Textbook of Nephro-Endocrinology PDF Download
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Author: Ajay K. Singh
Publisher: Academic Press
ISBN: 0080920462
Category : Medical
Languages : en
Pages : 534
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Book Description
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
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Languages : en
Pages :
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Author: Amy M. Fowler
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Category :
Languages : en
Pages : 226
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Languages : en
Pages : 0
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Critical predictions as to the biological behavior, and thus the appropriate therapeutic strategy, of breast cancers can be made based upon the status of the estrogen receptor (ER). In support of DOD grant # DAMD-17-97-1-7069, our goal is to better understand the mechanisms by which ER controls the expression of target genes and therefore mediates the biological effects upon gene regulation and cell cycle progression. Our detailed studies of the regions of ER that control cell cycle progression in breast cancer cell lines have indicated an absolute requirement for the Activating Function-2 (AF-2) region of ER for hormone-dependent cell cycle progression. In many different classes of nuclear receptors, this area has been vigorously studied and has been shown to be important for the physical interaction between hormone bound receptors and coactivators. Our studies have demonstrated that mechanisms involving the chemical and structural modification of chromatin are critical for transcriptional responses to estrogen and may also be important for estrogen-dependent cell cycle progression.
Author: Miao Sun
Publisher:
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Category :
Languages : en
Pages : 175
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Breast cancer is a serious public health issue, and a full understanding of its etiology and pathophysiology is a primary focus in the field. Molecularly, the combined action of a plethora of factors in multiple pathways is involved in the regulation of the breast tumoriogenic process. Characterization of a more complete spectrum of the molecular factors will provide insights into the development of new and improved diagnostic, prognostic and therapeutic tools for treating breast cancer. To this end, my studies utilize a combination of molecular biology and bioinformatic methods, to uncover the mechanisms underlying the regulation of gene expression and growth in human breast cancer cells. To investigate the molecular crosstalk of the estrogen and c-Jun N-terminal kinase 1 (JNK1) signaling pathways, I monitored the genomic localization of estrogen receptor [alpha] (ER[alpha]) and JNK1 in basal and estrogen-stimulated MCF-7 breast cancer cells. I found that JNK1 binds to the promoter of many genes. ER[alpha] is required for the binding of JNK1 to the estrogen-induced sites, and JNK1 in turn functions as a coregulator of ER[alpha]. The convergence of ER[alpha] and JNK1 at target promoters regulates estrogen-dependent gene expression, as well as downstream estrogendependent cell growth responses. Furthermore, the implication of long noncoding RNAs (lncRNAs) in breast cancer is also coming to light. I developed a computational approach that integrates information from multiple genomic datasets, and generated a comprehensive catalog of 1888 expressed lncRNA genes in MCF-7 cells. Almost half of them are first annotated in this study, and more than a quarter are estrogen-regulated. Close examination revealed many interesting features. Interestingly, cell type-specific expression of lncRNAs predicts the intrinsic molecular subtypes of breast cancer, suggesting its potential utility as prognostic marker. Lastly, by selecting lncRNAs with elevated expression in breast tumors, and whose differential expression across a wide spectrum of tissues and cell types correlates with important cell viability genes, we identified a number of lncRNAs that are required for the normal growth of human breast cancer cells. Collectively, my studies expanded our understanding of the molecular mechanisms underlying breast cancer biology, and suggested new targets for therapeutic interventions.
Author: Joseph Sin
Publisher:
ISBN:
Category : Breast
Languages : en
Pages : 42
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Prolonged exposure to increased levels of estrogen has been shown to increase the risk of breast cancer. In addition, estrogen has been shown to cause breast cancer cell proliferation. A common form of breast cancer treatment involved selective estrogen receptor modulation. A molecular explanation of how this works is that estrogen regulates and binds to estrogen receptor (ER), a ligand-dependent transcription factor. ER associated with estrogen induces gene transcription by translocating into the nucleus and binding to estrogen response element. ER also recruits cofactor proteins, which results in chromatin remodeling and gene expression regulation through interacting with histone acetylases or transcriptional machinery. Most studies have focused on the study of how ER can activate gene transcription. Recently, ER has been shown to also repress gene transcription. my research has two parts. The first part was to find genes that were down regulated by estrogen in order to increase the data pool of genes down-regulated by estrogen. Four target genes, ARGN, MGC16169, CALML5, and NFIB are suspected to be involved in down-regulation by ER. However, after conducting validation tests, these genes were determined to not be repressed. The second part includes characterizing the specific effects of co-repressors NCoR, NRIP1, and SMRT. Removal of these co-repressors and subsequent effect of their removal on following four ER target sites, HES1, PSCA, SLC35A1, and MME were studied. A knock down of a single co-repressor did not affect the majority of transcriptional activity in ER repressed target genes. A triple knock down was also conducted in hope that removal of multiple co-repressors might affect repression. However, the triple knock down was a failure and future experiments need to be done. Understanding the mechanisms of ER transcriptional repression would significantly aid the creation of effective treatments for breast cancer.
Author: Lawanda Schief
Publisher: Page Publishing Inc
ISBN: 1642148903
Category : Health & Fitness
Languages : en
Pages : 162
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Book Description
Have you ever wondered how chemicals in the environment affect cancer? Well, this book can give you some scientific insight on how common pesticide chemicals and industrial waste can affect the growth of breast cancer cells.
Author: Kyuri Kim
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Category :
Languages : en
Pages :
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Estrogens 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.
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Category :
Languages : en
Pages : 230
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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.
Author: Daniel H. Barnett
Publisher:
ISBN:
Category :
Languages : en
Pages :
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The physiological effects of natural and synthetic estrogens are mediated by estrogen receptor alpha (ER alpha), and estrogen receptor beta (ER beta). Within the nucleus of target cells, ER alpha and ER beta serve as ligand-activated transcription factors to stimulate or repress the transcription of estrogen receptor regulated genes. ER alpha and ER beta may be co-expressed in estrogen-responsive cells, but may also be differentially expressed in a cell- and tissue-specific manner. In addition, within a given context these two receptors have different ligand binding and transcriptional activities. Taken together, these attributes underlie differences in target gene regulation, and overall, different physiological actions by ER subtypes. The work described here is an attempt to understand the roles of ER alpha and ER beta in target tissues (e.g. bone, breast, uterus) including the gene networks and cell signaling pathways under ER regulation. We have also characterized the regulation of one of the ER-regulated genes, Carbonic Anhydrase XII, and examined its regulation by ER alpha through use of a conserved distal enhancer. The work described here reports the characterization of individual gene regulatory actions of ER alpha and ER beta. To investigate the individual actions of ER alpha or ER beta, we utilized Affymetrix oligonucleotide arrays to profile transcripts regulated by 17beta-estradiol (E2) in U2OS-ER alpha and U2OS-ER beta cells. These cell lines were constructed by stable integration of ER alpha or ER beta into human osteoblast-like U2OS osteosarcoma cells and initially characterized for ER subtype expression, E2-binding, and cellular responses to E2, including proliferation, motility, and adhesion. Cells expressing apo-ER alpha or apo-ER beta did not show significant alteration in adhesion or proliferation after addition of E2, however there was a significant stimulation of migration in E2-treated ER beta-expressing cells. U2OS-ER alpha, and U2OS-ER beta cells were treated with 10 nM E2 for 0, 4, 8, 24, and 48 hours and total RNA was collected and hybridized to Affymetryx U95Av2 GeneChips and subjected to a Confidence Score to determine E2-regulated RNAs. Of the ca. 100 stimulated or repressed genes identified, some were stimulated by E2 equally through ER alpha and ER beta, whereas others were selectively stimulated via ER alpha or ER beta. The E2-regulated genes showed three distinct temporal patterns of expression over the 48 hour time course studied. Among stimulated genes, ER alpha-containing cells exhibited a greater number of regulated transcripts, and overall magnitude of stimulation was increased as compared those regulated by ER beta. Of the functional categories of the E2-regulated genes, most numerous were those encoding cytokines and factors associated with immune response, signal transduction, and cell migration and cytoskeleton regulation, indicating that E2 can exert effects on multiple pathways in these osteoblast-like cell lines. Of note, E2 up-regulated several genes associated with cell motility selectively via ER beta, in keeping with the selective E2 enhancement of the motility of ER beta-containing cells. On genes regulated equally by E2 via ER alpha or ER beta, the phytoestrogen genistein preferentially stimulated gene expression via ER beta. These studies indicate both common as well as distinct target genes for these two ERs, and identify many novel genes not previously known to be under estrogen regulation. We have examined the ER regulation of the Carbonic Anhydrase XII (CA12) gene, a gene identified as E2-regulated in the studies described above. We investigated the expression of CA12 and its and regulation of by 17beta-estradiol and selective estrogen receptor modulators in breast cancer cells, and characterize the ER usage of a distal enhancer necessary for CA12 gene regulation. We find that CA12 expression is highly correlated with ER alpha expression in human breast tumors. We demonstrate that E2 and SERMS increase CA12 mRNA and protein in multiple breast cancer cell types expressing ER alpha, and that CA12 regulation by estrogen is a primary transcriptional response mediated by ER alpha. By genome-wide chromatin immunoprecipitation (ChIP) and ChIP scanning of the CA12 locus, we find E2-occupied ER alpha is recruited to a distal region 6.1 kb upstream of the CA12 transcription start site (TSS) in vivo. We find that E2 treatment results in recruitment of RNA polymerase II and steroid receptor coactivators SRC-2 and SRC-3 to the CA12 genomic locus and is correlated with increased histone H4 acetylation. Mutagenesis of an imperfect estrogen-responsive element within this -6.1kb distal enhancer region abolishes estrogen-dependent heterologous reporter activity. Chromosome conformation capture (3C) and chromatin immunoprecipitation assays demonstrate that this distal enhancer communicates with the transcriptional start site of the CA12 gene via intra-chromosomal looping upon hormone treatment. This distal enhancer element is observed in the homologous mouse genomic sequence, and the expression of the mouse homolog, Car12, is rapidly and robustly stimulated by estradiol in the mouse uterus in vivo, suggesting that the ER regulation of CA12 is mechanistically and evolutionarily conserved. Our findings highlight the crucial role of ER in regulation of the CA12 gene, and provide insight into the transcriptional regulatory mechanism that accounts for the strong association of CA12 and ER in human breast cancers. In addition, our findings imply that involvement of long distance enhancers in regulation of estrogen-responsive genes in breast cancer may be more frequent than previously appreciated.
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Languages : en
Pages : 35
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The goal of this research is to study the association of the estrogen receptor with the nuclear matrix, and to identify the nuclear matrix acceptor sites for the estrogen receptor. We have constructed an ER fusion protein (GFP-ER) with a His(6) tag, HA tag, and the green fluorescent protein. In transiently transfected ER negative cells GFP-ER causes the ligand dependent transactivation of an ERE-reporter construct. Using confocal fluorescent microscopy we observed the cellular localization of GFP-ER in living cells. GFP-ER is localized to the nuclei, with exclusion from the nucleoli, both in absence of ligand, and when 17 beta-estradiol, or 4-hydroxytamoxifen are added. In MCF7 cells (ER+), the nuclear distribution has a speckled or punctate pauern which does not change with the addition of ligand. In MDA MB 231 cells (ER-), the distribution of GFP-ER in cells without ligand added is fuzzy or diffuse, with the addition of ligand the nuclear distribution becomes more localized or granular. The pattern of distribution of GFP-ER appears the same on nuclear matrices isolated on slides as in living cells. We corroborated this by extracting nuclear matrix in solution and detecting the presence of GFP-ER by Western blotting with HA-antibody.
