Identification and Characterization of Novel Functional Interactions of Ligand-dependent CoRepressor

Identification and Characterization of Novel Functional Interactions of Ligand-dependent CoRepressor

Author: Mario Ramiro Calderon

Publisher:

Published: 2013

Total Pages:

ISBN-13:

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"Gene transcription is highly regulated by proteins called transcription factors, which bind to specific DNA sequences, and recruit a plethora of cofactors that directly modify the chemical composition of N-terminal histone tails or recruit enzymes that do so. These modifications alter the structure of chromatin, and can prime it for or render it refractory to transcription. Many of these recruited cofactors, termed transcriptional coactivators or corepressors, can interact with several classes of transcription factors. Initially characterized as an inhibitor of nuclear receptor-mediated transactivation, Ligand-dependent CoRepressor (LCoR) represses transcription through recruitment of specific C-terminal binding proteins (CtBPs) and histone deacetylases (HDACs) via defined domains. We were interested in determining whether LCoR also serves as a coregulator of other classes of transcription factors. Using yeast two-hybrid screens with the open reading frame of LCoR as bait, we found novel interactions with the transcription factor Krüppel-like factor 6 (KLF6) and another transcriptional coregulator Krüppel-Associated Box (KRAB)-associated protein 1 (KAP-1). KLF6 may act as a tumour suppressor in certain malignancies, while KAP-1 is a corepressor that functions through many zinc finger transcription factors. Functional characterization of these interactions revealed that LCoR regulates the expression of the genes cyclin-dependent kinase inhibitor 1A (CDKN1A) and cadherin 1 (CDH1) in specific prostate cancer cells via KLF6, and growth arrest and DNA-damage-inducible alpha (GADD45A) and fibroblast growth factor 2 (FGF2) in specific breast cancer cells through KAP-1. CDKN1A expression is regulated by the hormone insulin-like growth factor 1 (IGF-1) in certain cell types, and levels of IGF-1 and CDKN1A are elevated in prostate cancer. We found that LCoR and CDKN1A levels were enhanced in prostate cancer tissue and in IGF-1 treated prostate cancer cells. Additionally, the transcriptional response of a complex composed of KLF6 and LCoR may be altered by IGF-1 as we found that treatment of prostate cancer cells transiently overexpressing KLF6 and LCoR with IGF-1 abrogated their repression of a reporter gene. Hence, IGF-1-mediated transcriptional expression of CDKN1A may occur through KLF6 and LCoR and have implications for prostate cancer development. Similarly, the expression of FGF2 is frequently lost and associated with a more malignant phenotype in breast cancer. Our results show that a transcriptional complex composed of LCoR, KAP-1, and the transcription factor ZBRK1 suppresses the expression of the FGF2 gene in breast cancer cells, which enhanced cell viability. The identification of this transcriptional silencing complex provides a mechanism for the lack of expression of FGF2 in breast cancer. The work presented in this thesis contains four major contributions to further the understanding of the biological function of LCoR. In addition to identifying novel molecular interactions with (1) KLF6 and (2) KAP-1, which illustrate that LCoR can function in transcription independent of nuclear receptors, the functional characterization of these interactions revealed potential roles for LCoR in (3) breast and (4) prostate tumour development." --


Nuclear Receptor Coregulators

Nuclear Receptor Coregulators

Author:

Publisher: Academic Press

Published: 2004-08-11

Total Pages: 299

ISBN-13: 0080522882

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First published in 1943, Vitamins and Hormones is the longest-running serial published by Academic Press. In the early days of the Serial, the subjects of vitamins and hormones were quite distinct. The Editorial Board now reflects expertise in the field of hormone action, vitamin action, X-ray crystal structure, physiology, and enzyme mechanisms. Under the capable and qualified editorial leadership of Dr. Gerald Litwack, Vitamins and Hormones continues to publish cutting-edge reviews of interest to endocrinologists, biochemists, nutritionists, pharmacologists, cell biologists, and molecular biologists. Others interested in the structure and function of biologically active molecules like hormones and vitamins will, as always, turn to this series for comprehensive reviews by leading contributors to this and related disciplines. *First published in 1943, Vitamins and Hormones is AP's longest running serial *Each volume contains cutting edge reviews by leading contributors


Signaling at the Cell Surface in the Circulatory and Ventilatory Systems

Signaling at the Cell Surface in the Circulatory and Ventilatory Systems

Author: Marc Thiriet

Publisher: Springer Science & Business Media

Published: 2011-12-14

Total Pages: 988

ISBN-13: 1461419913

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The volumes in this authoritative series present a multidisciplinary approach to modeling and simulation of flows in the cardiovascular and ventilatory systems, especially multiscale modeling and coupled simulations. The cardiovascular and respiratory systems are tightly coupled, as their primary function is to supply oxygen to and remove carbon dioxide from the body's cells. Because physiological conduits have deformable and reactive walls, macroscopic flow behavior and prediction must be coupled to nano- and microscopic events in a corrector scheme of regulated mechanisms when the vessel lumen caliber varies markedly. Therefore, investigation of flows of blood and air in physiological conduits requires an understanding of the biology, chemistry, and physics of these systems together with the mathematical tools to describe their functioning. Volume 3 is devoted to the set of mediators of the cell surface, especially ion and molecular carriers and catalytic receptors that, once liganded and activated, initiate signal transduction pathways. Intracellular cascades of chemical reactions trigger the release of substances stored in cellular organelles and/or gene transcription and protein synthesis. Primary mediators are included in models of regulated cellular processes, but multiple secondary signaling components are discarded to allow simple, representative modeling and to manage their inverse problems.


Comprehensive Toxicology

Comprehensive Toxicology

Author:

Publisher: Elsevier

Published: 2010-06-01

Total Pages: 6448

ISBN-13: 0080468845

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An explosive increase in the knowledge of the effects of chemical and physical agents on biological systems has led to an increased understanding of normal cellular functions and the consequences of their perturbations. The 14-volume Second Edition of Comprehensive Toxicology has been revised and updated to reflect new advances in toxicology research, including content by some of the leading researchers in the field. It remains the premier resource for toxicologists in academia, medicine, and corporations. Comprehensive Toxicology Second Edition provides a unique organ-systems structure that allows the user to explore the toxic effects of various substances on each human system, aiding in providing diagnoses and proving essential in situations where the toxic substance is unknown but its effects on a system are obvious. Comprehensive Toxicology Second Edition is the most complete and valuable toxicology work available to researchers today. Contents updated and revised to reflect developments in toxicology research Organized with a unique organ-system approach Features full color throughout Available electronically on sciencedirect.com, as well as in a limited-edition print version


Principles of Molecular Oncology

Principles of Molecular Oncology

Author: Miguel H. Bronchud

Publisher: Springer Science & Business Media

Published: 2003-12-03

Total Pages: 716

ISBN-13: 1592596649

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At the midpoint of the 20th century, our knowledge of cancer was based on epide- ology and pathology, and treatment consisted of surgery and radiation therapy. At mid-century, Medawar and colleagues initiated the understanding of transplantation immunology, Farber described the first use of an antifolic drug to treat leukemia, and Jacobson and coworkers described the irradiation-protection effect of spleen cells. These observations opened the door to the development of chemotherapy and tra- plantation in the treatment of cancer. Despite the rapid development of these new disciplines, progress was usually based on empiric observations and clinical trials. The rapid advances in molecular biology at the end of the 20th century mark a new era in our knowledge of cancer. Molecular immunology, molecular genetics, mole- lar pharmacology, and the Human Genome Project are in the process of providing a level of understanding of cancer undreamed of in the past. Optimism is based on the firm belief that understanding at the molecular level will lead to better and earlier di- nosis, to new forms of treatment, and, most importantly, eventually to prevention of many types of cancer.


Regulatory Mechanisms in Transcriptional Signaling

Regulatory Mechanisms in Transcriptional Signaling

Author:

Publisher: Academic Press

Published: 2009-07-25

Total Pages: 413

ISBN-13: 0080911986

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Regulatory Mechanisms in Transcriptional Signaling, volume of Progress in Molecular Biology and Translational Science, includes in-depth discussion on roles of Chromatin remodeling proteins in nuclear receptor signaling, and the ANCCA regulator in cancer. This important resource, edited by Dr. Debabrata (Debu) Chakravarti, offers research on the progesterone receptor action in leiomyoma and endometrial cancer and emerging roles of the ubiquitin protein system in nuclear hormone receptor signaling to provide the reader with expert discussions of up-to-date research.


Molecular Mechanisms of Hormone Actions on Behavior

Molecular Mechanisms of Hormone Actions on Behavior

Author: Anne M. Etgen

Publisher: Academic Press

Published: 2010-03-16

Total Pages: 1100

ISBN-13: 0080958583

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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


NR Coregulators and Human Diseases

NR Coregulators and Human Diseases

Author: Rakesh Kumar (Ph. D.)

Publisher: World Scientific

Published: 2008

Total Pages: 615

ISBN-13: 9812819177

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This book serves as a treasure for all those who have an interest in nuclear receptor coregulators and human diseases. Written by experts in the field, each chapter provides comprehensive, up-to-date information on the physiologic and pathologic roles of coregulators in specific organ systems, giving biomedical students; basic and clinical researchers; and educators in diverse sub-specialties a thorough summary of the overall subject. Readers will be able to understand the important current information and views on specific coactivators and corepressors and their roles in the pathogenesis of human diseases in areas outside their own expertise or experience. A special emphasis is placed on the OC classicOCO papers as well as perspectives on future directions for the field. Sample Chapter(s). Chapter 1: Nuclear Receptor Coregulators in Human Diseases (839 KB). Contents: Nuclear Receptor Coregulators in Human Diseases (R B Lanz et al.); p160 Coactivators: Critical Mediators of Transcriptional Activation by Nuclear Receptors (J H Kim & M R Stallcup); Regulation of Nuclear Hormone Receptor Functions by Ubiquitin-Proteasome Pathway (A Ismail et al.); Coregulators as Oncogenes and Tumor Suppressors (R Kumar & A E Gururaj); A Central Role of SRC-3/AIB1 in Tumorigenesis (J Yan et al.); Thyroid Hormone Receptors, Coregulators, and Disease (M L Privalsky); Androgen Receptor Coactivators in Prostate Cancer (N L Weigel & I U Agoulnik); PGC-1 and Metabolic Control in Skeletal and Cardiac Muscle (Z Arany & B M Spiegelman); Coregulators in Metabolic and Neurodegenerative Diseases (J N Feige et al.); Role of the RIP140 Corepressor in Metabolic Regulation (M G Parker et al.); Nuclear Receptor Corepressors and Metabolism (T Alenghat & M A Lazar); Coregulators in CNS Function and Disease (O C Meijer & E R de Kloet); Tissue Repair and Cancer Control Through PPARs and Their Coregulators (L Michalik & W Wahli); Coregulators and Inflammation (S Ghisletti & W Huang); Nuclear Receptor Coactivators in the Cardiovascular System (J-M Xu); Coregulators as Determinants of Selective Receptor Modulator (SRM) Activity (M C Pace & C L Smith); Coregulators in Toxicology (J Regg et al.); Nuclear Receptor Coactivators Co-ordinate Metabolic Responses to Hormonal and Environmental Stimuli (R M Evans et al.); Nuclear Receptor Cofactor Interactions as Targets for New Drug Discovery (L L Grasfeder & D P McDonnell). Readership: Academic, medical students, residents, fellow and biomedical research students."


Steroid Receptors—Advances in Research and Application: 2012 Edition

Steroid Receptors—Advances in Research and Application: 2012 Edition

Author:

Publisher: ScholarlyEditions

Published: 2012-12-26

Total Pages: 421

ISBN-13: 146499384X

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Steroid Receptors—Advances in Research and Application: 2012 Edition is a ScholarlyEditions™ eBook that delivers timely, authoritative, and comprehensive information about Steroid Receptors. The editors have built Steroid Receptors—Advances in Research and Application: 2012 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Steroid Receptors in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Steroid Receptors—Advances in Research and Application: 2012 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.