Ligand- and Phosphorylation-dependent Modulation of Estrogen Receptor Target Gene Expression
Author:
Publisher:
Published: 2005
Total Pages:
ISBN-13:
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Effects of Phosphorylation on the DNA Binding Properties of Estrogen Receptor-alpha
Author: Kyle Thomas Helzer
Publisher:
Published: 2019
Total Pages: 0
ISBN-13:
DOWNLOAD EBOOKEstrogen receptor-[small alpha] (ER) is a major driver of breast cancer growth and development making it a common target for therapies. Understanding the activation and control of the ER signaling pathway is critical for developing new breast cancer treatments as well as combating resistance to current treatments. Activation of ER can occur in a ligand-dependent manner by 17[uppercase beta]-estradiol (E2) or in a ligand-independent manner through various growth factors or other stimuli. A common feature to both signaling pathways is the induction of ER phosphorylation at serine 118 (pS118-ER). Previous work has found that pS118-ER is an important modulator of ER-dependent gene transcription. A crucial step in the ER signaling pathway which allows for the altering of target gene expression is the binding of ER to DNA. While much work has been done to define the genome-wide binding profile (cistrome) of ER, the effect of phosphorylation on the distribution of ER across the genome is not well understood. In the work presented here, I aim to define the cistrome of pS118-ER and identify defining characteristics of sites occupied by the phosphorylated receptor compared to all ER occupancy sites. Using a comprehensive approach with multiple pS118-ER specific antibodies, I find that pS118-ER occupies a subset of ER sites in the human genome, with these sites being enriched for enhancer marks as well as the DNA-binding motif for the transcription factor grainyhead-like 2 (GRHL2). Additionally, analysis of these sites on in vitro DNA-binding arrays revealed an association between pS118-ER and direct DNA-binding. Finally, I developed a mutant MCF-7 cell line expressing ER with an S118A mutation to interrogate the biology of pS118-ER in a cell line which is dependent on ER. Consistent with previous reports, I found that E2-dependent ER downregulation was impaired in the S118A ER mutant. Interestingly, the downregulation of the ESR1 gene in response to E2 was also prevented indicating the control of pS118-ER over ER levels is not limited to post-translational mechanisms. These studies further the knowledge of how phosphorylation affects ER biology and may serve as a target for future breast cancer therapies.
Ligand-dependent Corepressor LCoR
Author: Ana Palijan
Publisher:
Published: 2009
Total Pages:
ISBN-13:
DOWNLOAD EBOOKPhosphorylation-dependent Prolyl Cis/trans Isomerase Pin1 Regulation of Estrogen Receptor-alpha Functions in Breast Cancer
Author:
Publisher:
Published: 2015
Total Pages: 230
ISBN-13:
DOWNLOAD EBOOKEstrogen 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.
Endocrine Disruption and Human Health
Author: Philippa D. Darbre
Publisher: Academic Press
Published: 2015-03-21
Total Pages: 390
ISBN-13: 0128011203
DOWNLOAD EBOOKEndocrine 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
Regulation of Estrogen Receptor-alpha Mediated Gene Expression and Endocrine Resistance Through Estrogen Receptor-alpha Phosphorylation and Micro-RNA in Breast Cancer
Author: Kyuri Kim
Publisher:
Published: 2011
Total Pages:
ISBN-13:
DOWNLOAD EBOOKEstrogens are associated with the development and progression of breast cancer in addition to their role in normal reproductive physiology, and estrogen receptors (ER) mediate the actions of estrogen in target tissues by regulating the expression of numerous biologically important target genes. The progression of human breast cancer and the development of resistance to endocrine therapies are thought to be associated with ER phosphorylation. We generated multiple combinations of ER phospho-mutants, at residues serine 104, 106, 118, 167, 236, and 305, and examined their impact on receptor half-life, the agonist and antagonist balance of selective estrogen receptor modulators (SERMs) and selective estrogen receptor downregulators (SERDs), the regulation of ER transcriptional activity, and stimulation of cell proliferation in response to estradiol and SERMs/SERD. We showed that changes in ER affecting the phosphorylation status of the receptor greatly impact receptor function and differential SERM and SERD modulated cellular responses that could contribute to resistance to endocrine therapies in breast cancer. We also studied the regulation of microRNAs (miRNAs) by estradiol and growth factors through ER and extracellular signal-regulated kinase 2 (ERK2) in order to understand their physiological impact on breast cancer. We identified nine miRNA- encoding genes harboring overlapping ER and ERK2 binding sites close to their transcription start sites, which require ER and ERK2 for transcriptional induction as well as estradiol- mediated miRNA regulation. We then identified TP63, a target of miR-101, miR-190 and miR- 196a2, and showed that TP63 plays an important role in estradiol- or growth factor-mediated cellular response in breast cancer cells (MCF-7 and MDA-MB-231) by increasing tumor cell growth and in vitro invasion mainly controlled by miR-196a2 action. These results suggest a tumor-suppressive role of miR-196a2 in regulating TP63 expression and the aggressive behavior of breast cancers.
Nuclear Hormone Receptors
Author: Malcolm G. Parker
Publisher:
Published: 1991
Total Pages: 434
ISBN-13:
DOWNLOAD EBOOKAn 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.
Cyclin Dependent Kinase 5 (Cdk5)
Author: Nancy Y. Ip
Publisher: Springer Science & Business Media
Published: 2009-02-28
Total Pages: 326
ISBN-13: 0387788875
DOWNLOAD EBOOKCyclin Dependent Kinase 5 provides a comprehensive and up-to-date collection of reviews on the discovery, signaling mechanisms and functions of Cdk5, as well as the potential implication of Cdk5 in the treatment of neurodegenerative diseases. Since the identification of this unique member of the Cdk family, Cdk5 has emerged as one of the most important signal transduction mediators in the development, maintenance and fine-tuning of neuronal functions and networking. Further studies have revealed that Cdk5 is also associated with the regulation of neuronal survival during both developmental stages and in neurodegenerative diseases. These observations indicate that precise control of Cdk5 is essential for the regulation of neuronal survival. The pivotal role Cdk5 appears to play in both the regulation of neuronal survival and synaptic functions thus raises the interesting possibility that Cdk5 inhibitors may serve as therapeutic treatment for a number of neurodegenerative diseases.
G Protein-Coupled Receptors in Energy Homeostasis and Obesity Pathogenesis
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Publisher: Academic Press
Published: 2013-01-10
Total Pages: 403
ISBN-13: 0123869528
DOWNLOAD EBOOKObesity 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
Gene Regulation, Epigenetics and Hormone Signaling
Author: Subhrangsu S. Mandal
Publisher: John Wiley & Sons
Published: 2017-10-23
Total Pages: 678
ISBN-13: 3527322817
DOWNLOAD EBOOKThe first of its kind, this reference gives a comprehensive but concise introduction to epigenetics before covering the many interactions between hormone regulation and epigenetics at all levels. The contents are very well structured with no overlaps between chapters, and each one features supplementary material for use in presentations. Throughout, major emphasis is placed on pathological conditions, aiming at the many physiologists and developmental biologists who are familiar with the importance and mechanisms of hormone regulation but have a limited background in epigenetics.
