hypoxia causes up-regulation and activation of xanthine dehydrogenase/xanthine oxidase (XDH/XO) in vitro and in the lungs in vivo. This up-regulation, and the likely corresponding production of reactive oxygen species, may underlie the pathogenesis of an array of disorders. Thus, compounds that prevent hypoxia-induced increase in XDH/XO activity may provide a therapeutic strategy in such disorders. The antioxidant properties of estrogens have been demonstrated in several studies. However, the effect of these compounds on XDH/XO has not been explored previously. The aim of this study was to investigate the effects of estrogen on hypoxia-induced increase in XDH/XO activity. Rat pulmonary artery microvascular endothelial cells were exposed to normoxia or hypoxia in the presence or absence of 17beta- or 17alpha-estradiol. The XDH/XO enzyme and gene promoter activities were measured in different groups of cells. Hypoxia caused a twofold increase in XDH/XO enzymatic and promoter activity. Either of the estradiol stereoisomers prevented the hypoxia-induced increase in XDH/XO enzymatic activity, but not the promoter activity. ICI 182,780, an antagonist of the estrogen receptor, failed to block the inhibitory effect of estradiol on XDH/XO. In conclusion, 17alpha- and 17beta-estradiol modulate the hypoxia-induced regulation of XDH/XO activity at a posttranscriptional level by a receptor-independent mechanism.

  2. Downregulation of miR-151-5p contributes to increased susceptibility to arrhythmogenesis during myocardial infarction with estrogen deprivation.

    Directory of Open Access Journals (Sweden)

    Ying Zhang

    Full Text Available Estrogen deficiency is associated with increased incidence of cardiovascular diseases. But merely estrogen supplementary treatment can induce many severe complications such as breast cancer. The present study was designed to elucidate molecular mechanisms underlying increased susceptibility of arrhythmogenesis during myocardial infarction with estrogen deprivation, which provides us a new target to cure cardiac disease accompanied with estrogen deprivation. We successfully established a rat model of myocardial ischemia (MI accompanied with estrogen deprivation by coronary artery ligation and ovariectomy (OVX. Vulnerability and mortality of ventricular arrhythmias increased in estrogen deficiency rats compared to non estrogen deficiency rats when suffered MI, which was associated with down-regulation of microRNA-151-5p (miR-151-5p. Luciferase Reporter Assay demonstrated that miR-151-5p can bind to the 3'-UTR of FXYD1 (coding gene of phospholemman, PLM and inhibit its expression. We found that the expression of PLM was increased in (OVX+MI group compared with MI group. More changes such as down-regulation of Kir2.1/IK1, calcium overload had emerged in (OVX+MI group compared to MI group merely. Transfection of miR-151-5p into primary cultured myocytes decreased PLM levels and [Ca(2+]i, however, increased Kir2.1 levels. These effects were abolished by the antisense oligonucleotides against miR-151-5p. Co-immunoprecipitation and immunofluorescent experiments confirmed the co-localization between Kir2.1 and PLM in rat ventricular tissue. We conclude that the increased ventricular arrhythmias vulnerability in response to acute myocardial ischemia in rat is critically dependent upon down-regulation of miR-151-5p. These findings support the proposal that miR-151-5p could be a potential therapeutic target for the prevention of ischemic arrhythmias in the subjects with estrogen deficiency.

  3. Chronic exposure of killifish to a highly polluted environment desensitizes estrogen-responsive reproductive and biomarker genes

    Energy Technology Data Exchange (ETDEWEB)

    Bugel, Sean M., E-mail: Sean.Bugel@oregonstate.edu [Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States); Bonventre, Josephine A. [Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States); White, Lori A. [Department of Biochemistry and Microbiology, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901 (United States); Tanguay, Robert L. [Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States); Cooper, Keith R. [Department of Biochemistry and Microbiology, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901 (United States)

    2014-07-01

    Highlights: • Reproductive biomarker genes in Newark Bay killifish are desensitized to estrogen. • Gene desensitization indicates pre-transcriptional effects on estrogen signaling. • Desensitization does not have a metabolic or epigenetic basis (gene methylation). • Modulation of vitellogenin and choriogenin genes correlates with reproductive impacts. • Choriogenin L appears less prone to false negatives and may be a sensitive biomarker. - Abstract: Reproductive and endocrine disruption is commonly reported in aquatic species exposed to complex contaminant mixtures. We previously reported that Atlantic killifish (Fundulus heteroclitus) from the chronically contaminated Newark Bay, NJ, exhibit multiple endocrine disrupting effects, including inhibition of vitellogenesis (yolk protein synthesis) in females and false negative vitellogenin biomarker responses in males. Here, we characterized the effects on estrogen signaling and the transcriptional regulation of estrogen-responsive genes in this model population. First, a dose–response study tested the hypothesis that reproductive biomarkers (vtg1, vtg2, chg H, chg Hm, chg L) in Newark Bay killifish are relatively less sensitive to 17β-estradiol at the transcriptional level, relative to a reference (Tuckerton, NJ) population. The second study assessed expression for various metabolism (cyp1a, cyp3a30, mdr) and estrogen receptor (ER α, ER βa, ER βb) genes under basal and estrogen treatment conditions in both populations. Hepatic metabolism of 17β-estradiol was also evaluated in vitro as an integrated endpoint for adverse effects on metabolism. In the third study, gene methylation was evaluated for promoters of vtg1 (8 CpGs) and vtg2 (10 CpGs) in both populations, and vtg1 promoter sequences were examined for single nucleotide polymorphism (SNPs). Overall, these studies show that multi-chemical exposures at Newark Bay have desensitized all reproductive biomarkers tested to estrogen. For example, at 10 ng

  4. The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy.

    Science.gov (United States)

    Iorga, Andrea; Cunningham, Christine M; Moazeni, Shayan; Ruffenach, Gregoire; Umar, Soban; Eghbali, Mansoureh

    2017-10-24

    Epidemiologic studies have previously suggested that premenopausal females have reduced incidence of cardiovascular disease (CVD) when compared to age-matched males, and the incidence and severity of CVD increases postmenopause. The lower incidence of cardiovascular disease in women during reproductive age is attributed at least in part to estrogen (E2). E2 binds to the traditional E2 receptors (ERs), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ), as well as the more recently identified G-protein-coupled ER (GPR30), and can exert both genomic and non-genomic actions. This review summarizes the protective role of E2 and its receptors in the cardiovascular system and discusses its underlying mechanisms with an emphasis on oxidative stress, fibrosis, angiogenesis, and vascular function. This review also presents the sexual dimorphic role of ERs in modulating E2 action in cardiovascular disease. The controversies surrounding the clinical use of exogenous E2 as a therapeutic agent for cardiovascular disease in women due to the possible risks of thrombotic events, cancers, and arrhythmia are also discussed. Endogenous local E2 biosynthesis from the conversion of testosterone to E2 via aromatase enzyme offers a novel therapeutic paradigm. Targeting specific ERs in the cardiovascular system may result in novel and possibly safer therapeutic options for cardiovascular protection.

  5. Investigations on the estrogenic activity of the metallohormone cadmium in the rat intestine

    Energy Technology Data Exchange (ETDEWEB)

    Hoefer, Nicola; Kluxen, Felix M. [German Sports University Cologne, Institute of Cardiovascular Research and Sports Medicine, Department of Molecular and Cellular Sports Medicine, Koeln (Germany); IfADo - Leibniz Research Centre for Working Environment and Human Factors at the TU Dortmund, Dortmund (Germany); Diel, Patrick [German Sports University Cologne, Institute of Cardiovascular Research and Sports Medicine, Department of Molecular and Cellular Sports Medicine, Koeln (Germany); Wittsiepe, Juergen; Wilhelm, Michael [Ruhr-University Bochum, Department of Hygiene, Social- and Environmental Medicine, Bochum (Germany); Degen, Gisela H. [IfADo - Leibniz Research Centre for Working Environment and Human Factors at the TU Dortmund, Dortmund (Germany)

    2010-07-15

    Cadmium (Cd), a toxic heavy metal and an important environmental pollutant, is now also regarded as potential endocrine disruptor. Its estrogenic effects have been examined so far just in classical target tissues, e.g. uterus, and mostly upon intraperitoneal (i.p.) injection of CdCl{sub 2}. Yet, estrogen receptors are also expressed in the gut, and food is the main source of cadmium intake in the general population. Therefore, possible estrogenic effects were now investigated in the intestine of ovariectomized Wistar rats after oral short- and long-term administration of CdCl{sub 2} (0.05-4 mg/kg bw on 3 days by gavage and 0.4-9 mg/kg bw for 4 weeks in drinking water) or upon i.p. injection (0.00005-2 mg CdCl{sub 2}/kg bw), and compared to steroid estrogen (estradiol or ethinylestradiol) treated groups. Analysis of Cd in kidneys and small intestine by atomic absorption spectrometry showed dose-dependent increases in tissue levels with rather high Cd concentrations in the gut, both after oral and i.p. administration. Expression of metallothionein (MT1a), a typical metal response parameter, was clearly induced in kidney and small intestine of several CdCl{sub 2} treated groups, but also notably increased by steroid estrogens. Levels of estrogen-regulated genes, i.e. pS2/TFF1, vitamin D receptor (VDR), and estrogen receptor {alpha} and {beta} (ER {alpha}/{beta}) were studied as parameters of hormonal activity: The intestinal mRNA expression of pS2/TFF1 was significantly decreased in the estrogen reference groups, but also after single i.p. injection and oral long-term administration of CdCl{sub 2}. In contrast, the mRNA and protein expression of the VDR were unaffected by long-term administration of Cd via drinking water. We detected expression of ER{beta}, but not ER{alpha} in the small intestine of OVX rats. ER{beta} mRNA and protein expression were significantly down-regulated by Cd, similar to the ethinylestradiol reference group. The mRNA expression and

  6. MOLECULAR DOCKING OF COMPOUNDS FROM Chaetomium Sp. AGAINST HUMAN ESTROGEN RECEPTOR ALPHA IN SEARCHING ANTI BREAST CANCER

    Directory of Open Access Journals (Sweden)

    Maywan Hariono

    2016-05-01

    Full Text Available A study on molecular docking-based virtual screening has been conducted to select virtual hit of compounds, reported its existence in fungal endophytes of Chaetomium sp. as cytotoxic agent of breast cancer. The ligands were docked into Human Estrogen Receptor alpha (HERa as the protein which regulates the breast cancer growth via estradiol-estrogen receptor binding intervention. The results showed that two compounds bearing xanthone and two compounds bearing benzonaphtyridinedione scaffolds were selected as virtual hit ligands for HERa leading to the conclusion that these compounds were good to be developed as anti breast cancer.

  7. Cell Cycle Regulation of Estrogen and Androgen Receptor

    Science.gov (United States)

    2001-07-01

    hypersensitivity as- the transiently transfected MMTV promoter as shown say was performed as described previously [18]. In brief, cells were previously [3, 41...per 1 F 108 cells, in 10 mM his tris propane , pH 7, 10 mM MgC12, 1 mM DTT) significant increase of CAT activity was observed. Pre- and incubated for 15...within nucleosome B, which is remodeled and becomes hypersensitive to restriction enzyme (SstI) cleavage during androgen that at no time point during the

  8. Gene expression signature of estrogen receptor α status in breast cancer

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    Baggerly Keith

    2005-03-01

    Full Text Available Abstract Background Estrogens are known to regulate the proliferation of breast cancer cells and to modify their phenotypic properties. Identification of estrogen-regulated genes in human breast tumors is an essential step toward understanding the molecular mechanisms of estrogen action in cancer. To this end we generated and compared the Serial Analysis of Gene Expression (SAGE profiles of 26 human breast carcinomas based on their estrogen receptor α (ER status. Thus, producing a breast cancer SAGE database of almost 2.5 million tags, representing over 50,000 transcripts. Results We identified 520 transcripts differentially expressed between ERα-positive (+ and ERα-negative (- primary breast tumors (Fold change ≥ 2; p Estrogen Responsive Elements (EREs distributed on the promoter regions of 163 out of the 473 up-modulated genes in ERα (+ breast tumors. In brief, we observed predominantly up-regulation of cell growth related genes, DNA binding and transcription factor activity related genes based on Gene Ontology (GO biological functional annotation. GO terms over-representation analysis showed a statistically significant enrichment of various transcript families including: metal ion binding related transcripts (p = 0.011, calcium ion binding related transcripts (p = 0.033 and steroid hormone receptor activity related transcripts (p = 0.031. SAGE data associated with ERα status was compared with reported information from breast cancer DNA microarrays studies. A significant proportion of ERα associated gene expression changes was validated by this cross-platform comparison. However, our SAGE study also identified novel sets of genes as highly expressed in ERα (+ invasive breast tumors not previously reported. These observations were further validated in an independent set of human breast tumors by means of real time RT-PCR. Conclusion The integration of the breast cancer comparative transcriptome analysis based on ERα status coupled to

  9. Pulmonary embolism due to exogenous estrogen intoxication.

    Science.gov (United States)

    Çelik, Caner; Carus, Murat; Büyükcam, Fatih

    2017-12-01

    Pulmonary embolism is a relatively common clinical presentation of venous thromboembolism, which develops in relation to acute pulmonary arterial occlusion mostly caused by thrombi of the lower limbs. 29year old female admitted to emergency department with pulmonary thromboembolism due to an ingestion of 17 Diana 35 pills (2 mg cyproterone acetate and 0.035mg ethinyl estradiol) in a suicide attempt without any previously known predisposing factors. After thrombolytic therapy, the patient was discharged with oral warfarin treatment. We know that exogenous estrogen increase the risk of venous thromboembolism in therapeutic use. It should be kept in mind that even single ingestion of a single high-dose exogenous estrogen intake may induce pulmonary thromboembolism. Copyright © 2017. Published by Elsevier Inc.

  10. Estrogen protects the blood-brain barrier from inflammation-induced disruption and increased lymphocyte trafficking.

    Science.gov (United States)

    Maggioli, E; McArthur, S; Mauro, C; Kieswich, J; Kusters, D H M; Reutelingsperger, C P M; Yaqoob, M; Solito, E

    2016-01-01

    Sex differences have been widely reported in neuroinflammatory disorders, focusing on the contributory role of estrogen. The microvascular endothelium of the brain is a critical component of the blood-brain barrier (BBB) and it is recognized as a major interface for communication between the periphery and the brain. As such, the cerebral capillary endothelium represents an important target for the peripheral estrogen neuroprotective functions, leading us to hypothesize that estrogen can limit BBB breakdown following the onset of peripheral inflammation. Comparison of male and female murine responses to peripheral LPS challenge revealed a short-term inflammation-induced deficit in BBB integrity in males that was not apparent in young females, but was notable in older, reproductively senescent females. Importantly, ovariectomy and hence estrogen loss recapitulated an aged phenotype in young females, which was reversible upon estradiol replacement. Using a well-established model of human cerebrovascular endothelial cells we investigated the effects of estradiol upon key barrier features, namely paracellular permeability, transendothelial electrical resistance, tight junction integrity and lymphocyte transmigration under basal and inflammatory conditions, modeled by treatment with TNFα and IFNγ. In all cases estradiol prevented inflammation-induced defects in barrier function, action mediated in large part through up-regulation of the central coordinator of tight junction integrity, annexin A1. The key role of this protein was then further confirmed in studies of human or murine annexin A1 genetic ablation models. Together, our data provide novel mechanisms for the protective effects of estrogen, and enhance our understanding of the beneficial role it plays in neurovascular/neuroimmune disease. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

  11. The potential therapeutic benefits of vitamin D in the treatment of estrogen receptor positive breast cancer.

    Science.gov (United States)

    Krishnan, Aruna V; Swami, Srilatha; Feldman, David

    2012-09-01

    Calcitriol (1,25-dihydroxyvitamin D(3)), the hormonally active form of vitamin D, inhibits the growth of many malignant cells including breast cancer (BCa) cells. The mechanisms of calcitriol anticancer actions include cell cycle arrest, stimulation of apoptosis and inhibition of invasion, metastasis and angiogenesis. In addition we have discovered new pathways of calcitriol action that are especially relevant in inhibiting the growth of estrogen receptor positive (ER+) BCa cells. Calcitriol suppresses COX-2 expression and increases that of 15-PGDH thereby reducing the levels of inflammatory prostaglandins (PGs). Our in vitro and in vivo studies show that calcitriol decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis selectively in BCa cells and in the mammary adipose tissue surrounding BCa, by a direct repression of aromatase transcription via promoter II as well as an indirect effect due to the reduction in the levels of PGs, which are major stimulator of aromatase transcription through promoter II. Calcitriol down-regulates the expression of ERα and thereby attenuates estrogen signaling in BCa cells including the proliferative stimulus provided by estrogens. Thus the inhibition of estrogen synthesis and signaling by calcitriol and its anti-inflammatory actions will play an important role in inhibiting ER+BCa. We hypothesize that dietary vitamin D would exhibit similar anticancer activity due to the presence of the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) in breast cells ensuring conversion of circulating 25-hydroxyvitamin D to calcitriol locally within the breast micro-environment where it can act in a paracrine manner to inhibit BCa growth. Cell culture and in vivo data in mice strongly suggest that calcitriol and dietary vitamin D would play a beneficial role in the prevention and/or treatment of ER+BCa in women. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Estrogen receptor silencing induces epithelial to mesenchymal transition in human breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Sanaa Al Saleh

    Full Text Available We propose the hypothesis that loss of estrogen receptor function which leads to endocrine resistance in breast cancer, also results in trans-differentiation from an epithelial to a mesenchymal phenotype that is responsible for increased aggressiveness and metastatic propensity. siRNA mediated silencing of the estrogen receptor in MCF7 breast cancer cells resulted in estrogen/tamoxifen resistant cells (pII with altered morphology, increased motility with rearrangement and switch from a keratin/actin to a vimentin based cytoskeleton, and ability to invade simulated components of the extracellular matrix. Phenotypic profiling using an Affymetrix Human Genome U133 plus 2.0 GeneChip indicated geometric fold changes ≥ 3 in approximately 2500 identifiable unique sequences, with about 1270 of these being up-regulated in pII cells. Changes were associated with genes whose products are involved in cell motility, loss of cellular adhesion and interaction with the extracellular matrix. Selective analysis of the data also showed a shift from luminal to basal cell markers and increased expression of a wide spectrum of genes normally associated with mesenchymal characteristics, with consequent loss of epithelial specific markers. Over-expression of several peptide growth factors and their receptors are indicative of an increased contribution to the higher proliferative rates of pII cells as well as aiding their potential for metastatic activity. Signalling molecules that have been identified as key transcriptional drivers of epithelial to mesenchymal transition were also found to be elevated in pII cells. These data support our hypothesis that induced loss of estrogen receptor in previously estrogen/antiestrogen sensitive cells is a trigger for the concomitant loss of endocrine dependence and onset of a series of possibly parallel events that changes the cell from an epithelial to a mesenchymal type. Inhibition of this transition through targeting of

  13. Identification of reproduction-specific genes associated with maturation and estrogen exposure in a marine bivalve Mytilus edulis.

    Directory of Open Access Journals (Sweden)

    Corina M Ciocan

    Full Text Available BACKGROUND: While it is established that vertebrate-like steroids, particularly estrogens (estradiol, estrone and androgens (testosterone, are present in various tissues of molluscs, it is still unclear what role these play in reproductive endocrinology in such organisms. This is despite the significant commercial shellfishery interest in several bivalve species and their decline. METHODOLOGY/PRINCIPAL FINDINGS: Using suppression subtraction hybridisation of mussel gonad samples at two stages (early and mature of gametogenesis and (in parallel following controlled laboratory estrogen exposure, we isolate several differentially regulated genes including testis-specific kinases, vitelline lysin and envelope sequences. CONCLUSIONS: The differentially expressed mRNAs isolated provide evidence that mussels may be impacted by exogenous estrogen exposure.

  14. Effects of 7-O Substitutions on Estrogenic and Antiestrogenic Activities of Daidzein Analogues in MCF-7 Breast Cancer Cells

    Science.gov (United States)

    Jiang, Quan; Payton-Stewart, Florastina; Elliott, Steven; Driver, Jennifer; Rhodes, Lyndsay V.; Zhang, Qiang; Zheng, Shilong; Bhatnagar, Deepak; Boue, Stephen M.; Collins-Burow, Bridgette M.; Sridhar, Jayalakshmi; Stevens, Cheryl; McLachlan, John A.; Wiese, Thomas E.; Burow, Matthew E.; Wang, Guangdi

    2010-01-01

    Daidzein (1) is a natural estrogenic isoflavone. We report here that 1 can be transformed into antiestrogenic ligands by simple alkyl substitutions of the 7-hydroxyl hydrogen. To test the effect of such structural modifications on the hormonal activities of the resulting compounds, a series of daidzein analogues have been designed and synthesized. When MCF-7 cells were treated with the analogues, those resulting from hydrogen substitution by isopropyl (3d), isobutyl (3f), cyclopentyl (3g), and pyrano- (2), inhibited cell proliferation, estrogen-induced transcriptional activity, and estrogen receptor (ER) regulated progesterone receptor (PgR) gene expression. However, methyl (3a) and ethyl (3b) substitutions of the hydroxyl proton only led to moderate reduction of the estrogenic activities. These results demonstrated the structural requirements for the transformation of daidzein from an ER agonist to an antagonist. The most effective analogue, 2 was found to reduce in vivo estrogen stimulated MCF-7 cell tumorigenesis using a xenograft mouse model. PMID:20669983

  15. Placental expression of estrogen receptor beta and its hormone binding variant – comparison with estrogen receptor alpha and a role for estrogen receptors in asymmetric division and differentiation of estrogen-dependent cells

    Directory of Open Access Journals (Sweden)

    Henley Donald C

    2003-04-01

    differentiation, the ER-alpha is associated with a less, and ER-beta with the more differentiated state. Enhanced expression of ~64 kDa ER-beta variant in trophoblast cultures suggests a unique role of ER-beta hormone binding domain in the regulation of trophoblast differentiation. Our data also indicate that asymmetric segregation of ER-alpha may play a role in asymmetric division of estrogen-dependent cells.

  16. Re-Opening the Critical Window for Estrogen Therapy.

    Science.gov (United States)

    Bean, Linda A; Kumar, Ashok; Rani, Asha; Guidi, Mike; Rosario, Awilda M; Cruz, Pedro E; Golde, Todd E; Foster, Thomas C

    2015-12-09

    expression of the estrogen receptors ERα and ERβ and demonstrate that the window for estradiol's beneficial effects on memory and hippocampal synaptic function can be reinstated by enhancing the expression of ERα. Our findings suggest that the activity of ERα controls the therapeutic window by regulating synaptic plasticity mechanisms involved in memory. Copyright © 2015 the authors 0270-6474/15/3516077-17$15.00/0.

  17. Can estrogens promote hypertension during systemic lupus erythematosus?

    Science.gov (United States)

    Venegas-Pont, Marcia; Ryan, Michael J

    2010-11-01

    SLE is a chronic autoimmune inflammatory disorder that predominantly affects young women. Based on this observation, it has been speculated that sex steroids, particularly estrogens, contribute to SLE disease progression. Young women with SLE are at an increased risk for the development of hypertension yet the reasons for this are unclear. One potential mechanism for the increased risk of hypertension during SLE is the chronic inflammation caused by immune complex mediated tissue injury. Estrogens are known to have an immunomodulatory role that can lead to the production of characteristic autoantibodies important for immune complex formation. Therefore, it is conceivable that during SLE estrogens contribute to tissue injury, increased inflammation and hypertension. This brief review discusses the increased risk for hypertension during SLE, the role of estrogens in immune system function, evidence for estrogens in SLE, and a possible link between estrogens and SLE hypertension. Copyright 2010 Elsevier Inc. All rights reserved.

  18. The role of estrogen in bipolar disorder, a review

    DEFF Research Database (Denmark)

    Meinhard, Ninja; Kessing, Lars Vedel; Vinberg, Maj

    2014-01-01

    BACKGROUND: It appears that the female reproductive events and hormonal treatments may impact the course of bipolar disorder in women. In particular, childbirth is known to be associated with onset of affective episodes in women with bipolar disorder. During the female reproductive events the sex...... hormones, e.g. estrogen, are fluctuating and particularly postpartum there is a steep fall in the levels of serum estrogen. The role of estrogen in women with bipolar disorder is, however, not fully understood. AIM: The main objective of this review is to evaluate the possible relation between serum...... estrogen levels and women with bipolar disorder including studies of the anti manic effects of the selective estrogen receptor modulator tamoxifen. METHOD: A systematically literature search on PubMed was conducted: two studies regarding the connection between serum estrogen levels and women with bipolar...

  19. Computational estimation of rainbow trout estrogen receptor binding affinities for environmental estrogens.

    Science.gov (United States)

    Shyu, Conrad; Cavileer, Timothy D; Nagler, James J; Ytreberg, F Marty

    2011-02-01

    Environmental estrogens have been the subject of intense research due to their documented detrimental effects on the health of fish and wildlife and their potential to negatively impact humans. A complete understanding of how these compounds affect health is complicated because environmental estrogens are a structurally heterogeneous group of compounds. In this work, computational molecular dynamics simulations were utilized to predict the binding affinity of different compounds using rainbow trout (Oncorhynchus mykiss) estrogen receptors (ERs) as a model. Specifically, this study presents a comparison of the binding affinity of the natural ligand estradiol-17β to the four rainbow trout ER isoforms with that of three known environmental estrogens 17α-ethinylestradiol, bisphenol A, and raloxifene. Two additional compounds, atrazine and testosterone, that are known to be very weak or non-binders to ERs were tested. The binding affinity of these compounds to the human ERα subtype is also included for comparison. The results of this study suggest that, when compared to estradiol-17β, bisphenol A binds less strongly to all four receptors, 17α-ethinylestradiol binds more strongly, and raloxifene has a high affinity for the α subtype only. The results also show that atrazine and testosterone are weak or non-binders to the ERs. All of the results are in excellent qualitative agreement with the known in vivo estrogenicity of these compounds in the rainbow trout and other fishes. Computational estimation of binding affinities could be a valuable tool for predicting the impact of environmental estrogens in fish and other animals. Copyright © 2010 Elsevier Inc. All rights reserved.

  20. Selectivity of natural, synthetic and environmental estrogens for zebrafish estrogen receptors

    Energy Technology Data Exchange (ETDEWEB)

    Pinto, Caroline [Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5056 (United States); Grimaldi, Marina; Boulahtouf, Abdelhay [Institut de Recherche en Cancérologie de Montpellier, Institut National de la Santé de la Recherche Médicale U896, Institut Régional de Cancérologie de Montpellier, Université Montpellier 1, 34298 Montpellier (France); Pakdel, Farzad [Institut de Recherche sur la Santé, Environnement et Travail (IRSET), INSERM U1085, Université de Rennes 1, Rennes (France); Brion, François; Aït-Aïssa, Sélim [Unité Écotoxicologie In Vitro et In Vivo, INERIS, Parc ALATA, 60550 Verneuil-en-Halatte (France); Cavaillès, Vincent [Institut de Recherche en Cancérologie de Montpellier, Institut National de la Santé de la Recherche Médicale U896, Institut Régional de Cancérologie de Montpellier, Université Montpellier 1, 34298 Montpellier (France); Bourguet, William [U1054, Centre de Biochimie Structurale, CNRS UMR5048, Université Montpellier 1 et 2, 34290 Montpellier (France); Gustafsson, Jan-Ake [Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5056 (United States); Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge (Sweden); and others

    2014-10-01

    Zebrafish, Danio rerio, is increasingly used as an animal model to study the effects of pharmaceuticals and environmental estrogens. As most of these estrogens have only been tested on human estrogen receptors (ERs), it is necessary to measure their effects on zebrafish ERs. In humans there are two distinct nuclear ERs (hERα and hERβ), whereas the zebrafish genome encodes three ERs, zfERα and two zfERβs (zfERβ1 and zfERβ2). In this study, we established HeLa-based reporter cell lines stably expressing each of the three zfERs. We first reported that estrogens more efficiently activate the zfERs at 28 °C as compared to 37 °C, thus reflecting the physiological temperature of zebrafish in wildlife. We then showed significant differences in the ability of agonist and antagonist estrogens to modulate activation of the three zfER isotypes in comparison to hERs. Environmental compounds (bisphenol A, alkylphenols, mycoestrogens) which are hER panagonists and hERβ selective agonists displayed greater potency for zfERα as compared to zfERβs. Among hERα selective synthetic agonists, PPT did not activate zfERα while 16α-LE2 was the most zfERα selective compound. Altogether, these results confirm that all hER ligands control in a similar manner the transcriptional activity of zfERs although significant differences in selectivity were observed among subtypes. The zfER subtype selective ligands that we identified thus represent new valuable tools to dissect the physiological roles of the different zfERs. Finally, our work also points out that care has to be taken in transposing the results obtained using the zebrafish as a model for human physiopathology. - Highlights: • Zebrafish is increasingly used to study the effects of estrogens. • We assessed the activity of pharmaceutical and environmental estrogens on zfERs. • Environmental estrogens displayed greater potency for zfERα compared to zfERβs. • hERβ selective agonists displayed greater potency for zf

  1. Estrogen receptor mRNA in mineralized tissues of rainbow trout: calcium mobilization by estrogen.

    Science.gov (United States)

    Armour, K J; Lehane, D B; Pakdel, F; Valotaire, Y; Graham, R; Russell, R G; Henderson, I W

    1997-07-07

    RT-PCR was undertaken on total RNA extracts from bone and scales of the rainbow trout, Oncorhynchus mykiss. The rainbow trout estrogen receptor (ER)-specific primers used amplified a single product of expected size from each tissue which, using Southern blotting, strongly hybridized with a 32P-labelled rtER probe under stringent conditions. These data provide the first in vivo evidence of ER mRNA in bone and scale tissues of rainbow trout and suggest that the effects of estrogen observed in this study (increased bone mineral and decreased scale mineral contents, respectively) may be mediated directly through ER.

  2. Estrogen signaling in the proliferative endometrium: implications in endometriosis

    Directory of Open Access Journals (Sweden)

    Rita de Cássia Pereira da Costa e Silva

    2016-02-01

    Full Text Available SUMMARY Even though the physiological role of estrogen in the female reproductive cycle and endometrial proliferative phase is well established, the signaling pathways by which estrogen exerts its action in the endometrial tissue are still little known. In this regard, advancements in cell culture techniques and maintenance of endometrial cells in cultures enabled the discovery of new signaling mechanisms activated by estrogen in the normal endometrium and in endometriosis. This review aims to present the recent findings in the genomic and non-genomic estrogen signaling pathways in the proliferative human endometrium specifically associated with the pathogenesis and development of endometriosis.

  3. Insights from the Study of Animals Lacking Functional Estrogen Receptor

    Science.gov (United States)

    Korach, Kenneth S.

    1994-12-01

    Estrogen hormones produce physiological actions within a variety of target sites in the body and during development by activating a specific receptor protein. Hormone responsiveness for the estrogen receptor protein was investigated at different stages of development with the use of gene knockout techniques because no natural genetic mutants have been described. A mutant mouse line without a functional estrogen receptor was created and is being used to assess estrogen responsiveness. Both sexes of these mutant animals are infertile and show a variety of phenotypic changes, some of which are associated with the gonads, mammary glands, reproductive tracts, and skeletal tissues.

  4. Mouse models to evaluate the role of estrogen receptor α in skeletal maintenance and adaptation.

    Science.gov (United States)

    Rooney, Amanda M; van der Meulen, Marjolein C H

    2017-12-01

    Estrogen signaling and mechanical loading have individual and combined effects on skeletal maintenance and adaptation. Previous work investigating estrogen signaling both in vitro and in vivo using global estrogen receptor α (ERα) gene knockout mouse models has provided information regarding the role of ERα in regulating bone mass and adaptation to mechanical stimulation. However, these models have inherent limitations that confound interpretation of the data. Therefore, recent studies have focused on mice with targeted deletion of ERα from specific bone cells and their precursors. Cell stage, tissue type, and mouse sex all influence the effects of ERα gene deletion. Lack of ERα in osteoblast progenitor and precursor cells generally affects the periosteum of female and male mice. The absence of ERα in differentiated osteoblasts, osteocytes, and osteoclasts in mice generally resulted in reduced cancellous bone mass, with differing reports of the effect by animal sex and greater deficiencies in bone mass typically occurring in cancellous bone in female mice. Limited data exist for the role of bone cell-specific ERα in skeletal adaptation in vivo. Cell-specific ERα gene knockout mice provide an excellent platform for investigating the function of ERα in regulating skeletal phenotype and response to mechanical loading by sex and age. © 2017 New York Academy of Sciences.

  5. Effect of estrogen receptor-subtype-specific ligands on fertility in adult male rats.

    Science.gov (United States)

    Dumasia, Kushaan; Kumar, Anita; Kadam, Leena; Balasinor, N H

    2015-06-01

    Maintenance of normal male fertility relies on the process of spermatogenesis which is under complex endocrine control by mechanisms involving gonadotropin and steroid hormones. Although testosterone is the primary sex steroid in males, estrogen is locally produced in the testis and plays a very crucial role in male fertility. This is evident from presence of both the estrogen receptors alpha (ERα) and beta (ERβ) in the testis and their absence, as in the case of knockout mice models, leads to sterility. The present study was undertaken to understand individual roles of the two ERs in spermatogenesis and their direct contribution towards the maintenance of male fertility using receptor-subtype-specific ligands. Administration of ERα and β agonists to adult male rats for 60 days results in a significant decrease in fertility, mainly due to an increase in pre- and post-implantation loss and a concomitant decrease in litter size and sperm counts. Our results indicate that ERα is mainly involved in negative feedback regulation of gonadotropin hormones, whereas both ERs are involved in regulation of prolactin and testosterone production. Histological examinations of the testis reveal that ERβ could be involved in the process of spermiation since many failed spermatids were observed in stages IX-XI following ERβ agonist treatment. Our results indicate that overactivation of estrogen signaling through either of its receptors can have detrimental effects on the fertility parameters and that the two ERs have both overlapping and distinct roles in maintenance of male fertility. © 2015 Society for Endocrinology.

  6. TNF-{alpha} mediates the stimulation of sclerostin expression in an estrogen-deficient condition

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Beom-Jun [Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap2-Dong, Seoul (Korea, Republic of); Bae, Sung Jin [Health Promotion Center, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap2-Dong, Seoul (Korea, Republic of); Lee, Sun-Young; Lee, Young-Sun; Baek, Ji-Eun; Park, Sook-Young [Asan Institute for Life Sciences, 388-1 Poongnap2-Dong, Seoul (Korea, Republic of); Lee, Seung Hun [Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap2-Dong, Seoul (Korea, Republic of); Koh, Jung-Min, E-mail: jmkoh@amc.seoul.kr [Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap2-Dong, Seoul (Korea, Republic of); Kim, Ghi Su [Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap2-Dong, Seoul (Korea, Republic of)

    2012-07-20

    Highlights: Black-Right-Pointing-Pointer Estrogen deprivation stimulates the bony sclerostin levels with reversal by estrogen. Black-Right-Pointing-Pointer TNF-{alpha} increases the activity and expression of MEF2 in UMR-106 cells. Black-Right-Pointing-Pointer TNF-{alpha} blocker prevents the stimulation of bony sclerostin expression by ovariectomy. Black-Right-Pointing-Pointer No difference in bony sclerostin expression between sham-operated and ovariectomized nude mice. -- Abstract: Although recent clinical studies have suggested a possible role for sclerostin, a secreted Wnt antagonist, in the pathogenesis of postmenopausal osteoporosis, the detailed mechanisms how estrogen deficiency regulates sclerostin expression have not been well-elucidated. Bilateral ovariectomy or a sham operation in female C57BL/6 mice and BALB/c nude mice was performed when they were seven weeks of age. The C57BL/6 mice were intraperitoneally injected with phosphate-buffered serum (PBS), 5 {mu}g/kg {beta}-estradiol five times per week for three weeks, or 10 mg/kg TNF-{alpha} blocker three times per week for three weeks. Bony sclerostin expression was assessed by immunohistochemistry staining in their femurs. The activity and expression of myocyte enhancer factors 2 (MEF2), which is essential for the transcriptional activation of sclerostin, in rat UMR-106 osteosarcoma cells were determined by luciferase reporter assay and western blot analysis, respectively. Bony sclerostin expression was stimulated by estrogen deficiency and it was reversed by estradiol supplementation. When the UMR-106 cells were treated with well-known, estrogen-regulated cytokines, only TNF-{alpha}, but not IL-1 and IL-6, increased the MEF2 activity. Consistently, TNF-{alpha} also increased the nuclear MEF2 expression. Furthermore, the TNF-{alpha} blocker prevented the stimulation of bony sclerostin expression by ovariectomy. We also found that there was no difference in sclerostin expression between ovariectomized

  7. Dioxin increases the interaction between aryl hydrocarbon receptor and estrogen receptor alpha at human promoters

    DEFF Research Database (Denmark)

    Ahmed, Shaaima; Valen, Eivind; Sandelin, Albin Gustav

    2009-01-01

    Recent studies have shown that activated aryl hydrocarbon receptor (AHR) induced the recruitment of estrogen receptor- (ER ) to AHR-regulated genes and that AHR is recruited to ER -regulated genes. However, these findings were limited to a small number of well-characterized AHR- or ER -responsive...... regions bound by both AHR and ER . Conventional and sequential ChIPs confirmed the recruitment of AHR and ER to many of the identified regions. Transcription factor binding site analysis revealed an overrepresentation of aryl hydrocarbon receptor response elements in regions bound by both AHR and ER...

  8. c-Src modulates estrogen-induced stress and apoptosis in estrogen-deprived breast cancer cells

    Science.gov (United States)

    Fan, Ping; Griffith, Obi L; Agboke, Fadeke; Anur, Pavana; Zou, Xiaojun; McDaniel, Russell E; Creswell, Karen; Kim, Sung Hoon; Katzenellenbogen, John A; Gray, Joe W; Jordan, V Craig

    2013-01-01

    The emergence of antiestrogen resistance in breast cancer is an important clinical phenomenon affecting long-term survival in this disease. Identifying factors that convey cell survival in this setting may guide improvements in treatment. Estrogen (E2) can induce apoptosis in breast cancer cells that have been selected for survival after E2 deprivation for long periods (MCF-7:5C cells), but the mechanisms underlying E2-induced stress in this setting have not been elucidated. Here, we report that the c-Src kinase functions as a key adapter protein for the estrogen receptor (ER, ESR1) in its activation of stress responses induced by E2 in MCF-7:5C cells. E2 elevated phosphorylation of c-Src which was blocked by 4-hydroxytamoxifen (4-OHT), suggesting that E2 activated c-Src through the ER. We found that E2 activated the sensors of the unfolded protein response (UPR), IRE1α (ERN1) and PERK kinase (EIF2AK3), the latter of which phosphorylates eukaryotic translation initiation factor-2α (eIF2α). E2 also dramatically increased reactive oxygen species (ROS) production and up-regulated expression of heme oxygenase HO-1 (HMOX1), an indicator of oxidative stress, along with the central energy sensor kinase AMPK (PRKAA2). Pharmacological or RNAi-mediated inhibition of c-Src abolished the phosphorylation of eIF2α and AMPK, blocked E2-induced ROS production, and inhibited E2-induced apoptosis. Together, our results establish that c-Src kinase mediates stresses generated by E2 in long-term E2-deprived cells that trigger apoptosis. This work offers a mechanistic rationale for a new approach in the treatment of endocrine-resistant breast cancer. PMID:23704208

  9. Distinct effects of loss of classical estrogen receptor signaling versus complete deletion of estrogen receptor alpha on bone.

    Science.gov (United States)

    Syed, Farhan A; Fraser, Daniel G; Monroe, David G; Khosla, Sundeep

    2011-08-01

    Estrogen receptor (ER) α is a major regulator of bone metabolism which can modulate gene expression via a "classical" pathway involving direct DNA binding to estrogen-response elements (EREs) or via "non-classical" pathways involving protein-protein interactions. While the skeletal consequences of loss of ERE binding by ERα have been described, a significant unresolved question is how loss of ERE binding differs from complete loss of ERα. Thus, we compared the skeletal phenotype of wild-type (ERα(+/+)) and ERα knock out (ERα(-/-)) mice with that of mice in which the only ERα present had a knock-in mutation abolishing ERE binding (non-classical ERα knock-in [NERKI], ERα(-/NERKI)). All three groups were in the same genetic background (C57BL/6). As compared to both ERα(+/+) and ERα(-/-) mice, ERα(-/NERKI) mice had significantly reduced cortical volumetric bone mineral density and thickness at the tibial diaphysis; this was accompanied by significant decreases in periosteal and endocortical mineral apposition rates. Colony forming unit (CFU)-fibroblast, CFU-alkaline phosphatase, and CFU-osteoblast numbers were all increased in ERα(-/-) compared to ERα(+/+) mice, but reduced in ERα(-/NERKI) mice compared to the two other groups. Thus, using mice in identical genetic backgrounds, our data indicate that the presence of an ERα that cannot bind DNA but can function through protein-protein interactions may have more deleterious skeletal effects than complete loss of ERα. These findings suggest that shifting the balance of classical versus non-classical ERα signaling triggers pathways that impair bone formation. Further studies defining these pathways may lead to novel approaches to selectively modulate ER signaling for beneficial skeletal effects. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Linc-RoR promotes MAPK/ERK signaling and confers estrogen-independent growth of breast cancer.

    Science.gov (United States)

    Peng, Wan-Xin; Huang, Jian-Guo; Yang, Liu; Gong, Ai-Hua; Mo, Yin-Yuan

    2017-10-17

    , these results suggest that linc-RoR promotes estrogen-independent growth and activation of MAPK/ERK pathway of breast cancer cells by regulating the ERK-specific phosphatase DUSP7. Thus, this study might help not only in establishing a role for linc-RoR in estrogen-independent and tamoxifen resistance of ER+ breast cancer, but also suggesting a link between linc-RoR and MAPK/ERK pathway.

  11. Estrogens and cognition: Friends or foes?: An evaluation of the opposing effects of estrogens on learning and memory.

    Science.gov (United States)

    Korol, Donna L; Pisani, Samantha L

    2015-08-01

    This article is part of a Special Issue "Estradiol and cognition". Estrogens are becoming well known for their robust enhancement on cognition particularly for learning and memory that relies upon functioning of the hippocampus and related neural systems. What is also emerging is that estrogen modulation of cognition is not uniform, at times enhancing yet at other times impairing learning. This review explores the bidirectional effects of estrogens on learning from a multiple memory systems view, focusing on the hippocampus and striatum, whereby modulation by estrogens sorts according to task attributes and neural systems engaged during cognition. We highlight our findings showing that the ability to solve hippocampus-sensitive tasks typically improves under relatively high estrogen status while the ability to solve striatum-sensitive tasks degrades with estrogen exposures. Though constrained by dose and timing of exposure, these opposing enhancements and impairments of cognition can be observed following treatments with different estrogenic compounds including the hormone estradiol, the isoflavone genistein found in soybeans, and agonists that are selective for specific estrogen receptors, suggesting that activation of a single receptor type is sufficient to produce the observed shifts in learning strategies. Using this multi-dimensional framework will allow us to extend our thinking of the relationship between estrogens and cognition to other brain regions and cognitive functions. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Role of estrogen receptor signaling in skeletal response to leptin in female ob/ob mice.

    Science.gov (United States)

    Turner, Russell T; Philbrick, Kenneth A; Kuah, Amida F; Branscum, Adam J; Iwaniec, Urszula T

    2017-06-01

    Leptin, critical in regulation of energy metabolism, is also important for normal bone growth, maturation and turnover. Compared to wild type (WT) mice, bone mass is lower in leptin-deficient ob/ob mice. Osteopenia in growing ob/ob mice is due to decreased bone accrual, and is associated with reduced longitudinal bone growth, impaired cancellous bone maturation and increased marrow adipose tissue (MAT). However, leptin deficiency also results in gonadal dysfunction, disrupting production of gonadal hormones which regulate bone growth and turnover. The present study evaluated the role of increased estrogen in mediating the effects of leptin on bone in ob/ob mice. Three-month-old female ob/ob mice were randomized into one of the 3 groups: (1) ob/ob + vehicle (veh), (2) ob/ob + leptin (leptin) or (3) ob/ob + leptin and the potent estrogen receptor antagonist ICI 182,780 (leptin + ICI). Age-matched WT mice received vehicle. Leptin (40 µg/mouse, daily) and ICI (10 µg/mouse, 2×/week) were administered by subcutaneous injection for 1 month and bone analyzed by X-ray absorptiometry, microcomputed tomography and static and dynamic histomorphometry. Uterine weight did not differ between ob/ob mice and ob/ob mice receiving leptin + ICI, indicating that ICI successfully blocked the uterine response to leptin-induced increases in estrogen levels. Compared to leptin-treated ob/ob mice, ob/ob mice receiving leptin + ICI had lower uterine weight; did not differ in weight loss, MAT or bone formation rate; and had higher longitudinal bone growth rate and cancellous bone volume fraction. We conclude that increased estrogen signaling following leptin treatment is dispensable for the positive actions of leptin on bone and may attenuate leptin-induced bone growth. © 2017 Society for Endocrinology.

  13. Inhibitory effect of estrogen receptor beta on P2X3 receptors during inflammation in rats.

    Science.gov (United States)

    Jiang, Qian; Li, Wen-Xin; Sun, Jia-Run; Zhu, Tian-Tian; Fan, Juan; Yu, Li-Hua; Burnstock, Geoffrey; Yang, Hua; Ma, Bei

    2017-03-01

    Estrogen receptor beta (ERβ) has been shown to play a therapeutic role in inflammatory bowel disease (IBD). However, the mechanism underlying how ERβ exerts therapeutic effects and its relationship with P2X3 receptors (P2X3R) in rats with inflammation is not known. In our study, animal behavior tests, visceromotor reflex recording, and Western blotting were used to determine whether the therapeutic effect of ERβ in rats with inflammation was related with P2X3R. In complete Freund adjuvant (CFA)-induced chronic inflammation in rats, paw withdrawal threshold was significantly decreased which were then reversed by systemic injection of ERβ agonists, DPN or ERB-041. In 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats, weight loss, higher DAI scores, increased visceromotor responses, and inflammatory responses were reversed by application of DPN or ERB-041. The higher expressions of P2X3R in dorsal root ganglia (DRG) of CFA-treated rats and those in rectocolon and DRG of TNBS-treated rats were all decreased by injection of DPN or ERB-041. DPN application also inhibited P2X3R-evoked inward currents in DRG neurons from TNBS rats. Mechanical hyperalgesia and increased P2X3 expression in ovariectomized (OVX) CFA-treated rats were reversed by estrogen replacements. Furthermore, the expressions of extracellular signal-regulated kinase (ERK) in DRG and spinal cord dorsal horn (SCDH) and c-fos in SCDH were significantly decreased after estrogen replacement compared with those of OVX rats. The ERK antagonist U0126 significantly reversed mechanical hyperalgesia in the OVX rats. These results suggest that estrogen may play an important therapeutic role in inflammation through down-regulation of P2X3R in peripheral tissues and the nervous system, probably via ERβ, suggesting a novel therapeutic strategy for clinical treatment of inflammation.

  14. Progressive increase of glucose transporter-3 (GLUT-3) expression in estrogen-induced breast carcinogenesis.

    Science.gov (United States)

    Kocdor, M A; Kocdor, H; Pereira, J S; Vanegas, J E; Russo, I H; Russo, J

    2013-01-01

    Increased glucose uptake and glycolysis are main metabolic characteristics of malignant cells. A family of glucose transporters (GLUTs) facilitates glucose movement across the plasma membranes in a tumor-specific manner. Glucose transporter-1 (GLUT-1), GLUT-3 and recently GLUT-12, have been previously shown in breast cancer cells and are found to be associated with poor prognosis. In addition, it has been shown that estrogen plays critical roles in GLUT regulation, however, the stage-specific GLUT regulation of mammary carcinogenesis is unclear. GLUT expression patterns were investigated in an in vitro-in vivo progressive, estrogen-induced, mammary carcinogenesis model which consisted of four cell lines, with same genetic background. In this model, different stages of tumor initiation and progression are represented, MCF-10F being the normal stage, E2 cells the transformed stage by estrogen, C5 cells, the invasive stage, and T4 cells the tumorigenic stage. In addition, loss of ductulogenesis and solid mass formation in collagen matrix and invasiveness of the cells were counted. Real time PCR showed that GLUT1 expression was downregulated in MCF10F after treatment with 17β-estradiol (E2), and in the invasive cell type (C5), but not in the tumor cells (T4), which had no changes compared to MCF10F. C5 and T4 cells showed the highest rate of GLUT-3 expression. These cells were also found to be associated with loss of ductulogenesis, solid mass formation and higher invasive capacity, whereas, GLUT-12 was downregulated in C5 and T4 cells. Estrogen-induced malignant transformation is associated with remarkable and progressive GLUT-3 expression, GLUT-1 re-expression at further stages, as well as GLUT-12 downregulation.

  15. Emerging Estrogenic Pollutants in the Aquatic Environment and Breast Cancer

    Science.gov (United States)

    Lecomte, Sylvain; Charlier, Thierry D.; Pakdel, Farzad

    2017-01-01

    The number and amount of man-made chemicals present in the aquatic environment has increased considerably over the past 50 years. Among these contaminants, endocrine-disrupting chemicals (EDCs) represent a significant proportion. This family of compounds interferes with normal hormonal processes through multiple molecular pathways. They represent a potential risk for human and wildlife as they are suspected to be involved in the development of diseases including, but not limited to, reprotoxicity, metabolic disorders, and cancers. More precisely, several studies have suggested that the increase of breast cancers in industrialized countries is linked to exposure to EDCs, particularly estrogen-like compounds. Estrogen receptors alpha (ERα) and beta (ERβ) are the two main transducers of estrogen action and therefore important targets for these estrogen-like endocrine disrupters. More than 70% of human breast cancers are ERα-positive and estrogen-dependent, and their development and growth are not only influenced by endogenous estrogens but also likely by environmental estrogen-like endocrine disrupters. It is, therefore, of major importance to characterize the potential estrogenic activity from contaminated surface water and identify the molecules responsible for the hormonal effects. This information will help us understand how environmental contaminants can potentially impact the development of breast cancer and allow us to fix a maximal limit to the concentration of estrogen-like compounds that should be found in the environment. The aim of this review is to provide an overview of emerging estrogen-like compounds in the environment, sum up studies demonstrating their direct or indirect interactions with ERs, and link their presence to the development of breast cancer. Finally, we emphasize the use of in vitro and in vivo methods based on the zebrafish model to identify and characterize environmental estrogens. PMID:28914763

  16. Factor XII mutations, estrogen-dependent inherited angioedema, and related conditions

    National Research Council Canada - National Science Library

    Binkley, Karen E

    2010-01-01

    The clinical, biochemical and genetic features of the conditions known as estrogen-dependent inherited angioedema, estrogen-associated angioedema, hereditary angioedema with normal C-1 inhibitor, type...

  17. The in vivo estrogenic and in vitro anti-estrogenic activity of permethrin and bifenthrin

    Science.gov (United States)

    Brander, Susanne M.; He, Guochun; Smalling, Kelly L.; Denison, Michael S.; Cherr, Gary N.

    2012-01-01

    Pyrethroids are highly toxic to fish at parts per billion or parts per trillion concentrations. Their intended mechanism is prolonged sodium channel opening, but recent studies reveal that pyrethroids such as permethrin and bifenthrin also have endocrine activity. Additionally, metabolites may have greater endocrine activity than parent compounds. We evaluated the in vivo concentration-dependent ability of bifenthrin and permethrin to induce choriogenin (an estrogen-responsive protein) in Menidia beryllina, a fish species known to reside in pyrethroid contaminated aquatic habitats. We then compared the in vivo response to an in vitro assay: CALUX (Chemical Activated Luciferase Gene Expression). Juvenile Menidia beryllina exposed to bifenthrin (1, 10, 100 ng/L), permethrin (0.1, 1, 10 µg/L), and ethinylestradiol (1, 10, 50 ng/L) had significantly higher ng/mL choriogenin (Chg) measured in whole body homogenate than controls. While Chg expression in fish exposed to ethinylestradiol (EE2) exhibited a traditional sigmoidal concentration-response, curves fit to Chg expressed in fish exposed to pyrethroids suggest a unimodal response, decreasing slightly as concentration increases. While the in vivo response indicated that bifenthrin and permethrin or their metabolites act as estrogen agonists, the CALUX assay demonstrated estrogen antagonism by the pyrethroids. Our results, supported by evidence from previous studies, suggest that bifenthrin and permethrin, and/or their metabolites, appear to act as estrogen receptor (ER) agonists in vivo, and that the unmetabolized pyrethroids, particularly bifenthrin, act as an ER antagonists in cultured mammalian cells. PMID:23007834

  18. Neuroprotection by estrogenic compounds following inflammatory insult in the brain

    Directory of Open Access Journals (Sweden)

    Luis Miguel Garcia-Segura

    2015-02-01

    Full Text Available The steady-state microglia play an important role in monitoring and protecting the nerve tissue ensuring proper functioning of the Central Nervous System. Microglia respond to an immune stimulus with the subsequent activation of cascades that trigger the secretion of pro-inflammatory cytokines (IL-1, TNF-α, IL-12. Neurodegenerative diseases and disorders such as spinal cord injury, stroke, and head trauma are directly related to chronic activation of microglia. Depending on the injury severity, the microglial response and activity may range from acute (beneficial or chronic (detrimental, where this long-term activation are tightly associated to neurodegenerative processes. Several studies have reported that neuroactive steroids have protective effects and regulate the neuroinflammation associated to microglia. In cell therapy, microglia-induced inflammation may be modulated via the use of neurosteriods, due to their evidenced roles in the regulation of neuroinflammation. Estrogenic compounds, such as as SERM and STEARs, are currently under investigation. In this work, the regulatory mechanisms of inflammation of the microglia are discussed, including the reduction of inflammatory processes in the brain by treatment with neurosteroids.

  19. PPARα in Obesity: Sex Difference and Estrogen Involvement

    Directory of Open Access Journals (Sweden)

    Michung Yoon

    2010-01-01

    Full Text Available Peroxisome proliferator-activated receptor α (PPARα is a member of the steroid hormone receptor superfamily and is well known to act as the molecular target for lipid-lowering drugs of the fibrate family. At the molecular level, PPARα regulates the transcription of a number of genes critical for lipid and lipoprotein metabolism. PPARα activators are further shown to reduce body weight gain and adiposity, at least in part, due to the increase of hepatic fatty acid oxidation and the decrease in levels of circulating triglycerides responsible for adipose cell hypertrophy and hyperplasia. However, these effects of the PPARα ligand fenofibrate on obesity are regulated with sexual dimorphism and seem to be influenced by the presence of functioning ovaries, suggesting the involvement of ovarian steroids in the control of obesity by PPARα. In female ovariectomized mice, 17β-estradiol inhibits the actions of fenofibrate on obesity through its suppressive effects on the expression of PPARα target genes, and these processes may be mediated by inhibiting the coactivator recruitment of PPARα. Thus, it is likely that PPARα functions on obesity may be enhanced in estrogen-deficient states.

  20. Ovary-independent estrogen receptor expression in neonatal porcine endometrium.

    Science.gov (United States)

    Tarleton, B J; Wiley, A A; Spencer, T E; Moss, A G; Bartol, F F

    1998-04-01

    Effects of age and ovariectomy (OVX) at birth on uterine growth, endometrial development, and estrogen receptor (ER) expression were determined for intact and OVX gilts (n = 5 per day) hysterectomized on postnatal days (PND) 0, 15, 30, 60, 90, or 120. Uteri were evaluated histologically, and ER protein and mRNA expression were characterized immunohistochemically and by in situ hybridization. OVX did not affect uterine weight or endometrial thickness until after PND 60, when both increased more rapidly in intact gilts. Neither did it affect genesis of uterine glands, which were present and which proliferated after PND 0, or endometrial ER expression patterns in glandular epithelium (GE), luminal epithelium (LE), or stroma (S) between PND 0 and 120. Endometrium was ER negative at birth. On PND 15, the ER signal was strong in GE, weak in S, and effectively absent in LE. Thereafter, although the ER signal remained strong in GE and increased through PND 60 in S, it was not evident consistently until after PND 30 in LE. The data indicate that 1) porcine uterine growth and endometrial morphogenesis are ovary-independent processes before PND 60; 2) uterine gland genesis is associated temporally with development of ER-positive endometrial GE and S; and 3) regulation of endometrial ER expression is ovary independent between PND 0 and 120. The results establish the ER as a marker of GE differentiation and implicate this receptor in mechanisms regulating endometrial morphogenesis in the neonatal pig.

  1. Caffeine, coffee, and tea intake and urinary estrogens and estrogen metabolites in premenopausal women.

    Science.gov (United States)

    Sisti, Julia S; Hankinson, Susan E; Caporaso, Neil E; Gu, Fangyi; Tamimi, Rulla M; Rosner, Bernard; Xu, Xia; Ziegler, Regina; Eliassen, A Heather

    2015-08-01

    Prior studies have found weak inverse associations between breast cancer and caffeine and coffee intake, possibly mediated through their effects on sex hormones. High-performance liquid chromatography/tandem mass spectrometry was used to quantify levels of 15 individual estrogens and estrogen metabolites (EM) among 587 premenopausal women in the Nurses' Health Study II with mid-luteal phase urine samples and caffeine, coffee, and/or tea intakes from self-reported food frequency questionnaires. Multivariate linear mixed models were used to estimate geometric means of individual EM, pathways, and ratios by intake categories, and P values for tests of linear trend. Compared with women in the lowest quartile of caffeine consumption, those in the top quartile had higher urinary concentrations of 16α-hydroxyestrone (28% difference; Ptrend = 0.01) and 16-epiestriol (13% difference; Ptrend = 0.04), and a decreased parent estrogens/2-, 4-, 16-pathway ratio (Ptrend = 0.03). Coffee intake was associated with higher 2-catechols, including 2-hydroxyestradiol (57% difference, ≥4 cups/day vs. ≤6 cups/week; Ptrend = 0.001) and 2-hydroxyestrone (52% difference; Ptrend = 0.001), and several ratio measures. Decaffeinated coffee was not associated with 2-pathway metabolism, but women in the highest (vs. lowest) category of intake (≥2 cups/day vs. ≤1-3 cups/month) had significantly lower levels of two 16-pathway metabolites, estriol (25% difference; Ptrend = 0.01) and 17-epiestriol (48% difference; Ptrend = 0.0004). Tea intake was positively associated with 17-epiestriol (52% difference; Ptrend = 0.01). Caffeine and coffee intake were both associated with profiles of estrogen metabolism in premenopausal women. Consumption of caffeine and coffee may alter patterns of premenopausal estrogen metabolism. ©2015 American Association for Cancer Research.

  2. Dietary Estrogens Act through Estrogen Receptor-Mediated Processes and Show No Antiestrogenicity in Cultured Breast Cancer Cells.

    Science.gov (United States)

    Makela; Davis; Tally; Korkman; Salo; Vihko; Santti; Korach

    1994-06-01

    Dietary estrogens are believed to exert their estrogenic or antiestrogenic (chemopreventive) action in estrogen responsive cells by interacting with the estrogen receptor (ER). The present study was undertaken to evaluate a direct role of ER in estrogenic or antiestrogenic activities of three dietary estrogens (coumestrol, genistein and zearalenone). HeLa cells were transiently co-transfected with an expression vector for ER and an estrogen-responsive reporter gene construct. Coumestrol, genistein, and zearalenone all increased the activity of the reporter gene, only in the presence of the ER, and the activation was blocked with the ER antagonist ICI 164,384, demonstrating an ER-specific, agonist response. In addition, in MCF-7 cells, coumestrol and zearalenone increased the expression of the estrogen-responsive pS2 gene. Coumestrol and genistein inhibited the purified estrogen-specific 17ß-hydroxysteroid oxidoreductase enzyme and the conversion of estrone to 17ß-estradiol in T-47D cells, which contain this enzyme. However, they did not inhibit the estrone-induced proliferation of T-47D cells. In conclusion, coumestrol, genistein, and zearalenone are all potent estrogens in vitro, and they act through ER mediated mechanism. Our findings give no evidence to support the idea that these compounds act as antiestrogens through competition for the binding sites of ER or by inhibition of the conversion of estrone to 17ß-estradiol in breast cancer cells, since this effect was nullified by their agonist action on cell proliferation. Therefore, their suggested chemopreventive action in estrogen-related cancers must be mediated through other mechanisms.

  3. Fate of estrogens in biological treatment of concentrated black water

    NARCIS (Netherlands)

    Mes, de T.Z.D.

    2007-01-01

    Feminisation of male fish is for a large part due to compounds entering surface waters via wastewater. For domestic wastewater, two natural estrogens, estrone and 17-estradiol and the synthetic estrogen, constituent of the contraceptive pill, are mainly responsible for this effect. These compounds

  4. Estrogen-related and other disease diagnoses preceding Parkinson's disease

    DEFF Research Database (Denmark)

    Latourelle, Jeanne C; Dybdal, Merete; Destefano, Anita L

    2010-01-01

    Estrogen exposure has been associated with the occurrence of Parkinson's disease (PD), as well as many other disorders, and yet the mechanisms underlying these relations are often unknown. While it is likely that estrogen exposure modifies the risk of various diseases through many different...

  5. Toxicogenomics-based in vitro alternatives for estrogenicity testing

    NARCIS (Netherlands)

    Wang, S.

    2013-01-01

    Testing chemicals for their endocrine-disrupting potential, including interference with estrogen receptor signaling, is an important aspect to assess the safety of currently used and newly developed chemicals. The standard test for disruption of normal estrogen function is the in vivo uterotrophic

  6. Phytoestrogenic property of Labisia pumila for use as an estrogen ...

    African Journals Online (AJOL)

    ... is still unknown. This is because the pathways which are affected by LP or the cross-talk with other estrogenic pathways are still unknown. Perhaps in future, these are areas in which research on LP could be focused on. Key words: Labisia pumila, Kacip Fatimah, traditional medicine, estrogen replacement therapy.

  7. Effect of high intratesticular estrogen on global gene expression and testicular cell number in rats

    Directory of Open Access Journals (Sweden)

    He Zuping

    2010-06-01

    Full Text Available Abstract Background The identification of estrogen receptors alpha and beta and aromatase in the testis has highlighted the important role of estrogens in regulating spermatogenesis. There is a wealth of information on the deleterious effects of fetal and neonatal exposure of estrogens and xenoestrogens in the testis, including spermiation failure and germ cell apoptosis. However, very little is known about gene transcripts affected by exogenous estradiol exposure in the testis. The objective of the present study was to unveil global gene expression profiles and testicular cell number changes in rats after estradiol treatment. Methods 17beta-estradiol was administered to adult male rats at a dose of 100 micrograms/kg body weight in saline daily for 10 days; male rats receiving only saline were used as controls. Microarray analysis was performed to examine global gene expression profiles with or without estradiol treatment. Real time RT-PCR was conducted to verify the microarray data. In silico promoter and estrogen responsive elements (EREs analysis was carried out for the differentially expressed genes in response to estradiol. Quantitation of testicular cell number based on ploidy was also performed using flow cytometry in rats with or without estradiol treatment. Results We found that 221 genes and expressed sequence tags (ESTs were differentially expressed in rat testes treated with estradiol compared to the control; the microarray data were confirmed by real time RT-PCR. Gene Ontology analysis revealed that a number of the differentially expressed genes are involved in androgen and xenobiotic metabolism, maintenance of cell cytoskeleton, endocytosis, and germ cell apoptosis. A total of 33 up-regulated genes and 67 down-regulated genes showed the presence of EREs. Flow cytometry showed that estradiol induced a significant decrease in 2n cells (somatic and germ cells and 4n cells (pachytene spermatocytes and a marked increase in the number of

  8. Wnt16 Is Associated with Age-Related Bone Loss and Estrogen Withdrawal in Murine Bone.

    Directory of Open Access Journals (Sweden)

    Henry Todd

    Full Text Available Genome Wide Association Studies suggest that Wnt16 is an important contributor to the mechanisms controlling bone mineral density, cortical thickness, bone strength and ultimately fracture risk. Wnt16 acts on osteoblasts and osteoclasts and, in cortical bone, is predominantly derived from osteoblasts. This led us to hypothesize that low bone mass would be associated with low levels of Wnt16 expression and that Wnt16 expression would be increased by anabolic factors, including mechanical loading. We therefore investigated Wnt16 expression in the context of ageing, mechanical loading and unloading, estrogen deficiency and replacement, and estrogen receptor α (ERα depletion. Quantitative real time PCR showed that Wnt16 mRNA expression was lower in cortical bone and marrow of aged compared to young female mice. Neither increased nor decreased (by disuse mechanical loading altered Wnt16 expression in young female mice, although Wnt16 expression was decreased following ovariectomy. Both 17β-estradiol and the Selective Estrogen Receptor Modulator Tamoxifen increased Wnt16 expression relative to ovariectomy. Wnt16 and ERβ expression were increased in female ERα-/- mice when compared to Wild Type. We also addressed potential effects of gender on Wnt16 expression and while the expression was lower in the cortical bone of aged males as in females, it was higher in male bone marrow of aged mice compared to young. In the kidney, which we used as a non-bone reference tissue, Wnt16 expression was unaffected by age in either males or females. In summary, age, and its associated bone loss, is associated with low levels of Wnt16 expression whereas bone loss associated with disuse has no effect on Wnt16 expression. In the artificially loaded mouse tibia we observed no loading-related up-regulation of Wnt16 expression but provide evidence that its expression is influenced by estrogen receptor signaling. These findings suggest that while Wnt16 is not an

  9. Seladin-1 is a fundamental mediator of the neuroprotective effects of estrogen in human neuroblast long-term cell cultures.

    Science.gov (United States)

    Luciani, Paola; Deledda, Cristiana; Rosati, Fabiana; Benvenuti, Susanna; Cellai, Ilaria; Dichiara, Francesca; Morello, Matteo; Vannelli, Gabriella Barbara; Danza, Giovanna; Serio, Mario; Peri, Alessandro

    2008-09-01

    Estrogen exerts neuroprotective effects and reduces beta-amyloid accumulation in models of Alzheimer's disease (AD). A few years ago, a new neuroprotective gene, i.e. seladin-1 (for selective AD indicator-1), was identified and found to be down-regulated in AD vulnerable brain regions. Seladin-1 inhibits the activation of caspase-3, a key modulator of apoptosis. In addition, it has been demonstrated that the seladin-1 gene encodes 3beta-hydroxysterol Delta24-reductase, which catalyzes the synthesis of cholesterol from desmosterol. We have demonstrated previously that in fetal neuroepithelial cells, 17beta-estradiol (17betaE2), raloxifene, and tamoxifen exert neuroprotective effects and increase the expression of seladin-1. The aim of the present study was to elucidate whether seladin-1 is directly involved in estrogen-mediated neuroprotection. Using the small interfering RNA methodology, significantly reduced levels of seladin-1 mRNA and protein were obtained in fetal neuroepithelial cells. Seladin-1 silencing determined the loss of the protective effect of 17betaE2 against beta-amyloid and oxidative stress toxicity and caspase-3 activation. A computer-assisted analysis revealed the presence of half-palindromic estrogen responsive elements upstream from the coding region of the seladin-1 gene. A 1490-bp region was cloned in a luciferase reporter vector, which was transiently cotransfected with the estrogen receptor alpha in Chinese hamster ovarian cells. The exposure to 17betaE2, raloxifene, tamoxifen, and the soy isoflavones genistein and zearalenone increased luciferase activity, thus suggesting a functional role for the half-estrogen responsive elements of the seladin-1 gene. Our data provide for the first time a direct demonstration that seladin-1 may be considered a fundamental mediator of the neuroprotective effects of estrogen.

  10. Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production.

    Science.gov (United States)

    Hox, Valerie; Desai, Avanti; Bandara, Geethani; Gilfillan, Alasdair M; Metcalfe, Dean D; Olivera, Ana

    2015-03-01

    Clinical observations suggest that anaphylaxis is more common in adult women compared with adult men, although the mechanistic basis for this sex bias is not well understood. We sought to document sex-dependent differences in a mouse model of anaphylaxis and explore the role of female sex hormones and the mechanisms responsible. Passive systemic anaphylaxis was induced in female and male mice by using histamine, as well as IgE or IgG receptor aggregation. Anaphylaxis was assessed by monitoring body temperature, release of mast cell mediators and/or hematocrit, and lung weight as a measure of vascular permeability. A combination of ovariectomy, estrogen receptor antagonism, and estrogen administration techniques were used to establish estrogen involvement. Anaphylactic responses were more pronounced in female than male mice. The enhanced severity of anaphylaxis in female mice was eliminated after pretreatment with an estrogen receptor antagonist or ovariectomy but restored after administration of estradiol in ovariectomized mice, demonstrating that the sex-specific differences are due to the female steroid estradiol. Estrogen did not affect mast cell responsiveness or anaphylaxis onset. Instead, it increased tissue expression of endothelial nitric oxide synthase (eNOS). Blockage of NOS activity with the inhibitor L-NG-nitroarginine methyl ester or genetic eNOS deficiency abolished the sex-related differences. Our study defines a contribution of estrogen through its regulation of eNOS expression and nitric oxide production to vascular hyperpermeability and intensified anaphylactic responses in female mice, providing additional mechanistic insights into risk factors and possible implications for clinical management in the further exploration of human anaphylaxis. Published by Elsevier Inc.

  11. Selective estrogen receptor modulators (SERMs): new alternatives for osteoarthritis?

    Science.gov (United States)

    Lugo, L; Villalvilla, A; Largo, R; Herrero-Beaumont, G; Roman-Blas, J A

    2014-04-01

    The dramatic rise in the prevalence rate of osteoarthritis (OA) after the menopause and the presence of estrogen receptors in joint tissues suggest that estrogen may help protect against the development of OA. Trials of estrogen therapy have produced inconclusive results, however, partly because of flaws in study design and partly because of the complexity of the mechanisms underlying estrogen's effects on joint tissues. Initial studies of the use of selective estrogen receptor modulators (SERMs) have reported beneficial effects in OA. These agents may exert both a direct effect upon joint cartilage and indirect effects on subchondral bone, synovium, muscle, tendons and ligaments. SERMs may be particularly beneficial for postmenopausal patients with osteoporotic OA, a phenotype defined by decreased bone density, associated with high remodeling in subchondral bone. More research is needed, though, before SERMs can become a therapeutic option for OA. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  12. Long-term use of estrogens: benefit or risk

    Directory of Open Access Journals (Sweden)

    Bogusława Pietrzak

    2015-03-01

    Full Text Available Estrogens are widely used in hormone replacement therapy, gynecology, urogynecology and rarely in dermatology. Non-therapeutic use of estrogens is very widespread. Estrogens are used as contraceptives, which cause a lot of serious side effects. A common clinical problem is skin hyperpigmentation (melasma, occurring mainly in women who take contraceptives with high doses of estrogens. But low doses of estrogens may also cause skin side effects. The mechanism of melasma development is very complicated and not fully understood. It is very likely that UV radiation and genetic background can affect melasma development. Effective therapy should lead to prevention or alleviation of relapses. Treatment should also reduce the area of lesions and improve the appearance of skin. There is no effective and universal pattern of treatment, in which only one substance or method is used. A combination of different methods is used to optimize the therapy. An important role is attributed to prevention, especially protection from UV radiation.

  13. Regioselective deuterium labeling of estrone and catechol estrogen metabolites.

    Science.gov (United States)

    Stack, Douglas E; Ritonya, Justin; Jakopovic, Scott; Maloley-Lewis, Brittney

    2014-12-01

    Increased exposure to estrogens and estrogen metabolites is linked with increased rates of breast, ovarian and other human cancers. Metabolism of estrogen can led to formation of electrophilic o-quinones capable of binding to DNA. In order to gain insight into the mechanism of estrogen-induced DNA damage, estrone and catechol estrogens derived from estrone, have been regioselectively labeled with deuterium at the 1-position. Estrone-1-d, estrone-1,2,4-d3, 4-hydroxyestrone-1-d and 2-hydroxyestrone-1-d have been synthesized with or without deuteriums at the 16-position. The key labeling step involves deuterated trifluoroacetic acid exchange catalyzed by t-butyl alcohol. This economical, straightforward labeling technique makes available a range of estrone compounds containing deuterium at the 1-position. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Window Of Opportunity: Estrogen As A Treatment For Ischemic Stroke✰

    Science.gov (United States)

    Liu, Ran; Yang, Shao-Hua

    2013-01-01

    The neuroprotection research in the last 2 decades has witnessed a growing interest in the functions of estrogens as neuroprotectants against neurodegenerative diseases including stroke. The neuroprotective action of estrogens has been well demonstrated in both in vitro and in vivo models of ischemic stroke. However, the major conducted clinical trials so far have raised concern for the protective effect of estrogen replacement therapy in postmenopausal women. The discrepancy could be partly due to the mistranslation between the experimental stroke research and clinical trials. While predominant experimental studies tested the protective action of estrogens on ischemic stroke using acute treatment paradigm, the clinical trials have mainly focused on the effect of estrogen replacement therapy on the primary and secondary stroke prevention which has not been adequately addressed in the experimental stroke study. Although the major conducted clinical trials have indicated that estrogen replacement therapy has an adverse effect and raise concern for long term estrogen replacement therapy for stroke prevention, these are not appropriate for assessing the potential effects of acute estrogen treatment on stroke protection. The well established action of estrogen in the neurovascular unit and its potential interaction with recombinant tissue plasminogen activator (rtPA) makes it a candidate for the combined therapy with rtPA for the acute treatment of ischemic stroke. On the other hand, the “critical period” and newly emerged “biomarkers window” hypotheses have indicated that many clinical relevant factors have been underestimated in the experimental ischemic stroke research. The development and application of ischemic stroke models that replicate the clinical condition is essential for further evaluation of acute estrogen treatment on ischemic stroke which might provide critical information for future clinical trials. PMID:23340160

  15. Contemporary alternatives to plant estrogens for menopause.

    Science.gov (United States)

    Geller, Stacie E; Studee, Laura

    2006-11-01

    Every year, millions of women begin the peri-menopause and may experience a number of symptoms related to this transition. Many women are reluctant to use exogenous hormone therapy for treatment of menopausal symptoms and are turning to botanical and dietary supplements (BDS) for relief. This paper reviews the literature on alternatives to plant estrogens for relief of menopausal symptoms. The MEDLINE database was searched for clinical trials of non-estrogenic plant extracts for menopausal symptoms. To be included, studies had to include peri- or postmenopausal women as subjects. All clinical trials (randomized-controlled trials, open trials, and comparison group studies) were included for this review. Black cohosh appears to be one of the most effective botanicals for relief of vasomotor symptoms, while St. John's wort can improve mood disorders related to the menopausal transition. Many other botanicals have limited evidence to demonstrate safety and efficacy for relief of symptoms related to menopause. A growing body of evidence suggests that some botanicals and dietary supplements could result in improved clinical outcomes. Health care providers should discuss these issues with their patients so they can assist them in managing these alternative therapies through an evidence-based approach.

  16. Androgens and estrogens in skeletal sexual dimorphism

    Directory of Open Access Journals (Sweden)

    Michaël Laurent

    2014-04-01

    Full Text Available Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone (T to estradiol (E2 by aromatase, or to dihydrotestosterone by 5α-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of (high resolution peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refi ned our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen defi ciency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the fi eld of sex steroid actions in male bone homeostasis.

  17. The relationship between estrogen, estrogen receptors and periodontal disease in adult women: a review of the literature.

    Science.gov (United States)

    Shapiro, Laurence F; Freeman, Katherine

    2014-04-01

    The literature supports the fact that estrogen plays an important role in skeletal maintenance and remodeling. Estrogen, acting through estrogen receptors in the cells of the periodontal ligament, has a regulatory interaction on bone dynamics through a complex set of basic multicellular units (BMUs). Deficiency of estrogen results in an increased number of BMUs and enhanced bone turnover. The impact of the changes in estrogen deficiency on bone dynamics is primarily mediated through osteoclasts, with greater interdiction of estrogen's actions on trabecular bone than on cortical bone. The purpose of this manuscript is to review the literature for evidence to support an association between estrogen and periodontal disease in adult women, as well as bone mineral density, and to help clarify the mechanism of action. We found in our review of all pertinent databases, including Cochrane, that there are few peer-reviewed clinical studies that examine the relationship between estrogen deficiency and periodontal disease, and bone mineral density (BMD) and periodontal disease. Thus, future research is needed to investigate these associations so that at-risk patients can be identified earlier to avoid functional and esthetic sequellae of periodontal disease.

  18. BMI-1 Mediates Estrogen-Deficiency-Induced Bone Loss by Inhibiting Reactive Oxygen Species Accumulation and T Cell Activation.

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    Li, Jinbo; Wang, Qian; Yang, Renlei; Zhang, Jiaqi; Li, Xing; Zhou, Xichao; Miao, Dengshun

    2017-05-01

    Previous studies have shown that estrogen regulates bone homeostasis through regulatory effects on oxidative stress. However, it is unclear how estrogen deficiency triggers reactive oxygen species (ROS) accumulation. Recent studies provide evidence that the B lymphoma Mo-MLV insertion region 1 (BMI-1) plays a critical role in protection against oxidative stress and that this gene is directly regulated by estrogen via estrogen receptor (ER) at the transcriptional level. In this study, ovariectomized mice were given drinking water with/without antioxidant N-acetyl-cysteine (NAC, 1 mg/mL) supplementation, and compared with each other and with sham mice. Results showed that ovariectomy resulted in bone loss with increased osteoclast surface, increased ROS levels, T cell activation, and increased TNF and RANKL levels in serum and in CD4 T cells; NAC supplementation largely prevented these alterations. BMI-1 expression levels were dramatically downregulated in CD4 T cells from ovariectomized mice. We supplemented drinking water to BMI-1-deficient mice with/without NAC and compared them with each other and with wild-type (WT) mice. We found that BMI-1 deficiency mimicked alterations observed in ovariectomy whereas NAC supplementation reversed all alterations induced by BMI-1 deficiency. Because T cells are critical in mediating ovariectomy-induced bone loss, we further assessed whether BMI-1 overexpression in lymphocytes can protect against estrogen deficiency-induced osteoclastogenesis and bone loss by inhibiting oxidative stress, T cell activation, and RANKL production. When WT and Eμ-BMI-1 transgenic mice with BMI-1 specifically overexpressed in lymphocytes were ovariectomized and compared with each other and with WT sham mice, we found that BMI-1 overexpression in lymphocytes clearly reversed all alterations induced by ovariectomy. Results from this study indicate that estrogen deficiency downregulates BMI-1 and subsequently increases ROS, T cell activation, and

  19. Consensus Modeling for Prediction of Estrogenic Activity of Ingredients Commonly Used in Sunscreen Products

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    Huixiao Hong

    2016-09-01

    Full Text Available Sunscreen products are predominantly regulated as over-the-counter (OTC drugs by the US FDA. The “active” ingredients function as ultraviolet filters. Once a sunscreen product is generally recognized as safe and effective (GRASE via an OTC drug review process, new formulations using these ingredients do not require FDA review and approval, however, the majority of ingredients have never been tested to uncover any potential endocrine activity and their ability to interact with the estrogen receptor (ER is unknown, despite the fact that this is a very extensively studied target related to endocrine activity. Consequently, we have developed an in silico model to prioritize single ingredient estrogen receptor activity for use when actual animal data are inadequate, equivocal, or absent. It relies on consensus modeling to qualitatively and quantitatively predict ER binding activity. As proof of concept, the model was applied to ingredients commonly used in sunscreen products worldwide and a few reference chemicals. Of the 32 chemicals with unknown ER binding activity that were evaluated, seven were predicted to be active estrogenic compounds. Five of the seven were confirmed by the published data. Further experimental data is needed to confirm the other two predictions.

  20. The applications of machine learning algorithms in the modeling of estrogen-like chemicals.

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    Liu, Huanxiang; Yao, Xiaojun; Gramatica, Paola

    2009-06-01

    Increasing concern is being shown by the scientific community, government regulators, and the public about endocrine-disrupting chemicals that, in the environment, are adversely affecting human and wildlife health through a variety of mechanisms, mainly estrogen receptor-mediated mechanisms of toxicity. Because of the large number of such chemicals in the environment, there is a great need for an effective means of rapidly assessing endocrine-disrupting activity in the toxicology assessment process. When faced with the challenging task of screening large libraries of molecules for biological activity, the benefits of computational predictive models based on quantitative structure-activity relationships to identify possible estrogens become immediately obvious. Recently, in order to improve the accuracy of prediction, some machine learning techniques were introduced to build more effective predictive models. In this review we will focus our attention on some recent advances in the use of these methods in modeling estrogen-like chemicals. The advantages and disadvantages of the machine learning algorithms used in solving this problem, the importance of the validation and performance assessment of the built models as well as their applicability domains will be discussed.

  1. Estrogen and extinction of fear memories: implications for posttraumatic stress disorder treatment.

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    Glover, Ebony M; Jovanovic, Tanja; Norrholm, Seth Davin

    2015-08-01

    Posttraumatic stress disorder (PTSD) is a psychiatric illness whose prevalence in women is more than twice the rate as men. Despite a burgeoning literature characterizing sex differences in PTSD incidence and its disproportionate burden on society, there is a dearth of literature describing biological mechanisms underlying these disparities. However, the recent identification of biomarkers of PTSD by translational neuroscientists offers a promising opportunity to explore sex interactions in PTSD phenotypes. A notable observation is that individuals with PTSD show deficits in their ability to inhibit conditioned fear responding after extinction training. Given that extinction procedures, via exposure-based cognitive behavioral therapy, make up one of the predominant modes of treatment in PTSD, there is a critical need for more research on sex interactions in this form of fear regulation. An emerging hypothesis is that fluctuating gonadal hormones, especially estrogen, in the menstrual cycle may play a critical role in fear extinction and, hence, PTSD vulnerability and symptom severity in women. The current review discusses how the study of putative activational effects of estrogen on fear extinction may be harnessed to advance the search for better treatments for PTSD in women. We conclude that estrogen treatment may be a putative pharmacologic adjunct in extinction-based therapies and should be tracked in the menstrual cycle during the course of PTSD treatment. Published by Elsevier Inc.

  2. Induction of the Estrogenic Marker Calbindn-D9k by Octamethylcyclotetrasiloxane

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    Dongoh Lee

    2015-11-01

    Full Text Available Interrupting the hormonal balance of an organism by interfering with hormones and their target receptors gives rise to various problems such as developmental disorders. Collectively, these reagents are known as endocrine disruptors (EDs. Cyclic volatile methyl siloxanes (cVMSs are a group of silicone polymers that including octamethylcyclotetrasiloxane (D4. In the present study, we examined the estrogenicity of D4 through in vitro and in vivo assays that employed calcium-binding protein 9K (calbindin-D9k; CaBP-9K as a biomarker. For in vitro investigation, GH3 rat pituitary cells were exposed to vehicle, 17β-estradiol (E2, or D4 with/without ICI 182 780 (ICI. CaBP-9K and progesterone receptor (PR both were up-regulated by E2 and D4 which were completely blocked by ICI. Transcription of estrogen receptor α (ER α was decreased by E2 and D4 but increased by ICI. D4 was also administered to immature female rats for an uterotrophic (UT assay and detection of CaBP-9K. Ethinyl estradiol (EE or D4 was administered subcutaneously with or without ICI. Although uterine weight was not significant altered by D4, an effect thought to be due to cytochrome P450 (CYP, it induced CaBP-9K and PR gene expression. Based on these results we reveal that D4 has estrogenic potential proven under in vitro and in vivo experimental conditions.

  3. Inhibitor of Differentiation-3 and Estrogenic Endocrine Disruptors: Implications for Susceptibility to Obesity and Metabolic Disorders

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    Mayur Doke

    2018-01-01

    Full Text Available The rising global incidence of obesity cannot be fully explained within the context of traditional risk factors such as an unhealthy diet, physical inactivity, aging, or genetics. Adipose tissue is an endocrine as well as a metabolic organ that may be susceptible to disruption by environmental estrogenic chemicals. Since some of the endocrine disruptors are lipophilic chemicals with long half-lives, they tend to bioaccumulate in the adipose tissue of exposed populations. Elevated exposure to these chemicals may predispose susceptible individuals to weight gain by increasing the number and size of fat cells. Genetic studies have demonstrated that the transcriptional regulator inhibitor of differentiation-3 (ID3 promotes high fat diet-induced obesity in vivo. We have shown previously that PCB153 and natural estrogen 17β-estradiol increase ID3 expression. Based on our findings, we postulate that ID3 is a molecular target of estrogenic endocrine disruptors (EEDs in the adipose tissue and a better understanding of this relationship may help to explain how EEDs can lead to the transcriptional programming of deviant fat cells. This review will discuss the current understanding of ID3 in excess fat accumulation and the potential for EEDs to influence susceptibility to obesity or metabolic disorders via ID3 signaling.

  4. Bioassay of estrogenic compounds in transgenic Arabidopsis plants carrying a recombinant human estrogen receptor gene and a GFP reporter gene.

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    Inui, Hideyuki; Sasaki, Hideaki; Chua, Nam-Hai; Ohkawa, Hideo

    2009-12-01

    Transgenic Arabidopsis plants carrying a recombinant human estrogen receptor gene and a green fluorescent protein reporter gene were used to bioassay estrogenic compounds. We constructed four recombinant human estrogen receptor genes by combining the DNA-binding domain of LexA, a synthetic nuclear localization signal, a ligand-binding domain of the human estrogen receptor, and a transactivation domain of VP16 in different orders; the XEV plants were the most sensitive, and were able to detect 0.001 ng ml(-1) of 17ss-estradiol (E(2)). The transgenic plants absorbed E(2) and 4-nonylphenol present in the nutrient solution, whereas most of the other compounds seemed to be retained in, or on, the roots. Estrone, methoxychlor, bisphenol A, 4-nonylphenol, and 4-t-octylphenol in the medium were clearly detected by RT-PCR and PCR of the genomic DNA. The transgenic Arabidopsis XEV plants thus have potential for the bioassay of estrogenic compounds.

  5. DNA microarray data integration by ortholog gene analysis reveals potential molecular mechanisms of estrogen-dependent growth of human uterine fibroids

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    Shou Jianyong

    2007-04-01

    Full Text Available Abstract Background Uterine fibroids or leiomyoma are a common benign smooth muscle tumor. The tumor growth is well known to be estrogen-dependent. However, the molecular mechanisms of its estrogen-dependency is not well understood. Methods Differentially expressed genes in human uterine fibroids were either retrieved from published papers or from our own statistical analysis of downloaded array data. Probes for the same genes on different Affymetrix chips were mapped based on probe comparison information provided by Affymetrix. Genes identified by two or three array studies were submitted for ortholog analysis. Human and rat ortholog genes were identified by using ortholog gene databases, HomoloGene and TOGA and were confirmed by synteny analysis with MultiContigView tool in the Ensembl genome browser. Results By integrated analysis of three recently published DNA microarray studies with human tissue, thirty-eight genes were found to be differentially expressed in the same direction in fibroid compared to adjacent uterine myometrium by at least two research groups. Among these genes, twelve with rat orthologs were identified as estrogen-regulated from our array study investigating uterine expression in ovariectomized rats treated with estrogen. Functional and pathway analyses of the twelve genes suggested multiple molecular mechanisms for estrogen-dependent cell survival and tumor growth. Firstly, estrogen increased expression of the anti-apoptotic PCP4 gene and suppressed the expression of growth inhibitory receptors PTGER3 and TGFBR2. Secondly, estrogen may antagonize PPARγ signaling, thought to inhibit fibroid growth and survival, at two points in the PPAR pathway: 1 through increased ANXA1 gene expression which can inhibit phospholipase A2 activity and in turn decrease arachidonic acid synthesis, and 2 by decreasing L-PGDS expression which would reduce synthesis of PGJ2, an endogenous ligand for PPARγ. Lastly, estrogen affects retinoic

  6. Estrogen in Cardiovascular Disease during Systemic Lupus Erythematosus

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    Gilbert, Emily L.; Ryan, Michael J.

    2015-01-01

    Purpose Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects women during their childbearing years. Cardiovascular disease is the leading cause of mortality in this patient population at an age when women often have low cardiovascular risk. Hypertension is a major cardiovascular disease risk factor, and its prevalence is markedly increased in women with SLE. Estrogen has traditionally been implicated in SLE disease progression because of the prevalence of the disease in women; however, its role in cardiovascular risk factors such as hypertension is unclear. The objective of this review is to discuss evidence for the role of estrogen in both human and murine SLE with emphasis on the effect of estrogen on cardiovascular risk factors, including hypertension. Methods PubMed was used to search for articles with terms related to estradiol and SLE. The references of retrieved publications were also reviewed. Findings The potential permissive role of estrogen in SLE development is supported by studies from experimental animal models of lupus in which early removal of estrogen or its effects leads to attenuation of SLE disease parameters, including autoantibody production and renal injury. However, data about the role of estrogens in human SLE are much less clear, with most studies not reaching firm conclusions about positive or negative outcomes after hormonal manipulations involving estrogen during SLE (ie, oral contraceptives, hormone therapy). Significant gaps in knowledge remain about the effect of estrogen on cardiovascular risk factors during SLE. Studies in women with SLE were not designed to determine the effect of estrogen or hormone therapy on blood pressure even though hypertension is highly prevalent, and risk of premature ovarian failure could necessitate use of hormone therapy in women with SLE. Recent evidence from an experimental animal model of lupus found that estrogen may protect against

  7. Determination of estrogen receptor {beta}-mediated estrogenic potencies of hydroxylated PCBS by a yeast two-hybrid assay

    Energy Technology Data Exchange (ETDEWEB)

    Kuroki, H.; Kumate, M.; Nakaoka, H.; Yonekura, S. [Daiichi Coll. of Pharmaceutical Sciences, Fukuoka (Japan); Nishikawa, J.; Nishihara, T. [Osaka Univ., Osaka (Japan)

    2004-09-15

    Several environmental phenolic chemicals such as Nonylphenol and Bisphenol A (BPA) have been previously shown to possess estrogenic properties. In the previous paper, we have investigated the estrogenic activity of a series of hydroxylated PCBs (OH-PCBs) by a yeast two-hybrid assay (estrogen receptor{alpha} (ER{alpha}) -TIF2), in which the expression of estrogenic activity is based on the interaction of chemicals with ER{alpha}, and demonstrated that 4'-OH-CB30 and 4'-OH-CB61 are more estrogenic than BPA, one of the environmental estrogens. We have showed that one chlorine substitution adjacent to 4-OH at 3- or 5-position significantly reduces the ER{alpha}-mediated estrogenic activity of 4-OH-PCBs. Thus, 4'-OH-CB25 and 4-OH-CB56 showed a very weak estrogenicity. We have also showed that 4-OH-PCBs with two chlorine substitutions adjacent to 4-OH at 3- and 5-position such as 4'-OH-CB79 (hydroxylated metabolite of CB77) and persistent 4-OH-PCBs retained in human blood (4-OH-CB107, 4-OH-CB146 and 4-OH-CB187) have no ER{alpha}-mediated estrogenic activity. ER is known to have two subtypes, namely ER{alpha} and ER{beta} and it is reported that ligand, some agonist and antagonist have a different binding affinity for ER{alpha} and ER{beta}. However, there is limited information on ER{beta}-mediated endocrine disrupting potency. In this study, we examined the ER{beta}-mediated estrogenic activity of a series of OH-PCBs, including environmentally relevant 4-OH-PCBs by a yeast two-hybrid assay (ER{beta}-TIF2).

  8. The Effects of Synthetic Estrogen Exposure on the Sexually Dimorphic Liver Transcriptome of the Sex-Role-Reversed Gulf Pipefish.

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    Emily Rose

    Full Text Available Species exhibiting sex-role reversal provide an unusual perspective on the evolution of sex roles and sex differences. However, the proximate effects of sex-role reversal are largely unknown. Endocrine disruptors provide an experimental mechanism to address hormonal regulation of sexually dimorphic gene expression in sex-role-reversed taxa. Here, we investigate gene expression patterns in the liver of the sex-role-reversed Gulf pipefish, because the liver is known to be sexually dimorphic and estrogen-regulated in species with conventional sex roles. Using next-generation RNA-sequencing technology (RNA-seq, we detected sexually dimorphic hepatic gene expression patterns, with a total of 482 differentially expressed genes between the sexes in Gulf pipefish. Two-thirds of these genes were over-expressed in females, and the sex-specific transcriptomes of this sex-role-reversed pipefish's liver were superficially similar to those of fishes with conventional sex-roles. We exposed females, pregnant males, and non-pregnant males to 17α-ethinylestradiol (EE2 at ecologically relevant concentrations of 5ng/L and compared gene expression patterns in the livers of exposed fish to control fish. Several genes that were up-regulated in EE2-exposed males relative to control males were also found to be female-biased in control animals. These genes included several of the classic estrogen biomarkers, such as vitellogenin, choriogenin, and zona pellucida. Thus, estrogen exposure induced feminization of the male liver transcriptome in a sex-role-reversed pipefish. These results suggest that the ancestral state of estrogen-regulated female reproductive physiology has been retained in all sex-role-reversed vertebrates thus far studied, despite substantial evolution of the hormonal regulation of ornamentation and mating behavior in these interesting taxa.

  9. Estrogen Receptor α Is Crucial in Zearalenone-Induced Invasion and Migration of Prostate Cancer Cells

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    Karolina Kowalska

    2018-02-01

    Full Text Available Zearalenone (ZEA, a mycotoxin produced in the genus Fusarium, binds to estrogen receptors (ER and is therefore regarded as an endocrine disruptor. ZEA has also been found to modulate the proliferation and apoptosis of prostate cancer cells in a dose-dependent manner. This study evaluates whether the effect of a low dose of ZEA (0.1 and 0.001 nM on the invasion and migration of prostate cancer cell line PC3 is associated with ERs expression. The invasion and migration was evaluated by modified Boyden chamber assay, scratch assay, gelatin zymography, Real Time qPCR (RTqPCR and Western blot. The involvement of ERs was evaluated with the selective ER antagonists: estrogen receptor α (ERα antagonist 1,3-bis (4-hydroxyphenyl-4-methyl-5-[4-(2-piperidinylethoxy phenol]-1H-pyrazole dihydrochloride (MPP and estrogen receptor β (ERβ antagonist 4-[2–phenyl-5,7–bis (trifluoromethyl pyrazolo [1,5-a]-pyrimidin-3-yl] phenol (PHTPP. ZEA was found to modulate cell motility dependent on estrogen receptors, particularly ERα. Increased cell migration and invasion were associated with increased MMP-2 and MMP-9 activity as well as the up-regulation of the EMT-associated genes vimentin (VIM, zinc finger E-box-binding homeobox 1/2 (ZEB1/2 and transforming growth factor β 1 (TGFβ1. In conclusion, ZEA might modulate the invasiveness of prostate cancer cells dependently on ERα expression.

  10. Relationship between serum estrogen levels and blood stasis syndrome in postmenopausal women with coronary heart disease.

    Science.gov (United States)

    Liu, Xin; Guo, Chunyu; Ma, Xiaojuan; Tian, Rui; Zhang, Ying; Yin, Huijun

    2015-01-01

    To investigate the difference of serum estrogen, serum lipids and inflammatory factors levels in postmenopausal women with coronary heart blood stasis syndrome and non-blood stasis syndrome. Twenty five healthy postmenopausal women were selected as a healthy control group who were compared with 43 postmenopausal women with coronary heart disease (CHD) first visiting a doctor for the CHD. Among the postmenopausal women with CHD, There were 23 patients with blood stasis syndrome (BSS) and 20 patients with non-blood stasis syndrome (NBSS). The levels of plasma triglyceride (TG), total cholesterol (TC) were determined in blood samples taken after patients' admission in Beijing Anzhen Hospital. The serum estradiol(E2) was measured by electrochemiluminescence assay and soluble intercellular adhesion molecule-1(sICAM-1) was measured by enzyme-linked immune sorbent assay (ELISA). Compared with the healthy control group, the levels of TG and TC, sICAM-1 in coronary heart disease group were all significantly increased (P0.05), and there was an increasing trend of serum sICAM-1 levels (P>0.05). There were negative significant correlations between serum E2 levels and TC, sICAM-1 levels in patient with coronary heart disease. The estrogen level of menopausal women with coronary heart disease is lower than healthy menopausal women. With the low estrogen levels, postmenopausal women tend to have high levels of blood lipids and sICAM-1, which elucidates that the estrogen could regulate lipids and attenuate inflammatory response to play a protective role on blood vessels.

  11. G-protein coupled estrogen receptor (GPER) inhibits final oocyte maturation in common carp, Cyprinus carpio.

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    Majumder, Suravi; Das, Sumana; Moulik, Sujata Roy; Mallick, Buddhadev; Pal, Puja; Mukherjee, Dilip

    2015-01-15

    GPR-30, now named as GPER (G protein-coupled estrogen receptor) was first identified as an orphan receptor and subsequently shown to be required for estrogen-mediated signaling in certain cancer cells. Later studies demonstrated that GPER has the characteristics of a high affinity estrogen membrane receptor on Atlantic croaker and zebra fish oocytes and mediates estrogen inhibition of oocyte maturation in these two distantly related teleost. To determine the broad application of these findings to other teleost, expression of GPER mRNA and its involvement in 17β-estradiol mediated inhibition of oocyte maturation in other cyprinid, Cyprinus carpio was investigated. Carp oocytes at pre-vitellogenic, late-vitellogenic and post-vitellogenic stages of development contained GPER mRNA and its transcribed protein with a maximum at late-vitellogenic oocytes. Ovarian follicular cells did not express GPER mRNA. Carp oocytes GPER mRNA was essentially identical to that found in other perciformes and cyprinid fish oocytes. Both spontaneous and 17,20β-dihydroxy-4-pregnen-3-one (17,20β-P)-induced oocyte maturation in carp was significantly decreased when they were incubated with either E2, or GPER agonist G-1. On the other hand spontaneous oocyte maturation was significantly increased when carp ovarian follicles were incubated with an aromatase inhibitor, fadrozole, GPER antagonist, G-15 and enzymatic removal of the ovarian follicle cell layers. This increase in oocyte maturation was partially reversed by co-treatment with E2. Consistent with previous findings with human and fish GPR30, E2 treatment in carp oocytes caused increase in cAMP production and simultaneously decrease in oocyte maturation, which was inhibited by the addition of 17,20β-P. The results suggest that E2 and GPER play a critical role in regulating re-entry in to meiotic cell cycle in carp oocytes. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Proteomic analysis of pathways involved in estrogen-induced growth and apoptosis of breast cancer cells.

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    Zhang-Zhi Hu

    Full Text Available Estrogen is a known growth promoter for estrogen receptor (ER-positive breast cancer cells. Paradoxically, in breast cancer cells that have been chronically deprived of estrogen stimulation, re-introduction of the hormone can induce apoptosis.Here, we sought to identify signaling networks that are triggered by estradiol (E2 in isogenic MCF-7 breast cancer cells that undergo apoptosis (MCF-7:5C versus cells that proliferate upon exposure to E2 (MCF-7. The nuclear receptor co-activator AIB1 (Amplified in Breast Cancer-1 is known to be rate-limiting for E2-induced cell survival responses in MCF-7 cells and was found here to also be required for the induction of apoptosis by E2 in the MCF-7:5C cells. Proteins that interact with AIB1 as well as complexes that contain tyrosine phosphorylated proteins were isolated by immunoprecipitation and identified by mass spectrometry (MS at baseline and after a brief exposure to E2 for two hours. Bioinformatic network analyses of the identified protein interactions were then used to analyze E2 signaling pathways that trigger apoptosis versus survival. Comparison of MS data with a computationally-predicted AIB1 interaction network showed that 26 proteins identified in this study are within this network, and are involved in signal transduction, transcription, cell cycle regulation and protein degradation.G-protein-coupled receptors, PI3 kinase, Wnt and Notch signaling pathways were most strongly associated with E2-induced proliferation or apoptosis and are integrated here into a global AIB1 signaling network that controls qualitatively distinct responses to estrogen.

  13. Aromatase expression and role of estrogens in male gonad : a review

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    Denis-Galeraud Isabelle

    2003-04-01

    Full Text Available Abstract The ability of the testis to convert irreversibly androgens into estrogens is related to the presence of a microsomal enzymatic complex named aromatase, which is composed of a specific glycoprotein, the cytochrome P450 aromatase (P450arom and an ubiquitous reductase. The aromatase gene is unique in humans and contained 18 exons, 9 of them being translated. In the rat testis we have immunolocalized the P450arom not only in Leydig cells but also in germ cells and especially in elongated spermatids. Related to the stage of germ cell maturation, we have shown that the level of P450arom mRNA transcripts decreases, it is much more abundant in pachytene spermatocytes and round spermatids than in mature germ cells whereas the aromatase activity is 2–4 fold greater in spermatozoa when compared to the younger germ cells. Using a highly specific quantitative competitive RT-PCR method we have evidenced that several factors direct the expression of the aromatase gene in Leydig cells, Sertoli cells, pachytene spermatocytes and round spermatids, and it is obvious that promoter PII is the main one but other promoters could be concerned. In the bank-vole testis we have observed a positive correlation between a fully developed spermatogenesis and a strong immunoreactivity for both P450arom and estrogen receptor β not only in Sertoli cells but also in pachytene spermatocytes and round spermatids. Our recent data obtained from ejaculated human spermatozoa demonstrate the presence of aromatase both in terms of mRNA and protein, and in addition, we suggest that aromatase could be involved in the acquisition of sperm motility. Indeed in men the congenital aromatase deficiency is associated with severe bone maturation problems and sterility. Together with the widespread distribution of estrogen receptors in testicular cells these data clearly show that estrogens play a physiological role in the regulation of spermatogenesis in mammals.

  14. Elsevier Trophoblast Research Award lecture: Molecular mechanisms underlying estrogen functions in trophoblastic cells--focus on leptin expression.

    Science.gov (United States)

    Gambino, Y P; Maymó, J L; Pérez Pérez, A; Calvo, J C; Sánchez-Margalet, V; Varone, C L

    2012-02-01

    The steroid hormone 17β-estradiol is an estrogen that influences multiple aspects of placental function and fetal development in humans. During early pregnancy it plays a role in the regulation of blastocyst implantation, trophoblast differentiation and invasiveness, remodeling of uterine arteries, immunology and trophoblast production of hormones such as leptin. Estradiol exerts some effects through the action of classical estrogen receptors ERα and ERβ, which act as ligand-activated transcription factors and regulate gene expression. In addition, estradiol can elicit rapid responses from membrane-associated receptors, like activation of protein-kinase pathways. Thus, the cellular effects of estradiol will depend on the specific receptors expressed and the integration of their signaling events. Leptin, the 16,000MW protein product of the obese gene, was originally considered an adipocyte-derived signaling molecule for the central control of metabolism. However, pleiotropic effects of leptin have been identified in reproduction and pregnancy. The leptin gene is expressed in placenta, where leptin promotes proliferation and survival of trophoblastic cells. Expression of leptin in placenta is highly regulated by key pregnancy molecules as hCG and estradiol. The aim of this paper is to review the molecular mechanisms underlying estrogen functions in trophoblastic cells; focusing on mechanisms involved in estradiol regulation of placental leptin expression. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. Appropriate 'housekeeping' genes for use in expression profiling the effects of environmental estrogens in fish

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    Tyler Charles R

    2007-02-01

    Full Text Available Abstract Background Attempts to develop a mechanistic understanding of the effects of environmental estrogens on fish are increasingly conducted at the level of gene expression. Appropriate application of real-time PCR in such studies requires the use of a stably expressed 'housekeeping' gene as an internal control to normalize for differences in the amount of starting template between samples. Results We sought to identify appropriate genes for use as internal controls in experimental treatments with estrogen by analyzing the expression of eight functionally distinct 'housekeeping' genes (18S ribosomal RNA [18S rRNA], ribosomal protein l8 [rpl8], elongation factor 1 alpha [ef1a], glucose-6-phosphate dehydrogenase [g6pd], beta actin [bactin], glyceraldehyde-3-phosphate dehydrogenase [gapdh], hypoxanthine phosphoribosyltransferase 1 [hprt1], and tata box binding protein [tbp] following exposure to the environmental estrogen, 17α-ethinylestradiol (EE2, in the fathead minnow (Pimephales promelas. Exposure to 10 ng/L EE2 for 21 days down-regulated the expression of ef1a, g6pd, bactin and gapdh in the liver, and bactin and gapdh in the gonad. Some of these effects were gender-specific, with bactin in the liver and gapdh in the gonad down-regulated by EE2 in males only. Furthermore, when ef1a, g6pd, bactin or gapdh were used for normalization, the hepatic expression of two genes of interest, vitellogenin (vtg and cytochrome P450 1A (cyp1a following exposure to EE2 was overestimated. Conclusion Based on the data presented, we recommend 18S rRNA, rpl8, hprt1 and/or tbp, but not ef1a, g6pd, bactin and/or gapdh, as likely appropriate internal controls in real-time PCR studies of estrogens effects in fish. Our studies show that pre-validation of control genes considering the scope and nature of the experiments to be performed, including both gender and tissue type, is critical for accurate assessments of the effects of environmental estrogens on gene

  16. TNF-α promotes osteoclastogenesis through JNK signaling-dependent induction of Semaphorin3D expression in estrogen-deficiency induced osteoporosis.

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    Sang, Chenglin; Zhang, Jiefeng; Zhang, Yongxian; Chen, Fangjing; Cao, Xuecheng; Guo, Lei

    2017-12-01

    Tumor necrosis factor α (TNF-α)-induced osteoclast formation have been demonstrated to play an important role in the pathogenesis of estrogen deficiency-mediated bone loss, but the exact mechanisms by which TNF-α enhanced osteoclast differentiation were not fully elucidated. The class III semaphorins members were critical to regulate bone homeostasis. Here, we identified a novel mechanism whereby TNF-α increasing Semaphorin3D expression contributes to estrogen deficiency-induced osteoporosis. In this study, we found that Semaphorin3D expression was upregulated by TNF-α during the process of RANKL-induced osteoclast differentiation. Inhibition of Semaphorin3D in pre-osteoclasts could attenuate the stimulatory effects of TNF-α on osteoclast proliferation and differentiation. Mechanistically, blocking of the Jun N-terminal kinase (JNK) signaling markedly rescued TNF-α-induced Semaphorin3D expression, suggesting that JNK signaling was involved in the regulation of Semaphorin3D expression by TNF-α. In addition, silencing of Semaphorin3D in vivo could alleviate estrogen deficiency-induced osteoporosis. Our results revealed a novel function for Semaphorin3D and suggested that increased Semaphorin3D may contribute to enhanced bone loss by increased TNF-α in estrogen deficiency-induced osteoporosis. Thus, Semaphorin3D may provide a potential therapeutic target for the treatment of estrogen-deficiency induced osteoporosis. © 2017 Wiley Periodicals, Inc.

  17. 21 CFR 862.1270 - Estrogens (total, in pregnancy) test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Estrogens (total, in pregnancy) test system. 862... Test Systems § 862.1270 Estrogens (total, in pregnancy) test system. (a) Identification. As estrogens (total, in pregnancy) test system is a device intended to measure total estrogens in plasma, serum, and...

  18. Mixture Effects of Estrogenic Pesticides at the Human Estrogen Receptor α and β

    Science.gov (United States)

    Seeger, Bettina; Klawonn, Frank; Nguema Bekale, Boris; Steinberg, Pablo

    2016-01-01

    Consumers of fruits and vegetables are frequently exposed to small amounts of hormonally active pesticides, some of them sharing a common mode of action such as the activation of the human estrogen receptor α (hERα) or β (hERβ). Therefore, it is of particular importance to evaluate risks emanating from chemical mixtures, in which the individual pesticides are present at human-relevant concentrations, below their corresponding maximum residue levels. Binary and ternary iso-effective mixtures of estrogenic pesticides at effect concentrations eliciting a 1 or 10% effect in the presence or absence of 17β-estradiol were tested experimentally at the hERα in the yeast-based estrogen screen (YES) assay as well as in the human U2-OS cell-based ERα chemical-activated luciferase gene expression (ERα CALUX) assay and at the hERβ in the ERβ CALUX assay. The outcome was then compared to predictions calculated by means of concentration addition. In most cases, additive effects were observed with the tested combinations in all three test systems, an observation that supports the need to expand the risk assessment of pesticides and consider cumulative risk assessment. An additional testing of mixture effects at the hERβ showed that most test substances being active at the hERα could also elicit additive effects at the hERβ, but the hERβ was less sensitive. In conclusion, effects of the same ligands at the hERα and the hERβ could influence the estrogenic outcome under physiological conditions. PMID:26812056

  19. Mixture Effects of Estrogenic Pesticides at the Human Estrogen Receptor α and β.

    Directory of Open Access Journals (Sweden)

    Bettina Seeger

    Full Text Available Consumers of fruits and vegetables are frequently exposed to small amounts of hormonally active pesticides, some of them sharing a common mode of action such as the activation of the human estrogen receptor α (hERα or β (hERβ. Therefore, it is of particular importance to evaluate risks emanating from chemical mixtures, in which the individual pesticides are present at human-relevant concentrations, below their corresponding maximum residue levels. Binary and ternary iso-effective mixtures of estrogenic pesticides at effect concentrations eliciting a 1 or 10% effect in the presence or absence of 17β-estradiol were tested experimentally at the hERα in the yeast-based estrogen screen (YES assay as well as in the human U2-OS cell-based ERα chemical-activated luciferase gene expression (ERα CALUX assay and at the hERβ in the ERβ CALUX assay. The outcome was then compared to predictions calculated by means of concentration addition. In most cases, additive effects were observed with the tested combinations in all three test systems, an observation that supports the need to expand the risk assessment of pesticides and consider cumulative risk assessment. An additional testing of mixture effects at the hERβ showed that most test substances being active at the hERα could also elicit additive effects at the hERβ, but the hERβ was less sensitive. In conclusion, effects of the same ligands at the hERα and the hERβ could influence the estrogenic outcome under physiological conditions.

  20. Effect of steroid hormones, estrogen and progesterone, on epithelial mesenchymal transition in ovarian cancer development.

    Science.gov (United States)

    Jeon, So-Ye; Hwang, Kyung-A; Choi, Kyung-Chul

    2016-04-01

    As the primary female sex steroid hormones, estrogens and progesterone play important roles to regulate growth, differentiation, and function of a broad range of target tissues in the human body and maintain the function of female reproductive tissues. Ovarian cancer is the most cause of cancer death in gynecological malignancy. Despite enormous outcomes in the understanding of ovarian cancer pathology, this disease has resulted in poor survival rates since most patients are asymptomatic until the disease has been metastasized. The exact molecular events leading to metastasis of ovarian tumor cells have not yet been well elucidated, although it is recognized that the acquisition of capacity for migration and invasiveness would be a necessary prerequisite. During metastasis, epithelial-mesenchymal transition (EMT) is an important process, in which epithelial cells lose their intracellular adhesion and cell polarity and acquire increased motility and invasive properties to become mesenchymal like cells. The process of cancer cells to undergo EMT is regulated through the up- and down- regulation of a multiple cellular markers and signaling proteins. In this review, we focused the roles of women sex steroid hormones, estrogen and progesterone, in ovarian cancer, especially the ovarian cancer undergoing EMT and metastatic process. All things considered, we may suggest that progesterone is a potent hormone which inhibits the growth of human ovarian cancer cells and development to metastasis whereas estrogen may act as a risk factor of ovarian cancer progression and that progesterone therapy may be an alternative clinically effective tool for the treatment of human ovarian cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Estrogen-Like Properties of Fluorotelomer Alcohols as Revealed by MCF-7 Breast Cancer Cell Proliferation

    Science.gov (United States)

    Maras, Marleen; Vanparys, Caroline; Muylle, Frederik; Robbens, Johan; Berger, Urs; Barber, Jonathan L.; Blust, Ronny; De Coen, Wim

    2006-01-01

    We investigated estrogen-like properties of five perfluorinated compounds using a combination of three in vitro assays. By means of an E-screen assay, we detected the proliferation-promoting capacity of the fluorotelomer alcohols 1H,1H,2H,2H-perfluorooctan-1-ol (6:2 FTOH) and 1H,1H,2H,2H-perfluoro-decan-1-ol (8:2 FTOH). The more widely environmentally distributed compounds perfluoro-1-octane sulfonate, perfluorooctanoic acid, and perfluorononanoic acid did not seem to possess this hormone-dependent proliferation capacity. We investigated cell cycle dynamics using flow cytometric analyses of the DNA content of the nuclei of MCF-7 breast cancer cells. Exposure to both fluorotelomer alcohols stimulated resting MCF-7 cells to reenter the synthesis phase (S-phase) of the cell cycle. After only 24 hr of treatment, we observed significant increases in the percentage of cells in the S-phase. In order to further investigate the resemblance of the newly detected xenoestrogens to the reference compound 17β-estradiol (E2), gene expression of a number of estrogen-responsive genes was analyzed by real-time polymerase chain reaction. With E2, as well as 4-nonylphenol and the fluorotelomer alcohols, we observed up-regulation of trefoil factor 1, progesterone receptor, and PDZK1 and down-regulation of ERBB2 gene expression. We observed small but relevant up-regulation of the estrogen receptor as a consequence of exposures to 6:2 FTOH or 8:2 FTOH. The latter finding suggests an alternative mode of action of the fluorotelomer alcohols compared with that of E2. This study clearly underlines the need for future in vivo testing for specific endocrine-related end points. PMID:16393665

  2. Biomarker Genes for Detecting Estrogenic Activity of Endocrine Disruptors via Estrogen Receptors

    Directory of Open Access Journals (Sweden)

    Hyun Yang

    2012-02-01

    Full Text Available Endocrine disruptors (EDs are compounds used in various industrial products, drugs, and cosmetics. They can be found in the environment and disturb the endocrine and reproductive systems, resulting in adverse effects to humans and wildlife such as birth defects and developmental disorders. Since several EDs have a structure similar to that of endogenous steroid hormones such as estrogens, they intend to have an affinity for steroid hormone receptors and alter hormone-mediated metabolism by binding to these receptors. EDs are therefore a global concern and assays should be developed to efficiently determine whether these compounds are detrimental to biological systems. Diverse experimental methods may help determine the endocrine disrupting potential of EDs and evaluate the adverse effects of a single and/or combination of these reagents. Currently, biomarkers have been employed to objectively measure EDs potency and understand the underlying mechanisms. Further studies are required to develop ideal screening methods and biomarkers to determine EDs potency at environmentally relevant concentrations. In this review, we describe the biomarkers for estrogenicity of EDs identified both in vitro and in vivo, and introduce a biomarker, cabindin-D9k (CaBP-9k, that may be used to assess estrogenic activity of EDs.

  3. Effects of ICI 182780 on estrogen receptor expression, fluid absorption and sperm motility in the epididymis of the