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The role of the newly discovered steroid receptor RNA activator protein (SRAP) in the estrogen signaling pathway and its implication in breast cancerChooniedass, Shilpa 17 March 2011 (has links)
In 1999, the discovery of the Steroid Receptor RNA Activator (SRA) was unprecedented in the field of steroid receptor co-regulator research. It was the first time that an RNA molecule was demonstrated to function similarly to its protein counterpart and modulate the activity of steroid receptors. This peculiar steroid receptor co-activator thus attracted the attention of numerous research groups. Over the years, studies were reported deciphering SRA mechanisms of action, its role in co-regulating nuclear receptors and its possible implication in human diseases.
While SRA was originally thought to exist solely as a non-coding RNA, our laboratory has identified longer SRA RNA isoforms with the theoretical capacity to encode for a protein. This discovery impelled us to investigate the existence of a Steroid Receptor RNA Activator Protein or SRAP. In this thesis, we first demonstrated the existence and function of endogenous evolutionary conserved SRA proteins. Based on these results we further explored SRAP expression in breast tumors. Interestingly, Western blot analysis of a small cohort of estrogen positive breast tumors suggested that SRAP expression correlates with a better overall survival in patients treated with tamoxifen. This observation prompted us to explore the biological role of SRAP. We found that MCF-7 cells stably expressing coding SRA isoforms had lower ligand dependent estrogen receptor alpha transcriptional activity. In order to dissect the function of the protein independently of its RNA counterpart, we separated the functions of the protein by introducing extensive silent mutations into the RNA sequence. Using this model, we established that SRAP, independent of its RNA counterpart, enhances estrogen receptor alpha activity in a ligand and response-element dependent manner. Furthermore, we showed for the first time that SRAP physically interacts with multiple transcription factors and is recruited to specific promoter regions. Moreover, by artificially recruiting SRAP to the promoter of a luciferase reporter gene under the control of the strong transcriptional activator VP16, we observed a decrease in transcription. These latter results suggest that SRA could function as a repressor through direct association with promoters.
Overall, we believe that SRA is a very peculiar example of a bi-faceted system consisting of a functional RNA and its corresponding protein. Altogether our data suggest that SRAP, similarly to its RNA counterpart, is involved in many critical pathways that directly participate in gene expression regulation.
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Environmental Estrogens: Assessing Human Gestational Exposure and Interactions with the Estrogen ReceptorGraham, Lisa Anne January 2012 (has links)
Environmental xenoestrogens (EEs) are chemicals that when they enter the body, the body
responds to them as it would to endogenous estrogens. Humans are exposed to these
chemicals on a daily basis via natural components, additives and contaminants in food and
water, through the use of pharmaceuticals and personal care products such as sunscreens,
lotions and toothpaste. Exposure to EEs is thought to result in adverse effects on humans
such as decreased fertility, increased susceptibility to hormone-sensitive cancers, deformities
of the male genitalia and precocious puberty in females. The critical window of exposure is
thought to be early fetal development, when tissues are rapidly differentiating under the
control of endogenous estrogens. However, there is limited data in the literature on human
fetal exposure to EEs. The first objective of this study was to assess human fetal exposure to
a suite of 35 EEs by analysis of paired samples of amniotic fluid and maternal urine were
collected from 32 New Zealand women between 14 and 20 weeks gestation. The analytical
chemistry methods required for this study were developed and validated. The results
demonstrate that fetal exposure is highly correlated with maternal exposure. This study is the
first to report maternal urine levels of two UV filters and amniotic fluid levels of parabens,
UV filters and triclosan. A model based on simple additivity of effect was developed that
combined the measured concentrations with literature data on relative estrogenic potency to
assess the magnitude of the estrogen signal that may be attributed to the EEs. This model
suggests that the fetus may experience an estrogen signal due to the measured EEs that could
be as large as the endogenous estrogen signal. A second objective was to use computational
docking to study the interactions of the EEs with the human estrogen receptor (hER) protein.
The docking studies show that the rigid endogenous ligand, 17β-estradiol (E2) interacts with
the hER to produce a single, well-defined complex with the receptor and the flexible EEs
produce multiple, distinct energy-equivalent complexes. EEs are not able to interact with the
binding cavity to stabilise the rigid hER-E2-like topology of the complex. As a result, the
hER-EE complexes can be thought of as more pliable or ‘floppy’ and thus able to respond to
the cell context in multiple ways, leading to variations in gene expression in different target
tissues. These multiple pathways may explain the range of physiological responses attributed
to exposure that depend on the timing of exposure and the sex of the individual exposed.
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The role of the newly discovered steroid receptor RNA activator protein (SRAP) in the estrogen signaling pathway and its implication in breast cancerChooniedass, Shilpa 17 March 2011 (has links)
In 1999, the discovery of the Steroid Receptor RNA Activator (SRA) was unprecedented in the field of steroid receptor co-regulator research. It was the first time that an RNA molecule was demonstrated to function similarly to its protein counterpart and modulate the activity of steroid receptors. This peculiar steroid receptor co-activator thus attracted the attention of numerous research groups. Over the years, studies were reported deciphering SRA mechanisms of action, its role in co-regulating nuclear receptors and its possible implication in human diseases.
While SRA was originally thought to exist solely as a non-coding RNA, our laboratory has identified longer SRA RNA isoforms with the theoretical capacity to encode for a protein. This discovery impelled us to investigate the existence of a Steroid Receptor RNA Activator Protein or SRAP. In this thesis, we first demonstrated the existence and function of endogenous evolutionary conserved SRA proteins. Based on these results we further explored SRAP expression in breast tumors. Interestingly, Western blot analysis of a small cohort of estrogen positive breast tumors suggested that SRAP expression correlates with a better overall survival in patients treated with tamoxifen. This observation prompted us to explore the biological role of SRAP. We found that MCF-7 cells stably expressing coding SRA isoforms had lower ligand dependent estrogen receptor alpha transcriptional activity. In order to dissect the function of the protein independently of its RNA counterpart, we separated the functions of the protein by introducing extensive silent mutations into the RNA sequence. Using this model, we established that SRAP, independent of its RNA counterpart, enhances estrogen receptor alpha activity in a ligand and response-element dependent manner. Furthermore, we showed for the first time that SRAP physically interacts with multiple transcription factors and is recruited to specific promoter regions. Moreover, by artificially recruiting SRAP to the promoter of a luciferase reporter gene under the control of the strong transcriptional activator VP16, we observed a decrease in transcription. These latter results suggest that SRA could function as a repressor through direct association with promoters.
Overall, we believe that SRA is a very peculiar example of a bi-faceted system consisting of a functional RNA and its corresponding protein. Altogether our data suggest that SRAP, similarly to its RNA counterpart, is involved in many critical pathways that directly participate in gene expression regulation.
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In vivo and in vitro screening of endocrine disrupting chemicals with estrogenic activity in Japanese quailShimada, Kiyoshi, Ha, Yonju, Tsukada, Akira, Saito, Noboru, Maekawa, Shinobu, Nishizuka, Makoto, Imagawa, Masayoshi January 2005 (has links)
No description available.
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A bioinformatics approach to discovery of estrogen-responsive genetic pathways in breast cancerAlles, Marie Chehani, Clinical School - St Vincent's Hospital, Faculty of Medicine, UNSW January 2008 (has links)
Breast cancers fall into two major classes depending on their estrogen receptor (ER) status. ER+ and ER- tumors have very different molecular phenotypes, and may have distinct cells of origin. ER- tumors generally fail to respond to endocrine therapy and have a poorer prognosis. To develop a comprehensive understanding of the gene networks active in ER+ compared to ER- breast cancers, we performed a meta-analysis of Grade 3 breast cancers from five published datasets. A measure of association with ER status taking into account intra- and inter-study variability was calculated for every probe set. The meta-analysis revealed that ER-/Grade 3 tumors show increased expression of proliferation-associated functional categories when compared to ER+/Grade 3 tumors. Using Gene Set Enrichment Analysis we show that transcript levels of direct transcriptional targets of ER are lower in ER- tumors, but that expression of other estrogen-induced genes is higher in ER- tumors. Transcript levels of both direct and other targets of the estrogen-regulated MYC gene and the E2F family of genes are significantly higher in ER- tumors. The increased expression of targets of MYC and E2F is particularly pronounced in the "basal" subgroup of ER- tumors. This suggests that a study assessing the association of these genes with clinical outcome in ER- patients is warranted, but is not currently feasible due to lack of suitable publicly available data. The contribution of genes regulated or bound by estrogen, MYC or E2F to increased risk of relapse in ER+ tamoxifen-treated patients was assessed in a pilot study using Cox proportional hazards models and Gene Set Enrichment Analysis. The high expression of several gene sets containing genes induced by estrogen and/or MYC and direct targets of MYC and E2F was correlated with poor outcome in these patients. We conclude that over-expression or constitutive activation of MYC, possibly in conjunction with elevated E2F activity, may lead to the induction of a set of genes characteristic of the estrogen response thereby contributing to increased proliferation in ER- breast tumors, particularly in the basal subgroup. A pilot survival study indicated that MYC- and E2F-activity may play a role in tamoxifen-resistance.
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A novel role for estrogen receptor [beta] : defeminization of male brain and behavior /Kudwa, Andrea Elizabeth. January 2005 (has links)
Thesis (Ph. D.)--University of Virginia, 2005. / [beta] in the title is the Greek letter. Includes bibliographical references (leaves 200-228). Also available online through Digital Dissertations.
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Perinatal Nicotine Exposure Upregulates ERα In the Dentate Gyrus of Adult Male Rat OffspringBoucher, Julie January 2015 (has links)
Cigarette smoking during pregnancy contributes to the development of neurological health problems in offspring. As a result, public health organizations are recommending NRT to pregnant women to wean them off tobacco. If nicotine itself is injurious to the developing brain, then nicotine substitution may not eliminate the deleterious health outcomes of maternal smoking. In studies of cognitive decline, estradiol elicits a neuroprotective effect through ER activation. However, the underlying mechanism remains unclear. Evidence suggests that estrogen-mediated neuroprotection is activated through glial cell interaction, mitigating inflammation and protecting neurons critical for learning and memory. If NRT antagonizes these cellular targets, it may put individuals at risk for future cognitive impairments. Randomly assigned nulliparous female Wistar rats were injected subcutaneously with 1 mg/kg/day of nicotine bitartrate or saline for 2 weeks before mating until weaning (PND 21). Pups (saline n=6 and nicotine, n=6) were sacrificed at 26 weeks of age and the hippocampal formation was processed for Nissl and immunohistochemical staining for GFAP and ERα. Gestational exposure to nicotine only produced a significant increase in the expression of ERα in the DG of the hippocampus. While additional research is needed, these findings suggest that NRT might indeed interfere with proper brain development, making offspring increasingly susceptible to long-term adverse health effects.
Le tabac fumé pendant la grossesse affecte de manière importante le développement neurologique de la progéniture, y compris à long terme. C’est pourquoi, les autorités de la santé publique recommandent les substituts nicotiniques comme soutien au sevrage tabagique chez les femmes enceintes. Si le danger se situe dans la nicotine de la cigarette, alors les produits de substitution nicotiniques risquent également d’interférer avec le développement cérébral. De nombreuses données expérimentales convergent pour attribuer un rôle protecteur à l’oestradiol sur le fonctionnement cognitif. Par contre, le mécanisme sous-jacent est inconnu. Il se peut que l’oestradiol arrive à neutraliser la réaction inflammatoire provoquée par les cellules gliales, amoindrissant la détérioration des neurones impliqués au niveau de la mémoire. Ainsi, une perturbation de ce mécanisme par la nicotine pourrait engendrer une détérioration progressive des fonctions cognitives. Des rats femelles Wistars nullipares assignées de façon alléatoire à un groupe ont reçu soit une injection sous-cutanée de 1mg/kg/jour de nicotine bitartrate ou de saline, 2 semaines avant l’accouplement jusqu'au sevrage au jour 21 postnatal. A 26 semaines, les ratons furent sacrifiés (saline n=6 et nicotine, n=6) et une analyse du Nissl et immunohistochimique de GFAP et ERα furent réalisées sur les formations hippocampiques. L’exposition prénatale à la nicotine a seulement augmenté significativement l’expression de ERα dans le GD de l’hippocampe. Alors que des études plus approfondies sont nécessaires, ces résultats suggèrent que les substituts nicotiniques affectent le développement neurologique périnatal, ce qui risque d’entrainer des répercussions a long terme sur la santé.
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TMEM97/SIGMA 2 RECEPTOR INCREASES ESTROGEN RECEPTOR ΑLPHA ACTIVITY TO PROMOTE BREAST CANCER PROLIFERATIONZhang, Yuanqin 01 June 2021 (has links)
Breast cancer is the most common cancer in women among nearly every racial and ethnic group. About one in eight women in the US will get breast cancer in her lifetime. Sigma 2 receptor has long been implicated in breast carcinogenesis and compounds binding to this receptor have been developed as imaging agents for breast cancer, but its molecular identity had been elusive until 2017 when TMEM97 was identified as sigma 2 receptor. It is highly important to determine whether the biological functions of TMEM97 protein defined in previous studies are overlapping with those linked to sigma 2 receptor. In this study, we found that TMEM97 is highly expressed in ER positive breast tumors and its expression levels are associated with poor overall survival rate of breast cancer patients, and its expression patten is strongly correlated with ER and PR but not with HER2 status. Breast cancer cells with TMEM97 overexpression showed growth advantage over the control cells both in nutrition sufficient and starvation conditions. The differences were more pronounced under estrogen depleted conditions. In breast cancer MCF7 and T47D cells, TMEM97/sigma 2 receptor could regulate ERα transcriptional activities, and also regulate mTOR/S6K1 signaling pathways. The increased level of active, phosphorylated ERα, and the increased resistance to Tamoxifen treatment could be blocked by a mTOR inhibitor. TMEM97 in ER positive breast cancer cells could retard and delay the estradiol caused ERα turnover because of the accelerated the ERα protein synthesis offsetting the degradation caused by estradiol. TMEM97 increases the transactivated ERα, specifically for the nuclear soluble and chromatin bounded ERα. These observations suggest that TMEM97/sigma 2 receptor participates in breast tumor cell growth driven by estrogen signaling and further regulates the transcriptional activities of ERα through modulating ERα binding to estradiol and subsequent nuclear localization. Further, increased TMEM97 expression renders breast cancer cells with increased resistance toward endocrine therapeutics such as tamoxifen, which make TMEM97 a valid target of intervention to modulate ER activities to reduce resistance toward endocrine therapy.
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Monitoring Estrogen Receptor Dimerization via Bipartite Tetracysteine DisplayTang, Tang 23 September 2019 (has links)
No description available.
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Ligand- and Phosphorylation-dependent Modulation of Estrogen Reeptor Target Gene ExpressionKoterba, Kristen L. 07 February 2006 (has links)
No description available.
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