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Molecular mechanisms of protein kinase A signaling pathway : effect on estrogen receptor action in breast cancerAl-Dhaheri, Mariam Hamad. January 2006 (has links)
Thesis (Ph.D.)--University of Toledo, 2006. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Major advisor: Brian G. Rowan. Includes abstract. Document formatted into pages: iv, 204 p. Title from title page of PDF document. Title at ETD Web site: Molecular mechanisms of protein kinase a signaling pathway on estrogen receptor action in breast cancer . Bibliography: pages 59-65, 100-104, 137-150, 167-202.
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Transcriptional Regulation of dehydroepiandrosterone sulfotransferase (SULT2A1) by Estrogen-Related Receptor Alpha (ERR-alpha)Seely, Jeremiah Brent January 2006 (has links)
Thesis (M.D) -- University of Texas Southwestern Medical Center at Dallas, 2007. / Vita. Bibliography: pp. 35-37.
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Biophysical Studies of the Binding of ERα Nuclear Receptor to DNADeegan, Brian J 31 May 2011 (has links)
Estrogen receptor α (ERα) is a member of a family of ligand-modulated transcription factors that have come to be known as nuclear receptors. ERα mediates the action of estrogens and plays an integral role in a wide range of physiological processes ranging from embryonic development and morphogenesis to reproduction to cardiovascular health. Not surprisingly, malfunction of the estrogen system is associated with a host of pathological conditions such as osteoporosis, heart disease and most notably breast cancer. Essential to its functioning as a transcription factor are specific protein-DNA interactions which are mediated by the binding of the DNA-binding (DB) domain of ERα to particular DNA sequences located within target gene promoters called estrogen response elements (EREs). Here, using a diverse array of biophysical techniques, including in particular isothermal titration calorimetry coupled with molecular modeling and semi-empirical analysis, I provide new insights into the ERα-DNA interaction in thermodynamic and structural terms. My data show that the binding of the DB domain of ERα to DNA is coupled to protonation at two specific amino acids, H196 and E203. Protonation of these residues is non-trivial and is required for high affinity binding. Amino acid sequence alignment of the DB domains of the NR family suggests that this may be a hallmark feature common to the functioning of all nuclear receptors. Furthermore, I demonstrate that the DB domain can tolerate all single nucleotide substitutions within the ERE and bind in the physiologically relevant nanomolar to micromolar range. Comparative thermodynamic analysis reveals that the DB domain binds to these ERE sequences utilizing a considerable range of energetic signatures such that any one thermodynamic component of binding is not predictive of associated affinity. In addition, it is shown that nucleotide substitution results in significant changes in secondary and three-dimensional features of the oligonucleotides and may impact binding affinity. Finally, I demonstrate that the zinc-finger of the DB domain of ERα is relatively promiscuous and can accommodate several heavy-metal divalent cations. Other than zinc, only DB domains reconstituted with cobalt, cadmium and mercury were capable of binding DNA. Incorporation of the metals resulted in a wide range of CD spectroscopic features which were found not to be predictive of DNA binding capacity. Thus, isostructure does not equate to isofunction in the case of metal reconstituted DB domain of ERα. This analysis suggests that metal coordination is not likely to be required for domain folding, but rather is required to bind DNA. Taken together, this thesis provides novel insights into the physicochemical basis of a key protein-DNA interaction essential to human health and disease. My studies bear the potential to impact the development of novel therapies harboring greater efficacy coupled with lower toxicity for the treatment of disease.
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Energy Restriction Effects on Estrogen Status and the Skeletal Response to LoadingSwift, Sibyl Nichole 2010 August 1900 (has links)
Moderate energy restriction in young, exercising women attenuates the positive
effects of exercise on bone density. Studies have shown that in the absence of adequate
levels of circulating estrogen, there may not be enough functional estrogen receptor-a
(ER-a) to respond adequately to loading. The experiment described in this document is
significant because this model has not been explored under conditions of energy
restriction (EnR) which are known to reduce circulating estrogen levels; it has been
tested only in ovariectomized animals. The central hypothesis of this research is that
reductions in estrogen due to EnR limit the ability of bone to respond to mechanical
loading (LOAD) through a down-regulation of ER-a.
Study one determined which nutrient’s (calcium or energy) restriction (-40 percent)
had the greatest negative effects on the skeletal integrity of exercising female rats and
whether exercise (EX) could mitigate these deleterious changes. EnR caused
detrimental effects in many of the structural properties of bone; however EX attenuated
losses in cancellous bone.
Study two ascertained whether EX maintained cancellous bone mass in female
rats subjected to graded EnR (-20 or -40 percent) and whether changes in endocrine factors
were related. EX preserved cancellous bone volume and osteoblast activity under both
levels of EnR, in addition to total body lean mass and bone mineral content. A similar
maintenance of serum insulin-like growth factor and estradiol occurred in the
EX EnR(40 percent) group suggesting that these changes may be related to the protective
effects of EX.
Study three determined the effects of 40 percent EnR on bone formation rate to LOAD
in young adult female rats and tracked alterations in ovarian function (estradiol).
Although higher than non-loaded animals, the response of bone to LOAD in EnR
animals was dampened in comparison to energy-replete animals.
The experiments described in this document are significant because these are the
first experiments to explore the relationship between EnR and estrogen levels on
cancellous bone response to LOAD. This is particularly important for physically active,
energy restricted women because cancellous bone in these women will not experience
the same effects of loading which can increase their risk for developing osteoporosis.
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Transcriptional regulation of estrogen receptor alpha target genes by hexamethylene bisacetamide-inducible gene 1 (HEXIM1) and its role in mammary gland development and breast cancer /Ogba, Ndiya January 2010 (has links)
Thesis (Ph. D.)--Case Western Reserve University, 2010. / [School of Medicine] Department of Pharmacology. Includes bibliographical references.
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The Regulation of TiPARP by the Aryl Hydrocarbon Receptor, the Platelet-derived Growth Factor Receptor, and the Estrogen Receptor AlphaRajendra, Sharanya 10 December 2013 (has links)
TiPARP is a PARP-like mART that is induced by and negatively regulates AHR transactivation. Despite these insights, not much is known about TiPARP. This study aimed to characterize the regulation of TiPARP by AHR, PDGFR, and ERα, and investigate potential receptor interplay. Gene expression studies revealed that coactivation of AHR and PDGFR can enhance TiPARP expression after 3 h relative to activation of either receptor pathway alone. Gene expression and ChIP studies demonstrated that while co-activation of AHR and ER enhanced AHR, ARNT, and ERα recruitment to the regulatory region of TiPARP, TiPARP mRNA levels were not potentiated by co-activation relative to activation of either pathway. Dissection of the 5’ regulatory region of TiPARP using reporter gene assays revealed that a putative AHRE cluster and an ERE half-site were functional. Lastly, overexpression of TiPARP with an estrogen-responsive reporter revealed that TiPARP can repress ERα signalling and requires its catalytic activity.
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The Regulation of TiPARP by the Aryl Hydrocarbon Receptor, the Platelet-derived Growth Factor Receptor, and the Estrogen Receptor AlphaRajendra, Sharanya 10 December 2013 (has links)
TiPARP is a PARP-like mART that is induced by and negatively regulates AHR transactivation. Despite these insights, not much is known about TiPARP. This study aimed to characterize the regulation of TiPARP by AHR, PDGFR, and ERα, and investigate potential receptor interplay. Gene expression studies revealed that coactivation of AHR and PDGFR can enhance TiPARP expression after 3 h relative to activation of either receptor pathway alone. Gene expression and ChIP studies demonstrated that while co-activation of AHR and ER enhanced AHR, ARNT, and ERα recruitment to the regulatory region of TiPARP, TiPARP mRNA levels were not potentiated by co-activation relative to activation of either pathway. Dissection of the 5’ regulatory region of TiPARP using reporter gene assays revealed that a putative AHRE cluster and an ERE half-site were functional. Lastly, overexpression of TiPARP with an estrogen-responsive reporter revealed that TiPARP can repress ERα signalling and requires its catalytic activity.
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The role of estrogen receptor-Alpha 36 in the membrane effect of 17Beta-estraChaudhri, Reyhaan Ali 27 August 2014 (has links)
Breast cancer is a heterogeneous disease that afflicts all patients differently, and therefore requires individualized treatment depending on a large variety of factors. Several methods of classification exist to divide patients into meaningful groups in order to better personalize their treatment regimens. Healthcare is evolving into more use of personalized treatments that can more effectively treat patients on an individual level, rather than by using more generalized treatments that may not prove effective in all patients. In addition, personalized treatment also aims to reduce adverse effects, while increasing effectiveness. Estrogen receptor (ER) status is one such method of grouping breast cancer patients into different treatment groups. Based on stage diagnosis and determination of receptor status, initial treatments such as surgery or radiotherapy may be used. Standard chemotherapy is another method, however, side effects may vary among patients and may be quite adverse. Other treatments include hormone or receptor blocking. This thesis has identified an alternatively spliced variant of classical ERα that resides in the plasma membrane of breast cancer cells and plays a major role in rapid signaling by estrogen. The overall aim of this thesis was to examine the role of the membrane receptor for 17β-estradiol (E2) in breast cancer that enhances breast tumor aggressiveness and to evaluate the mechanisms by which it functions. The general hypothesis was that nonclassical estrogen signaling through the proposed membrane-associated ER, ERα36, can promote breast tumor aggressiveness by enhancing cell survivability while altering expression of angiogenic and metastatic factors. This work examined the mechanisms of ERα36-dependent signaling in breast cancer cells, and the correlation of ERα36 to clinical outcome in human breast cancer tissue through histological evaluation. These data provide significant research as they provide a greater understanding of estrogen signaling in breast cancer through ERα36 and its role in tumorigenicity and metastasis. This study also proposes further clinical examination of ERα36, and suggests drug design to target ERα36 followed by preclinical studies to determine if drugs targeting ERα36 would benefit breast cancer patients by reducing tumorigenicity and increasing survival.
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Molecular mechanisms of estrogen action in relation to metabolic disease /Lundholm, Lovisa, January 2007 (has links)
Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.
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Steroid regulation of seasonal territorial aggression in the male song sparrow, Melospiza melodia morphna /Wacker, Douglas W. January 2007 (has links)
Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 91-106).
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