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Inhibition Of Estrogen Receptor Dependent Gene Transcription By A Designed Ligand
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Book Synopsis Inhibition of Estrogen Receptor-Dependent Gene Transcription by a Designed Ligand by :
Download or read book Inhibition of Estrogen Receptor-Dependent Gene Transcription by a Designed Ligand written by and published by . This book was released on 1999 with total page 17 pages. Available in PDF, EPUB and Kindle. Book excerpt: The purpose of this study was to develop novel DNA ligands that offer the potential for the treatment of human breast cancer. The growth of many human breast carcinomas is regulated by the female hormone estrogen through the action of the estrogen receptor protein. The logic of our approach was to develop small, cell-permeable molecules that prevent the activation of downstream genes by the DNA-binding protein estrogen receptor. A series of pyrrole/imidizole polyamides have synthesized in the laboratory of Dr. Peter Dervan at The California Institute of Technology and supplied to our laboratory. These polyamides were designed to bind the 6 bp half-site recognized by estrogen receptor. Standard DNase footprinting methods were used to measure the binding affinities of the synthetic ligands for their target sequences. A series of polyamides were screened for binding affinities and sequence specificity. We have used recombinant human estrogen receptor protein in DNA binding studies with the same target ERE sequences. Using DNase footprinting methods and gel mobility shift assays, we optimized conditions for ER-DNA interactions and we have shown that the ERE-binding polyamides inhibit ER binding to EREs. Future studies will examine whether these compounds are effective inhibitors of ER-dependent gene transcription in breast carcinoma cells in culture.
Book Synopsis Inhibition of Estrogen Receptor-Dependent Gene Transcription By a Designed Ligant by :
Download or read book Inhibition of Estrogen Receptor-Dependent Gene Transcription By a Designed Ligant written by and published by . This book was released on 1998 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Antiestrogens, like tamoxifen, are currently being used for the treatment of many breast cancers, however, not without significant side effects. We proposed to use small molecules to inhibit binding of estrogen receptor to its DNA target sites, thereby blocking estrogen-responsive gene expression. We have shown that the small hairpin pyrrole/imidazole polyamides can be effective inhibitors of gene transcription in living cells. As the first objective, pyrrole-imidazole polyamides will be synthesized to bind sequences adjacent to the estrogen response element and their binding affinity will be determined by quantitative DNase I footprint experiments. For objective two we will determine whether these polyamides inhibit binding of the estrogen receptor to its recognition sequence. In objective three it will be determined whether the polyamides inhibit gene expression in vivo. The laboratory of Peter Dervan has synthesized a polyamide that specifically recognizes the estrogen response element of the pS2 gene. We have shown by quantitave DNase I footprinting experiments that this polyamide binds its recognition site with high affinity and high specificity. We are currently investigating whether this polyamide inhibits binding of recombinant estrogen receptor in vitro. Future studies will focus on the inhibition of transcription of the pS2 gene in living cells by this polyamide.
Book Synopsis Ligand- and Phosphorylation-dependent Modulation of Estrogen Receptor Target Gene Expression by :
Download or read book Ligand- and Phosphorylation-dependent Modulation of Estrogen Receptor Target Gene Expression written by and published by . This book was released on 2005 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Endocrine Disruption and Human Health by : Philippa D. Darbre
Download or read book Endocrine Disruption and Human Health written by Philippa D. Darbre and published by Academic Press. This book was released on 2015-03-21 with total page 390 pages. Available in PDF, EPUB and Kindle. Book excerpt: Endocrine Disruption and Human Health starts with an overview of what endocrine disruptors are, the issues surrounding them, and the source of these chemicals in the ecosystem. This is followed by an overview of the mechanisms of action and assay systems. The third section includes chapters written by specialists on different aspects of concern for the effects of endocrine disruption on human health. Finally, the authors consider the risk assessment of endocrine disruptors and the pertinent regulation developed by the EU, the US FDA, as well as REACH and NGOs. The book has been written for researchers and research clinicians interested in learning about the actions of endocrine disruptors and current evidence justifying concerns for human health but is useful for those approaching the subject for the first time, graduate students, and advanced undergraduate students. - Provides readers with access to a range of information from the basic mechanisms and assays to cutting-edge research investigating concerns for human health - Presents a comprehensive, translational look at all aspects of endocrine disruption and its effects on human health - Offers guidance on the risk assessment of endocrine disruptors and current relevant regulatory considerations
Book Synopsis Cross-talk Between Hormone-regulated Transcription Factors, STAT5b and ER, and Xenochemical Receptors, PPAR and AhR by : Jonathan M. Shipley
Download or read book Cross-talk Between Hormone-regulated Transcription Factors, STAT5b and ER, and Xenochemical Receptors, PPAR and AhR written by Jonathan M. Shipley and published by . This book was released on 2005 with total page 428 pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: Nuclear receptors are ligand-inducible transcription factors that bind to DNA-response elements of target genes as monomers, homodimers, or as heterodimers with the retinoid X receptor. Two members of the nuclear receptor superfamily are peroxisome proliferator activated receptors (PPAR) and the estrogen receptor (ER). JAK-STAT signaling is activated by multiple cytokines and hormones, including growth hormone (GH), and leads to the translocation of dimerized STAT proteins to the nucleus where they activate transcription of target genes. Previous studies have demonstrated that STAT5b can inhibit PPAR-regulated transcription. Herein this inhibitory cross-talk is shown to be mutual, and that GH-induced, STAT5b-regulated, luciferase reporter gene transcription is inhibited up to 80% by ligand-activated PPAR. Mechanistic studies characterize aspects of PPAR/STAT5b cross-talk, including the effect of PPAR on STAT5b protein levels and DNA-binding activity, as well as the role of specific PPAR protein domains. A PPAR-activated Renilla luciferase reporter plasmid was constructed and used in combination with a STAT5b firefly luciferase reporter to show that in cells co-stimulated with GH and a PPAR agonist, STAT5b inhibition of PPAR-regulated transcription occurs simultaneous with PPAR inhibition of STAT5b-regulated transcription. Another example of cross-talk involving a nuclear receptor is aryl hydrocarbon receptor (AhR) inhibition of ER-regulated transcription. Recent studies have demonstrated a pro-estrogenic action of the AhR that proceeds via the formation of an (AhR-Arnt)-ER complex, which binds to estrogen response elements (EREs) and stimulates transcription of ER target genes. Activation by the AhR ligand, 3-methylcholanthrene (3MC), of an ER-regulated luciferase reporter and ER target genes in the breast cancer cell line MCF-7 is demonstrated. ER reporter activity is additionally activated by 3MC in the AhR-positive mouse hepatoma 5L cell line and its AhR-negative variant BP8. The ability of 3MC to activate ER-regulated transcription in the absence of AhR suggests that this AhR ligand may activate ER directly, instead of, or in addition to, the AhR-dependent mechanism proposed. Together, these studies elucidate mechanisms through which the xenochemical receptors PPAR and AhR may respectively exert crosstalk with hormone-activated signaling pathways involving STAT5b and ER.
Book Synopsis Textbook of Nephro-Endocrinology by : Ajay K. Singh
Download or read book Textbook of Nephro-Endocrinology written by Ajay K. Singh and published by Academic Press. This book was released on 2009-01-12 with total page 534 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Textbook of Nephro-Endocrinology is the definitive translational reference in the field of nephro-endocrinology, investigating both the endocrine functions of the kidneys and how the kidney acts as a target for hormones from other organ systems. It offers researchers and clinicians expert, gold-standard analyses of nephro-endocrine research and translation into the treatment of diseases such as anemia, chronic kidney disease (CKD), rickets, osteoporosis, and, hypoparathyroidism. - Investigates both the endocrine functions of the kidneys and how the kidney acts as a target for hormones from other organ systems - Presents a uniquely comprehensive and cross-disciplinary look at all aspects of nephro-endocrine disorders in one reference work - Clear translational presentations by the top endocrinologists and nephrologists in each specific hormone or functional/systems field
Book Synopsis Mechanisms of Transcriptional Activation of Estrogen Responsive Genes in Breast Cancer Cells by : Chien-Cheng Chen
Download or read book Mechanisms of Transcriptional Activation of Estrogen Responsive Genes in Breast Cancer Cells written by Chien-Cheng Chen and published by . This book was released on 2010 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogen receptor (ER) acts as a ligand-activated transcription factor that regulates the expression of genes. The genomic mechanisms of ER action include ligand-induced dimerization of ER which binds estrogen responsive elements (EREs) in the promoters of target genes. There are also nongenomic mechanisms of ER action which are associated with membrane bound or cytosol ER-dependent activation of various protein-kinase cascades which also influence expression of target genes. Egr-1 is an immediate-early gene induced by 17B-estradiol (E2) in the rodent uterus and breast cancer cells. Deletion analysis of the Egr-1 promoter identified a minimal E2-responsive region that contained serum response element (SRE3) which bound Elk-1 and serum response factor (SRF) in gel mobility shift assays. Hormone-responsiveness of Egr-1 in MCF-7 cells was specifically inhibited by PD98059, a MAPKK inhibitor, but not by LY294002, an inhibitor of PI3-K. These results contrasted with the hormone-dependent activation of the SRE in the c-fos promoter, which was inhibited by both PD98059 and LY294002, suggesting that Egr-1, like c-fos, is activated through non-genomic pathways of estrogen action but through activation of different kinases. COUP-TFs are orphan nuclear receptors expressed in a variety of tissues where they regulate biological functions and organogenesis. In this study, we investigated coactivation of ERa by COUP-TF1 in cell lines transiently cotransfected with the pERE3 construct. COUP-TFI coactivated ERał-mediated transactivation, but unlike many other coactivators, COUP-TFI also enhanced transactivation of ERa when cells were cotransfected with the TAF1-ERa mutant or the 19c-ERa mutant. These data indicate that helix 12 of ERa is not required for coactivation by COUP-TFI when AF-1 of ERa is intact. However, when the AF-1 of ERa is deleted, the intact AF-2 function is required for coactivation by COUP-TFI. Analysis of multiple COUP-TFI deletion mutants showed that the DNA-binding domain and C-terminal region of COUP-TFI were important for coactivation of ERa. Point mutations of the DNA-binding domain of COUP-TFI resulted in loss of interactions with ERa, suggesting that the DNA-binding domain of COUP-TFI is important for its coactivation activity facilitating interactions with ERa. These results demonstrate that COUP-TFI coactivated ERa through a non-classical LXXLL-independent pathway.
Book Synopsis Ligand-dependent Corepressor LCoR by : Ana Palijan
Download or read book Ligand-dependent Corepressor LCoR written by Ana Palijan and published by . This book was released on 2009 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
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 Role of Estrogen Receptor Target Genes in Breast Cancer by :
Download or read book Role of Estrogen Receptor Target Genes in Breast Cancer written by and published by . This book was released on 1999 with total page 12 pages. Available in PDF, EPUB and Kindle. Book excerpt: Breast cancer requires estrogen for its initiation and maintenance before progressing into a more aggressive stage. We proposed to study the role of estrogen receptor (ER) target genes in the promotion of breast cancer. To achieve this goal we generated a regulable repressor KEDPK to directly turn-off the expression of ER target genes. The KEDPK contains an ER-DBD that recognizes the ERE elements of ER target genes, a KRAB repressive domain which can silence target genes when tethered to the promoter region and a mutated PR-LED which responds only to exogenous ligand. The KEDPK shows dose- dependent inhibition of ER target genes in transient transfections. The inhibitory activity of KEDPK is under the control of its ligand RU486 and is specific to ER target genes. Currently we have devoted our effort to generate stable cell lines expressing KEDPK and determine its ability to suppress the endogenous ER target genes. The success of developing these repressors will allow us to study the role of ER target genes in breast cancer progression. Results obtained in these studies will be highly relevant to efforts in optimization of current hormone therapy and gene therapy for breast cancer.
Book Synopsis Hormonally Active Agents in the Environment by : National Research Council
Download or read book Hormonally Active Agents in the Environment written by National Research Council and published by National Academies Press. This book was released on 2000-02-03 with total page 453 pages. Available in PDF, EPUB and Kindle. Book excerpt: Some investigators have hypothesized that estrogens and other hormonally active agents found in the environment might be involved in breast cancer increases and sperm count declines in humans as well as deformities and reproductive problems seen in wildlife. This book looks in detail at the science behind the ominous prospect of "estrogen mimics" threatening health and well-being, from the level of ecosystems and populations to individual people and animals. The committee identifies research needs and offers specific recommendations to decision-makers. This authoritative volume: Critically evaluates the literature on hormonally active agents in the environment and identifies known and suspected toxicologic mechanisms and effects of fish, wildlife, and humans. Examines whether and how exposure to hormonally active agents occursâ€"in diet, in pharmaceuticals, from industrial releases into the environmentâ€"and why the debate centers on estrogens. Identifies significant uncertainties, limitations of knowledge, and weaknesses in the scientific literature. The book presents a wealth of information and investigates a wide range of examples across the spectrum of life that might be related to these agents.
Book Synopsis Molecular and Cellular Changes in the Cancer Cell by :
Download or read book Molecular and Cellular Changes in the Cancer Cell written by and published by Academic Press. This book was released on 2016-11-16 with total page 618 pages. Available in PDF, EPUB and Kindle. Book excerpt: Molecular and Cellular Changes in the Cancer Cell,the latest volume in the Progress in Molecular Biology and Translational Science series, includes a comprehensive summary of the evidence accumulated thus far on the molecular and cellular regulation of the various adaptations taking place in response to exercise. This volume examines some of the latest advances, highlighting some of the most important molecular and cellular alterations and environmental influences that collectively cause a normal cell to become cancerous. Special emphasis is given to changes that take place at the molecular and cellular level. Comprehensive and up-to-date survey of current knowledge on the cancer cell Includes the latest advances and the most important molecular and cellular alterations and environmental influences collectively causing cells to become cancerous Written by leading experts in the field
Book Synopsis Nuclear Hormone Receptors by : Malcolm G. Parker
Download or read book Nuclear Hormone Receptors written by Malcolm G. Parker and published by . This book was released on 1991 with total page 434 pages. Available in PDF, EPUB and Kindle. Book excerpt: An overview of the supergene family made up of those nuclear hormone receptors which recognize thyroid and steroid hormones, vitamen D and retinoic acid and which are characterized by their ability to bind both ligands and the genes which respond to them.
Book Synopsis G Protein-Coupled Receptors in Energy Homeostasis and Obesity Pathogenesis by :
Download or read book G Protein-Coupled Receptors in Energy Homeostasis and Obesity Pathogenesis written by and published by Academic Press. This book was released on 2013-01-10 with total page 403 pages. Available in PDF, EPUB and Kindle. Book excerpt: Obesity is an epidemic with enormous health, economic and social burdens. Current drugs for obesity treatment are far from ideal in terms of efficacy and side effects. Reviews in this volume of Progress in Molecular Biology and Translational Science summarize current status in studies of a number of G protein-coupled receptors that were shown to be promising targets for obesity treatments. Some of these receptors also cause monogenic obesity in humans. - Subject matter: obesity is an epidemic and G protein-coupled receptors are promising drug targets, with significant potential as new anti-obesity drugs - Chapters are written by leading experts
Book Synopsis Estrogens and Antiestrogens by : Robert Lindsay
Download or read book Estrogens and Antiestrogens written by Robert Lindsay and published by Lippincott Williams & Wilkins. This book was released on 1997 with total page 312 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Molecular Mechanisms of Hormone Actions on Behavior by : Anne M. Etgen
Download or read book Molecular Mechanisms of Hormone Actions on Behavior written by Anne M. Etgen and published by Academic Press. This book was released on 2010-03-16 with total page 1100 pages. Available in PDF, EPUB and Kindle. Book excerpt: A single volume of 31 articles, Mechanisms of Hormone Actions on Behavior is an authoritative selection of relevant chapters from the Hormones Brain and Behavior 2e MRW, the most comprehensive source of neuroendocrinological information assembled to date (AP June 2009). The study of hormones as they impact the brain and, subsequently, behavior is a central topic in neuroscience, endocrinology and psychiatry. This volume offers an overview of neuroendocrinological topics, approaching the subject from the perspective of the mechanisms which control hormone actions on behavior. Female, male and stress hormones are discussed at the cellular, behavioral and developmental level, and sexual differentiation of the development of hormone-dependent neuronal systems, neuropeptides/neuromodulators, and steroid-inducedneuroplasticity are addressed. There is simply no other current single-volume reference with such comprehensive coverage and depth.Authors selected are the internationally renowned experts for the particular topics on which they write, and the volume is richly illustrated with over 175 figures (over 50 in color). A collection of articles reviewing our fundamental knowledge of the mechanisms of neuroendocrinology, the book provides an essential, affordable reference for researchers, clinicians and graduate students in the area. - The most comprehensive single-volume source of up-to-date data on the mechanisms behind neuroendocrinology, with review articles covering x,y z - Chapters synthesize information otherwise dispersed across a number of journal articles and book chapters, thus saving researchers the time consuming process of finding and integrating this information themselves - Offering outstanding scholarship, each chapter is written by an expert in the topic area and approximately 35% of chapters are written by international contributors - Provides more fully vetted expert knowledge than any existing work with broad appeal for the US, UK and Europe, accurately crediting the contributions to research in those regions - Heavily illustrated with 175 figures, approximately 54 in color - Presents material in most visually useful form for the reader
Book Synopsis Biomarkers in Breast Cancer by : Giampietro Gasparini
Download or read book Biomarkers in Breast Cancer written by Giampietro Gasparini and published by Springer Science & Business Media. This book was released on 2008-01-17 with total page 335 pages. Available in PDF, EPUB and Kindle. Book excerpt: Expert laboratory and clinical researchers from around the world review how to design and evaluate studies of tumor markers and examine their use in breast cancer patients. The authors cover both the major advances in sophisticated molecular methods and the state-of-the-art in conventional prognostic and predictive indicators. Among the topics discussed are the relevance of rigorous study design and guidelines for the validation studies of new biomarkers, gene expression profiling by tissue microarrays, adjuvant systemic therapy, and the use of estrogen, progesterone, and epidermal growth factor receptors as both prognostic and predictive indicators. Highlights include the evaluation of HER2 and EGFR family members, of p53, and of UPA/PAI-1; the detection of rare cells in blood and marrow; and the detection and analysis of soluble, circulating markers.
