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Estrogen Receptor Alpha Protein Interactions With Nuclear Components In Breast Cancer Cells
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Book Synopsis Estrogen Receptor Alpha Protein Interactions with Nuclear Components in Breast Cancer Cells by : Amy L. Weinberg
Download or read book Estrogen Receptor Alpha Protein Interactions with Nuclear Components in Breast Cancer Cells written by Amy L. Weinberg and published by . This book was released on 2007 with total page 230 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis A Non-Nuclear Role of the Estrogen Receptor Alpha in the Regulation of Cell-Cell Interactions by :
Download or read book A Non-Nuclear Role of the Estrogen Receptor Alpha in the Regulation of Cell-Cell Interactions written by and published by . This book was released on 2006 with total page 11 pages. Available in PDF, EPUB and Kindle. Book excerpt: Proliferation and metastasis of many breast cancers depend on the steroid hormone estrogen. The actions of estrogens are mediated by the estrogen receptors ERalpha and ERbeta. These hormone-regulated transcription factors translate the presence of estrogen into changes in gene expression. According to new findings, these receptors also act outside of the nucleus and are often found associated with the plasma membrane. In contrast to their roles in regulating cell proliferation, very little is known about the mechanisms by which estrogens promote metastasis. It has been suggested that estrogens aid this process by changing the expression of cell adhesion proteins, such as E-cadherin. However, results in our laboratory have opened the possibility that disruption of cell adhesions by estrogens involves the direct interaction of ER with cell adhesion proteins. The goal of this grant is to explore this possibility. If true, this mechanism would represent a novel example of a non-nuclear activity of the estrogen receptor, steer ongoing studies on the role of estrogens in the regulation of cellular adhesions into a new direction, and open new venues for the prevention, diagnosis and therapy of breast cancer.
Book Synopsis Molecular and Biochemical Studies of Several Novel Estrogen Receptor Alpha-interacting Proteins in Breast Cancer Cells by : Ahmed Edan Dhamad
Download or read book Molecular and Biochemical Studies of Several Novel Estrogen Receptor Alpha-interacting Proteins in Breast Cancer Cells written by Ahmed Edan Dhamad and published by . This book was released on 2017 with total page 402 pages. Available in PDF, EPUB and Kindle. Book excerpt: Breast cancer is the second leading cause of cancer-related death in women, and approximately 70% of incidences are estrogen receptor (ER)-positive breast cancer. ERÜ and its interacting proteins play a key role in the development and progression of breast cancer. However, how ERÜ regulates its target gene expression and hence cell proliferation is not fully understood. To enhance our understanding of the molecular mechanism by which ERÜ regulates gene expression, we used a quantitative proteomic method to identify cellular proteins that interact with ERÜ. The first group of proteins that were identified to associate with ERÜ are heat shock proteins (Hsps). We identified 21 Hsps and 3 Hsp cochaperones that were associated with ERÜ. Co-immunoprecipitation assay demonstrated that Hsp70-1 and Hsc70, the two most abundant ERÜ-associated proteins, interacted with ERÜ in both transcriptionally active and inactive chromatin of MCF7 cells. A novel of protein that was identified to interact with ERÜ is histone acetyltransferase 1 (HAT1). We showed that HAT1 physically binds ERÜ through the E domain of ERÜ, and silencing HAT1 by shRNA significantly increased the ERÜ-mediated transcription in MCF7 cells. Importantly, our data suggest that HAT1 regulates ERÜ transcriptional activity through affecting the interactions of ERÜ with histone proteins around the promoter region of ERÜ target genes in breast cancer cells. We also identified and confirmed that protein arginine methyltransferase 5 (PRMT5) is a new ERÜ interacting partner, and PRMT5 interacts with ERÜ preferentially in the cytoplasm of MCF7 cells. Functionally, we found that overexpression of PRMT5 in MCF7 cells significantly decreased ERÜ transcriptional activity. Finally, we demonstrated that chromatin target of PRMT1 (CHTOP) directly binds to ERÜ through the E domain of ERÜ. We found that knockout of CHTOP by CRISPR-Cas9 significantly decreased ERÜ transcriptional activity, and the effect is potentially through decreasing protein levels of MEP50, an ERÜ coactivator. In summary, we identified and characterized several novel ERÜ-interacting proteins that play significant roles in regulating ERÜ transcriptional activities. Our results provide new insight into the molecular mechanisms by which ERÜ controls its target gene expression and regulates cell proliferation in ERÜ-positive cells.
Book Synopsis Concentration-dependent Estrogen Receptor-alpha Transcriptional Function in Breast Cancer by : Amy M. Fowler
Download or read book Concentration-dependent Estrogen Receptor-alpha Transcriptional Function in Breast Cancer written by Amy M. Fowler and published by . This book was released on 2005 with total page 226 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Estrogens, Estrogen Receptor and Breast Cancer by : Fritz F. Parl
Download or read book Estrogens, Estrogen Receptor and Breast Cancer written by Fritz F. Parl and published by IOS Press. This book was released on 2000 with total page 280 pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogens have been implicated to play a role in the development of breast cancer. The purpose of this book is to provide a comprehensive analysis of experimental, clinical and epidemiological evidence in support of the carcinogenicity of estrogens.
Book Synopsis Estrogen Receptor Accessory Factors in Breast Cancer Cells by :
Download or read book Estrogen Receptor Accessory Factors in Breast Cancer Cells written by and published by . This book was released on 1997 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The goal of this investigation is to test the hypothesis that estrogen agonists and antagonists promote differential transcriptional activity of the estrogen receptor (ER) by altering accessory protein interactions. We have shown that one or more ER-associated proteins (hsp70, PDI, p48, p45) may be required for maximal interaction of ER with specific DNA sites (EREs) in responsive genes and that the same proteins contribute to the magnitude of DNA distortion without altering the direction of the ER-induced bend of ERE-containing DNA fragments, which is toward the major groove of the DNA helix. We have also used the ligand binding domain of the ER (aa 282-595), expressed in bacteria as a GST-fusion protein (GST-LBD), to capture proteins from mammalian cell extracts that associate with the ER. One protein retained by this technique is a kinase that phosphorylates ER only in the presence of estrogen agonists. Phosphoamino acid analysis and manual sequencing of tryptic peptides have identified the site of phosphorylation as serine 559, a putative casein kinase II phosphorylation site.
Book Synopsis Phosphorylation-dependent Prolyl Cis/trans Isomerase Pin1 Regulation of Estrogen Receptor-alpha Functions in Breast Cancer by :
Download or read book Phosphorylation-dependent Prolyl Cis/trans Isomerase Pin1 Regulation of Estrogen Receptor-alpha Functions in Breast Cancer written by and published by . This book was released on 2013 with total page 460 pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogen receptor-alpha (ER[alpha]) is a member of nuclear receptor superfamily of transcription factors. It is known to regulate carcinogenic gene expression programs that are involved in the development and progression of breast cancer. The transcriptional function of ER[alpha] is mediated by a C-terminal AF2 and an N-terminal AF1 activation domains. Ligand-dependent AF2 activity is well-characterized and serves as a basis for hormonal therapy for breast cancer. In contrast, structural and functional mechanisms governing AF1 functions remain poorly understood. AF1 activity of ER[alpha] is regulated by phosphorylation stemming from hormone, peptide growth factors, and second messenger pathways. Paradoxically, phosphorylation results in contrasting responses (differentiation and growth, protein stability and degradation, agonist and antagonist activities). How phosphorylation translates into diverse outcome is not clearly understood. The work presented in this thesis has uncovered a post-translation modification beyond phosphorylation that regulates the function and fate of ER[alpha]. I found that phosphorylation-dependent prolyl cis/trans isomerase, Pin1, causes structural changes at the AF1 region of ER[alpha]. These local changes allosterically regulate DNA binding and dimerization activities, enhancing overall ER[alpha] transcriptional function. Pin1 also stabilizes ER[alpha] protein by blocking its ubiquitination and degradation by the proteasome. Further studies in understanding the role of Pin1 in breast cancer led us to uncover the importance of Pin1 in proliferation of ER[alpha]-positive breast cancer cells and mammary tumors in rodent models. Pin1 overexpression was sufficient to overcome the antagonistic effects of tamoxifen and also contributed to tamoxifen resistance in breast cancer cells. Finally, the clinical relevance of Pin1 activity was confirmed by our findings in human breast tumors, where Pin1 levels were correlated with ER[alpha] protein levels, and ER[alpha]-positive tumor patients with high Pin1 levels had poor overall survival. Overall, the findings in this thesis have identified a new regulatory mechanism governing ER[alpha] AF1 function in breast cancer and discovered Pin1 as an important component modulating ER[alpha] protein levels and transactivation functions.
Book Synopsis Dissecting the Role of Estrogen Receptor Palmitoylation in Breast Cancer Cells by :
Download or read book Dissecting the Role of Estrogen Receptor Palmitoylation in Breast Cancer Cells written by and published by . This book was released on 2013 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogen signaling is primarily mediated by two estrogen receptors (ERs), ER[alpha] and ER[beta]. ER[alpha] is expressed in ~70% of breast cancers and is an important diagnostic and therapeutic target. Developing better treatment options and overcoming limitations of endocrine therapy depend on a detailed understanding of ER[alpha]-signaling pathways. ER[alpha], a member of the class I nuclear receptor superfamily of transcription factors, localizes mainly to the nucleus and interacts with DNA regulatory sequences either directly or through interaction with other transcription factors to regulate gene transcription. ER[alpha] is also rapidly activates signaling cascades. S-palmitoylation, a reversible lipid modification is catalyzed by palmitoyl acyl-transferases (PAT), which increase affinity of proteins to the membrane. Based on the results of previous studies, it is hypothesized that palmitoylation of ER[alpha] regulates extranuclear and nuclear signaling of ER[alpha]. We utilized palmitoylation-defective mutant ER[alpha]C447A-expressing MDA-MB-468 breast cancer cells to dissect the role of palmitoylation in a breast cancer cell line model. The substitution of ER[alpha] palmitoylation site abrogated ER[alpha] palmitoylation, membrane localization and estrogen-dependent phosphorylation of ERK1/2 in MDA-MB-468 cell line. Besides loss of E2-dependent extranuclear signaling, the substitution of palmitoylation sites led to the loss of other ER[alpha]-dependent events in ER[alpha]C447A-expressing MDA-MB-468 cells, such as decreased E2-dependent S118 phosphorylation, impaired regulation of certain target genes, and loss of estrogen-dependent cell cycle inhibition. This study thus highlights the importance of ER[alpha] palmitoylation in both nuclear and extranuclear ER signaling pathways in breast cancer cells. A better understanding of the mechanisms of estrogen action will help us to design more effective drugs affecting signal pathways depending on both membrane and nuclear receptors.
Book Synopsis Activation of Estrogen Receptor Alpha, Aryl Hydrocarbon Receptor, and Nuclear Factor Erythroid-2 Like 2 in Human Breast Cancer Cells by : Raymond Ho Fai Lo
Download or read book Activation of Estrogen Receptor Alpha, Aryl Hydrocarbon Receptor, and Nuclear Factor Erythroid-2 Like 2 in Human Breast Cancer Cells written by Raymond Ho Fai Lo and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Mechanisms of Aryl Hydrocarbon Receptor and Estrogen Receptor Action in Breast Cancer Cells by : Jeong Eun Lee
Download or read book Mechanisms of Aryl Hydrocarbon Receptor and Estrogen Receptor Action in Breast Cancer Cells written by Jeong Eun Lee and published by . This book was released on 2006 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: In MCF7 and T47D cells cotreated with 1 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) plus 0.1-10 uM 3̕,4̕ -dimethoxy flavone (DMF), there was a concentration-dependent decrease in the TCDD-induced ethoxyresorufin O-deethylase (EROD) activity. Gel mobility shift assays showed that 3̕,4̕ -DMF inhibited TCDD-induced aryl hydrocarbon receptor (AhR) transformation in rat liver cytosol and blocked TCDD-induced formation of the nuclear AhR complex in MCF7 and T47D cells. The antiestrogenic activity of TCDD in estrogen-induced transactivation assays in MCF7 cells was reversed by 3̕,4̕ -DMF, confirming the AhR antagonist activity of this compound in breast cancer cells. Cotreatment of T47D and MCF7 cells with TCDD and 10 uM resveratrol inhibited induction of CYP1A1 mRNA and EROD activity. Resveratrol did not inhibit TCDD-induced AhR transformation and reporter gene activity. Actinomycin D chase experiments in T47D cells showed that the mechanism of inhibition of CYP1A1 mRNA and EROD activity is due to an increased rate of CYP1A1 mRNA degradation, suggesting that resveratrol inhibits CYP1A1 via an AhR-independent post-transcriptional pathway. Vitamin D receptor-interacting protein 150 (DRIP150) coactivated estrogen receptor [alpha] (ER [alpha])-mediated transactivation and the response was AF2-dependent in ZR75 breast cancer cells. C-and N-terminal NR-boxes (amino acids 1186-1182 and 73-69, respectively) were not necessary for coactivation of ER [alpha]. Analysis of DRIP150 deletion mutants identified a 23 amino acid sequence (811-789) required for coactivation. The 23 amino acid contained two regions at amino acids 789-794 and 795-804 which resembled [alpha] -helical motifs identified in Lanuguinosa lipase/histamine N-methyl transferase and hepatocyte nuclear factor 1, respectively. A squelching assay using specific point mutations within each [alpha] -helix showed that the NIFSEVRVYN (795-804) region was the critical sequence required for the coactivator activity of DRIP150.
Book Synopsis Nuclear Receptor Interactions in Breast Cancer: The Role of Kinase Signaling Pathways by :
Download or read book Nuclear Receptor Interactions in Breast Cancer: The Role of Kinase Signaling Pathways written by and published by . This book was released on 2004 with total page 22 pages. Available in PDF, EPUB and Kindle. Book excerpt: Retinoids are vitamin A derivatives, which cause growth inhibition, differentiation and/or apoptosis in various cell types, including some breast cancer cells. In general, estrogen receptor (ER)-positive cells are retinoic acid (RA) sensitive, whereas ER-negative cells are resistant. I have showed that ER-negative MDA-MB-231 cells and MDA-MB-468 cells are strongly growth inhibited by retinoids in combination with PKC inhibition, and inhibition of PKC in particular. In this report, I show that the PKC inhibitor GF1092O3X increases gene regulation by RA, as shown by microarray studies, and identify certain genes/pathways that may be important. I also show that apoptosis following treatment with RA plus the PKC delta specific inhibitor Rottlerin involves loss of mitochondrial transmembrane potential and release of cytochrome c into the cytosol. Further, I report that while GF1O92O3X decreases phosphorylation of RARa in MDA-MB-231 cells, stable expression of ER alpha or beta in these cells leads to an increase in RA alpha or beta osphorylation.
Book Synopsis The Role of Estrogen Related Receptor in Modulating Estrogen Receptor Mediated Transcription in Breast Cancer Cells by :
Download or read book The Role of Estrogen Related Receptor in Modulating Estrogen Receptor Mediated Transcription in Breast Cancer Cells written by and published by . This book was released on 2004 with total page 13 pages. Available in PDF, EPUB and Kindle. Book excerpt: Unlike most nuclear receptors, the Estrogen Receptor-Related Receptors (ERRs) activate transcription constitutively, interacting with coactivators and target gene promoters in the absence of ligand. Structurally, this subfamily of receptors is related to the classical estrogen receptors and has been shown to positively regulate the transcription of several estrogen responsive genes. Interestingly, the transcriptional activity of ERRalpha is not inhibited by classical anti-estrogens suggesting that its ability to regulate ER- responsive genes may contribute to the development of tamoxifen resistant breast cancer. Without pharmacological agents to regulate ERRalpha activity it has been difficult to define the specific roles of this orphan receptor in the pathogenesis of breast cancer and thus its potential as a therapeutic target is unknown. To address this issue we have developed approaches to both positively and negatively regulate ERRalpha activity in target cells. Specifically, we have developed peptide antagonists to inhibit ERRalpha activity by blocking cofactor binding and have developed activating "protein ligands" by creating modified coactivators that selectively regulate ERRalpha transcriptional activity. With these tools, we have characterized the critical regions of the receptor important for coactivator binding and defined differential binding requirements between coactivator families. In addition, we are identifying the target genes and processes regulated by ERRalpha.
Book Synopsis Membrane Estrogen Receptor Alpha Targeting and Its Association With SHC in Regulating Breast Cancer Cell Proliferation by :
Download or read book Membrane Estrogen Receptor Alpha Targeting and Its Association With SHC in Regulating Breast Cancer Cell Proliferation written by and published by . This book was released on 2003 with total page 37 pages. Available in PDF, EPUB and Kindle. Book excerpt: 17BETA-ESTRADIOL (E2) induces rapid, non-genomic effect in MCF-7 breast cancer cells, including rapid activation of MAPK, phosphorylation of adapter protein Shc, increase of the interaction between Shc and estrogen receptor (ERalpha). More strikingly E2 also induced a rapid membrane association of ERalpha: (1) Further studying the structure and function of ERalpha, we demonstrated that only membrane-associated ERalpha, but not cytosol and nuclear ones, mediates E2 effect on MAPK activation. (2) To study the mechanism of ERalpha membrane association, we further investigated the role of Shc in estrogen action. Here we demonstrated that in MCF-7 cells, Shc acts as a chaperon linking ERalpha to the cell membrane by binding to a transmembrane receptor IGF-1R. Further study is under the way to investigate the molecular mechanism among these protein complex formation and their biological effects in estrogen non-genomic action.
Book Synopsis Mechanisms of Coactivation of Estrogen Receptor Alpha (ER Alpha)- and ER Alpha/Sp-mediated Gene Transactivation by Vitamin D Receptor Interacting Protein 205 (DRIP205) in Breast Cancer Cells by : Qian Wu
Download or read book Mechanisms of Coactivation of Estrogen Receptor Alpha (ER Alpha)- and ER Alpha/Sp-mediated Gene Transactivation by Vitamin D Receptor Interacting Protein 205 (DRIP205) in Breast Cancer Cells written by Qian Wu and published by . This book was released on 2010 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Estrogen-Related Receptor Alpha (ERRa)-Coactivator Interactions as Targets for Discovery of New Anti-Breast Cancer Therapeutics by :
Download or read book Estrogen-Related Receptor Alpha (ERRa)-Coactivator Interactions as Targets for Discovery of New Anti-Breast Cancer Therapeutics written by and published by . This book was released on 2006 with total page 12 pages. Available in PDF, EPUB and Kindle. Book excerpt: The nuclear receptor estrogen receptor alpha (ERalpha) is a primary focus of the therapy of breast cancers. ERalpha-positive breast cancers have traditionally been treated with the anti-estrogen tamoxifen, or with inhibitors of aromatase. ERalpha-negative breast cancers do not respond to anti-estrogen treatment; instead, current therapeutics, such as Herceptin, have focused on the transmembrane tyrosine kinase receptor ErbB2 (HER2) because it is often overexpressed in ERalpha-negative tumors and correlates with a poor prognosis. Estrogen-related receptor alpha (ERRalpha) has sequence similarity to ERalpha, but ERRalpha does not bind estrogens. In some cases ERRalpha is constitutively active, which is likely determined not only by its interaction with coactivators, but also in part by post-translational modifications occurring via the ErbB2 (HER2) signaling pathways. Thus, ERRalpha probably plays a key role in the etiology and progression of a subset of breast cancers. We believe that the ERRalpha-coactivator interaction is a promising target for new chemotherapeutic drug development. We have generated and characterized a set of murine monoclonal antibodies for use in studying the biology of ERRalpha. We are now using some of those antibodies in gentle immunoaffinity chromatography to determine ERRalpha-associated proteins. Using in vitro assays, we will study the binding properties of ERRalpha with known coactivators like transcriptional intermediary factor 2 (TIF2), as well as any ERRalpha-associated proteins we may find during immunopurification. In the future, using a luminescence resonance energy transfer-based high-throughput screen previously developed in our laboratory, we hope to identify small molecules that interfere with the binding of ERRalpha with these coactivators.
Book Synopsis The Nuclear Receptor Co-Activator 5 is a Potential New Co-regulator of the Estrogen Related Receptor [alpha] in Breast Cancer by : Amandine Laffitte
Download or read book The Nuclear Receptor Co-Activator 5 is a Potential New Co-regulator of the Estrogen Related Receptor [alpha] in Breast Cancer written by Amandine Laffitte and published by . This book was released on 2017 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Nuclear receptors are transcriptional factors that are essential for a wide range of biological processes. They are partly regulated through their interaction with co-regulatory proteins. Here, we focus on the orphan nuclear receptor ERRa and its potential new co-activator protein NCOA5. Using NCOA5 knockdown or overexpression via a lentiviral system, we investigated the role of NCOA5 in ERRa regulation in Her2-positive breast cancer cells and its effect on known targets of ERRa in this context, such as the ERBB2 amplicon transcription. We show that NCOA5 and ERRa can regulate each other, yet the precise mechanism remains to be elucidated. NCOA5 protein level affects ERR[alpha] transcription and protein level, also affecting the transcription of ERRa targets from the ERBB2 amplicon including the Her2 receptor itself. Modulation of NCOA5 levels leads to variation in cell proliferation and metabolism, thus revealing that NCOA5 is an important factor in the ERBB2 amplicon regulation." --
Book Synopsis Chromatin Interactions and Transcriptional Output by Protein Kinase-A Activated Estrogen Receptor Α by : Valérie Jean
Download or read book Chromatin Interactions and Transcriptional Output by Protein Kinase-A Activated Estrogen Receptor Α written by Valérie Jean and published by . This book was released on 2015 with total page 165 pages. Available in PDF, EPUB and Kindle. Book excerpt:
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