Dissertations / Theses on the topic 'Regulation function'
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Hillier, Stephen Gilbert. "Regulation of ovarian function." Thesis, University of Edinburgh, 1992. http://hdl.handle.net/1842/26607.
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(i) Basic Experimental studies Publications 1-35 deal mainly with the use of cultured rat and marmoset monkey granulosa cells to study endocrine and paracrine mechanisms underlying gonadotrophin action on the ovaries. Primary cell cultures were used to define the roles of FSH and LH in controlling granulosa cell function and to assess the intrafollicular functions of sex steroids and putative nonsteroidal regulatory factors, such as inhibin. A particular contribution was the demonstration that androgens produced by thecal cells exert specific (receptor-mediated) modulation of granulosa cell differentiation - notably expression of aromatase, the enzyme uniquely responsible for oestrogen synthesis. Synthesis of inhibin and expression of messenger RNA species encoding inhibin and activin subunits in granulosa cells were also shown to be under gonadotrophic control and modulated by sex steroids, leading to the suggestion that the androgen/oestrogen and inhibin/activin axes of the ovarian paracrine system are functionally interlinked. (ii) Basic Clinical Studies Publications 36-56 are concerned with in vitro research on 'normal' ovarian tissues obtained from women undergoing elective surgical procedures. Techniques and experience acquired from experimental work on animal ovarian tissues were used to study the regulation of steroid hormone synthesis in human follicular and luteal cells. This work demonstrated that granulosa cells are primary cellular sites of oestradiol biosynthesis in the human ovary. It also confirmed the potential that theca-derived androgens have to modulate FSH-induced granulosa cell function, including aromatase activity and inhibin production. Conversely, androgen production by thecal cells was shown to be promoted by inhibin. Based on these findings it is postulated that an intrafollicular positive feedback loop exists mediated by theca-derived androgen and granulosa-derived inhibin, which may underpin preovulatory follicular 'selection' and oestrogen synthesis in the human menstrual cycle.
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Clay, L. "CDC20 function, regulation and proteolysis." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597750.
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The destruction of mitotic cyclins and other key regulators uses ubiquitin mediated proteolysis controlled via the activation of the ubiquitin ligase the Anaphase Promoting Complex/Cyclosome (APC/C), and its adaptor proteins Cdc20 and Cdh1. The spindle assembly checkpoint coordinates the APC/C with microtubule attachment and sets the timing from NEBD to anaphase. Cdc20 is inactivated by the spindle assembly checkpoint to prevent premature anaphase onset. Once the spindle assembly checkpoint is satisfied, Cdc20 can be released and activate the APC/C. However, cyclin A is degraded independently of the spindle assembly checkpoint before cyclin B1 and the anaphase inhibitor Securin. How Cdc20 can target different substrates for degradation at different times during mitosis is not yet clear. Using live-cell imaging and RNA interference and immunofluorescence techniques, I have studied the degradation of endogenous and ectopicly expressed APC/C substrates in cells with reduced Cdc20 levels. In this dissertation, I show that cyclin A degradation strongly depends on Cdc20, whereas cyclin B1 and Securin degradation do not. I identified the region of Cdc20 required for cyclin A binding and by mutating this site, I found that Cdc20 was no longer properly localised. I also show that Cdc20 proteolysis in human somatic cells does not require the KEN motif and gone on to find the motif required for Cdc20 degradation. I also show that the function of Cdc20 in the spindle assembly checkpoint can be influenced by the serine/threonine kinase Aurora A. Co-expression of a fluorescently tagged Cdc20 and Aurora A in human somatic cells causes an accelerated progression through mitosis and premature substrate degradation.
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Brandao, Haga Raquel. "Function and regulation of RhoBTB1." Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/function-and-regulation-of-rhobtb1(0904ff24-d566-4987-8c61-440c09854eeb).html.
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Rho GTPases are a family of proteins known to be involved in cytoskeletal regulation and are important for several processes including cell migration, cell polarity, vesicle trafficking and cytokinesis. RhoBTB1 is an atypical member of the Rho GTPase family. It consists of a non-functional GTP-binding domain followed by a proline-rich region and two tandem BTB domains. The only known interacting partner for RhoBTB1 is cullin3, a scaffold protein in ubiquitin ligase complexes. So far RhoBTB1 has not been shown to affect the cytoskeleton and it has no known cellular function. Most Rho GTPases are regulated by GEFs, GAPs, RhoGDIs and post-translational lipid modifications at the C-terminus. However, RhoBTB1 is not regulated by any of these mechanisms. RhoBTB1 has additional domains that could be involved in protein-protein interaction, leading to an alternative mechanism for RhoBTB1 regulation. This project has shown that RhoBTB1 can interact with RhoA and ROCK1 as well as cullin3. The interaction between RhoA and RhoBTB1 was explored since RhoBTB1 has the potential to recruit substrates for ubiquitination by cullin3 complexes. The region of interaction between RhoA and RhoBTB1 was mapped and RhoBTB1 influenced the protein level of RhoA, suggesting that it inhibits RhoA degradation by the proteasome. RhoBTB1 was found to localise diffusely in the cytoplasm or to punctate structures. Knockdown of RhoBTB1 led to a change in cell morphology in a 3D Matrigel matrix, indicating that it influences cell shape in 3D, although it did not alter cell shape on 2D substrata. RhoBTB1 can be phosphorylated by ROCK1 in vitro and the region of interaction between RhoBTB1 and ROCK1 was mapped using ROCK1 deletion mutants. I hypothesize that RhoBTB1 interacts with RhoA to affect its ubiquitination and degradation and hence affects cell morphology in a 3D matrix, and that RhoBTB1 activity is regulated by ROCK1-mediated phosphorylation.
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Berry, David (David A. ). "Glycosaminoglycan regulation of cell function." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/34153.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2005.Includes bibliographical references (p. 252-285).
Glycosaminoglycans (GAGs) are complex polysaccharides that exist both on the cell surface and free within the extracellular matrix. The intrinsic sequence variety stemming from the large number of building blocks that compose this biopolymer leads to substantial information density as well as to the ability to regulate a wide variety of important biological processes. With the recent and progressive emergence of biochemical and analytical tools to probe GAG structure and function, efforts can be taken to understand the role of GAGs in cell biology and in disease in the various physiological locations where GAGs can exist. As a first step to probe the functions of GAGs, the heparin/heparan sulfate-GAG (HSGAG)-fibroblast growth factor (FGF) system was examined. Understanding the role of HSGAGs in inducing FGF2 dimerization led to the development of a novel engineered protein that was found to be effective at promoting functional recovery in stroke. Subsequently, methods to isolate HSGAGs from the cell surface were optimized and the ability of HSGAGs to support FGF signaling was investigated. Cell surface HSGAGs can define the responsiveness of a given cell to FGF1 and FGF2 through multiple receptor isoforms. Stromal cell derived HSGAGs were also identified as critical regulators of tumor cell growth and metastasis, effecting not only FGF2., but also 1-integrin signaling.
(cont.) Other GAGs, including dermatan sulfates, were characterized as modulators of FGFs and vascular endothelial growth factors. Finally, FGFs and HSGAGs were found to have important roles in maintaining epithelial monolayer integrity, with syndecan-l serving as a critical factor in inflammatory bowel disease. In addition to understanding HSGAGs in their normal physiological settings, techniques to internalize them were developed. Poly(3-amino ester)s were found to condense heparin and enable its endocytosis into cells. Internalized heparin is preferentially taken up by cancer cells, which often have a faster endocytic rate than non-transformed cells, and promotes apoptotic cell death. Internalized heparin can also be used as a tool to probe cell function. In Burkitt's lymphoma, poly(3-amino ester)-heparin conjugates served to identify cell surface HSGAGs as an important modulator of cell growth that can be harnessed to inhibit growth. Finally, studies that sought to broaden the scope of GAG biology were undertaken. Cell surface HSGA(:is were identified as mediators of vascular permeability. Furthermore a novel technique to immobilize GAGs was employed. The interactions between GAG and substrate were via hydrogen bonding. Immobilization of GAGs alters their properties, such that they can affect cells in ways distinct from GAGs free in the ECM.
(cont.) Furthermore, immobilized GAGs can regulate cancer cell adhesion, growth and progression, and may offer a new way to regulate the activity of cancer cells. In addition to directly providing new potential therapeutics and drug targets, these studies represent a foundation to enable additional studies of GAG function. Future work harnessing the techniques presented may open new avenues of research and facilitate the development of novel GAG-based therapeutics.
by David Berry.
Ph.D.
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Vespoli, Jessica L. "Genomic Regulation of Clock Function." Kent State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=kent1449500602.
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Tran, Stella Lê Minh. "Foxl2 regulation and function in gonadotropes." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116978.
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Pituitary follicle-stimulating hormone (FSH) is crucial for mammalian reproduction; it regulates gametogenesis and gonadal function. We know that impaired FSH production may leads to infertility, yet the mechanisms controlling FSH synthesis are poorly understood. Intra-pituitary activins stimulate FSHβ subunit (Fshb) gene transcription in gonadotrope cells, the rate-limiting step in FSH hormone synthesis. Studies conducted in immortalized gonadotrope cells indicate that activin A-stimulated Fshb gene transcription is dependent on homologs of Drosophila mothers against decapentaplegic (SMAD) proteins. More recently, the transcription factor forkhead box L2 (FOXL2) was reported to stimulate SMAD/activin A-induced Fshb transcription. Here, I focused on elucidating the mechanisms underlying Foxl2 regulation and function in gonadotrope cells. First, I demonstrated that overexpression of FOXL2 and SMAD 2, 3, and 4 confers activin-responsiveness to the murine Fshb promoter in heterologous cells. Upon activin A induction, FOXL2 synergizes with SMAD proteins to activate the Fshb promoter; this cooperation requires binding of both FOXL2 and SMAD3 (or SMAD4) to DNA. I showed that SMAD3-induction of the Fshb transcript is dependent on endogenous FOXL2 in homologous cells. I identified a proximal putative forkhead binding elements (FBE) and an adjacent SMAD binding element (SBE), that are crucial for FOXL2/SMAD3 induction of murine Fshb promoter-reporter activity. Based on previous data and my results, I propose a model where activins stimulate formation of FOXL2-SMAD2/3/4 complexes that drive murine Fshb transcription by binding to a conserved composite SBE/FBE element within the proximal promoter. FOXL2 plays a critical role in activin A-stimulated murine Fshb transcription in vitro. Next I tested the hypothesis that FOXL2 is required for FSH synthesis in vivo. Using a Cre/lox approach, I generated a conditional knockout (cKO) mouse where Foxl2 is selectively ablated in the anterior pituitary gonadotrope cells. I observed that cKO mice are hypogonadal and sub-fertile in adulthood. I showed that cKO mice exhibit impaired spermatogenesis and folliculogenesis. Indeed, cKO males have decreased sperm counts, whereas cKO females ovulate fewer oocytes during natural estrous cycles. I demonstrated that both male and female cKO mice are FSH-deficient, secondary to diminished pituitary Fshb mRNA production. In Foxl2-depleted primary pituitary cultures, both basal and activin A-stimulated Fshb expression is impaired. These results indicate that gonadotrope-specific FOXL2 is required for selective induction of FSH production in vivo. Besides its role in gonadotrope cells, FOXL2 is also expressed in the pituitary thyrotropes, the perioptic mesenchyme of the developing eyelid and the ovarian granulosa cells. However the mechanisms governing this selective expression have not been described. In order to study Foxl2 transcription, I cloned the murine promoter region of Foxl2. Next, I demonstrated a correlation between promoter CpG methylation status and gene expression, whereby methylation may repress Foxl2 expression in some heterologous cell lines. Our results indicate that Foxl2 is not regulated by its promoter sequence alone and unveil a possible role for CpG methylation in mediating Foxl2 cell-specific gene expression in the mouse. In summary, my thesis work defined a necessary role for pituitary FOXL2 in FSH synthesis and reproduction in vivo. The FSH deficiency observed in our gonadotrope-specific cKO mice is in agreement with the mechanisms describing a role for endogenous FOXL2 in murine Fshb transcription. Collectively, my research on pituitary FOXL2 is part of our unrelenting efforts to investigate the many factors implicated in FSH regulation, and ultimately required for normal reproductive function. This, in turn, may help identify causes of idiopathic infertility or novel drug targets for infertility and contraceptive treatments.L'hormone folliculo-stimulante de l'hypophyse (FSH) est cruciale car elle régule gamétogenèse et fonction gonadique chez les mammifères. Une diminution dans la production de FSH peut mener à l'infertilité, mais les mécanismes contrôlant la synthèse de FSH demeurent incompris. Les activines de l'hypophyse stimulent la transcription du gène FSH sous-unité β (Fshb) dans les cellules gonadotropes; ceci est l'étape limitante dans la synthèse de l'hormone FSH. Les résults provenant de lignée gonadotrope immortalisée indiquent que la transcription de Fshb est stimulée par l'activine A; ceci est dépend des protéines homologues de Drosophila mothers against decapentaplegic (SMAD). Récemment, Forkhead box L2 (FOXL2) a été décrite comme étant un facteur-clé dans la stimulation de la transcription de Fshb induite par les SMADs et l'activine A. Ici, je dissèque les mécanismes expliquant la régulation et fonction de Foxl2 dans les cellules gonadotropes. Tout d'abord, la surexpression de FOXL2 et SMAD 2, 3, et 4 confère une réactivité à l'activine au promoteur du gène murin Fshb dans les cellules hétérologues. Sous stimulation par l'activine A, FOXL2 coopère de façon synergétique avec les SMADs pour activer le promoteur Fshb; cela nécessite que FOXL2 et SMAD3 (ou SMAD4) lient l'ADN. L'l'induction via SMAD3 du gène Fshb dépend de FOXL2 endogène dans les cellules homologues. Un élément proximal forkhead binding element (FBE) et un élément adjacent SMAD binding element (SBE) sont essentiels pour l'induction de l'activité du promoteur-reporter Fshb par FOXL2/SMAD3. Basé sur ces résultats, je propose un modèle où les activines stimulent la formation de complexes FOXL2-SMAD2/3/4 induisant la transcription du gène murinFshb via liaison à un élément SBE/FBE conservé du promoteur proximal. J'ai ensuite testé l'hypothèse que FOXL2 est nécessaire pour la synthèse de FSH in vivo en utilisant une approche Cre/lox: j'ai généré une souris knock-out conditionnelle (cKO) où Foxl2 est sélectivement absent dans les cellules gonadotropes. J'ai observé que les souris cKO sont hypogonadiques et souffrent d'une baisse de fertilité à l'âge adulte. J'ai démontré que la spermatogenèse et la folliculogénèse sont altérées chez les souris cKO. En effet, les cKO mâles ont un nombre diminué de spermatozoïdes, tandis que femelles cKO ovulent moins d'ovocytes pendant leur cycle oestral. J'ai démontré que cKO mâles et femelles sont déficientes en FSH, découlant d'une diminution d'ARN Fshb dans l'hypophyse. Les cultures primaires de cellules hypophysaires où Foxl2 est absent ne réagissent pas à l'activine A : Fshb est diminuée, tant au niveau basal que dans sa réponse au ligand. Ces résultats indiquent que l'expression de Foxl2 dans les gonadotropes est requise pour l'induction sélective de la production de FSH in vivo. Outre son rôle dans les gonadotropes, FOXL2 est également détecté dans les cellules thyrotropes de l'hypophyse, dans la paupière en développement et les cellules granuleuses de l'ovaire. Cependant les mécanismes qui régissent cette expression sélective n'ont pas encore été décrits. Afin d'étudier ce qui contrôle la transcription de Foxl2, j'ai cloné la région du promoteur murin de Foxl2. Ensuite, j'ai démontré une corrélation entre l'état de méthylation des CpGs du promoteur et l'expression des gènes, par lequel la méthylation exerce une inhibition sur le gène Foxl2 dans certaines cellules hétérologues. Mes résultats indiquent que Foxl2 n'est pas seulement contrôlé par la séquence de son promoteur et dévoilent un rôle possible pour la méthylation des CpGs dans la régulation de l'expression spécifique de Foxl2 chez la souris. En résumé, ma thèse définit un rôle nécessaire pour FOXL2 exprimé dans les gonadotropes pour la synthèse de Fshb et FSH, ainsi que la reproduction in vivo. Collectivement, mes recherches sur FOXL2 hypophysaire contribueront à identifier des causes de l'infertilité idiopathique ou encore trouver de nouvelles cibles pharmacologiques.
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Cheng, C. W. "Regulation of endothelial and endometrial function." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597573.
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Angiogenesis is highly regulated during reproduction, as vessel growth, maturation and regression are observed in cyclic endometrium. This thesis investigates the possible regulation of endothelial and endometrial function, mainly focused on Wnt signalling, in angiogenesis and the female reproductive tract. The transcript profiles in a murine model of menstruation were also studied using two independent microarray experiments and platforms, which provide a broader view of molecular processes during menstruation. The major findings of this thesis include: 1) mRNAs encoding many Wnt signalling-related molecules are present in human umbilical vein endothelial cells and female reproductive tissues. 2) Wnt signalling has a role in endothelial cell growth control and this is mediated through cell-cell contact. 3) Wnt signalling is tightly regulated in endothelial cells and endometrium through the balance of positive and negative regulators of Wnt signalling pathway. There is also a tight balance between the canonical pathway and the non-canonical pathway. 4) Transcript levels of genes involved in many molecular processes changed during the time-course of a murine model of menstruation, suggesting that these molecule processes, including immune response, cell growth and maintenance, metabolism, transport and cell-cell interaction, are regulated during menstruation and participate in regulating endometrial function. These results provide further insights into the complexity of endometrial function and offer new therapeutic possibilities for the treatment of gynaecological disease.
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English, Jane Louise. "Cellular regulation of matrix metalloproteinase function." Thesis, University of East Anglia, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247107.
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Raghavan, Srikala. "Connectin function and regulation in Drosophila." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624670.
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BERCLAZ, PIERRE-YVES. "REGULATION OF ALVEOLAR MACROPHAGE IMMUNE FUNCTION." University of Cincinnati / OhioLINK, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1022869185.
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Roberts, Kate. "Regulation of neutrophil function by NAMPT." Thesis, University of Liverpool, 2012. http://livrepository.liverpool.ac.uk/8355/.
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Neutrophils have capacity to cause tissue damage in chronic inflammatory disease. In rheumatoid arthritis (RA) they infiltrate joints, secrete proteases and reactive oxygen species (ROS), and express cytokines. RA neutrophils express NAMPT which is a highly conserved, pleiotropic protein, that catalyses the rate-limiting step of the NAD salvage pathway, but also has cytokine-like activity. NAMPT is elevated in inflammation and exerts pro-inflammatory effects on neutrophils. The aim of this research was to determine the role of NAMPT, as a signalling molecule and as an enzyme, in regulating neutrophil activities of pathological importance. Neutrophils were isolated from the blood of healthy donors and either stimulated with NAMPT or else NAMPT was inhibited (with FK866), in the presence and absence of pro-inflammatory cytokines in vitro. Assays for specific neutrophil functions such as production of ROS, bacterial killing and apoptosis were performed, and expression of cytokines was also examined. Transcriptome sequencing of neutrophils treated with FK866 and TNFα in combination, was carried out to investigate the wider impact of NAMPT inhibition on neutrophil gene expression. NAMPT expression was also examined in control, cytokine treated and RA patient neutrophils. NAMPT had little capacity to prime neutrophils, although it did delay neutrophil apoptosis and stabilise the anti-apoptotic protein Mcl-1. NAMPT inhibition in neutrophils, depleted NAD(P)/H and had effects on neutrophil functions and gene expression. Notably, FK866 decreased ROS production but did not affect the ability of neutrophils to kill bacteria. NAMPT-inhibited neutrophils exhibited decreased activation of signalling pathways and a diminished response to cytokines; transcriptome analysis showed that FK866 decreased TNFα-induced expression of many genes. NAMPT expression was not dynamically regulated in control neutrophils, but in RA patient neutrophils, NAMPT mRNA correlated with TNFα expression in a cohort of patients, and NAMPT protein was elevated in synovial fluid neutrophils compared to those from paired blood. Thus, NAMPT is elevated in activated inflammatory neutrophils and correlates with other markers of inflammation in RA, suggesting that it may be a marker of inflammation in these cells. Also, as a NAD biosynthetic enzyme, NAMPT regulates neutrophil functions and gene products central to RA disease pathology, without affecting bacterial killing capacity. This suggests that inhibition of NAMPT may potentially have the capacity to decrease neutrophil mediated tissue-damage observed in chronic inflammation, without adversely compromising host defence, and thus may be a future treatment option for diseases such as RA.
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Jelic, Marko. "The function of Toc34 and its regulation." Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-14213.
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Li, Cathy Shije 1974. "Function and regulation of histone deacetylase 4." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=98750.
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Histone acetyltransferases and histone deacetylases (HDACs) maintain dynamic acetylation and deacetylation of histories and other proteins in vivo, and are actively involved in the control of gene transcription and other nuclear processes. One mechanism by which functions of these enzymes are regulated operates through differential intracellular compartmentalization. HDAC4, -5, -7 and -9, the four members of class IIa, shuttle between the nucleus and the cytoplasm in a manner dependent on specific phosphorylation stimulated by several known kinases, and these deacetylases possess intrinsic nuclear import and export signals for dynamic nucleocytoplasmic trafficking. The ability to change their intracellular localization implies that class IIa HDACs have some potential functions in different subcellular compartments. To gain additional insights into this, I first focused on studying the function and regulation of HDAC4. As a result, I identified protein kinase D3 as a novel kinase for HDAC4 and found that this kinase physically interacts with HDAC4 and stimulates its nuclear export. Then I tried to purify protein complexes of RFXANK and ANKRA2, two homologous ankyrin-repeat proteins that are known to associate with HDCA4, using the tandem affinity purification (TAP) strategy. The results that I have obtained reveal a novel mechanism for regulating the nuclear export of HDAC4 and suggest that its cytoplasmic localization may also be indicative of potential cytoplasmic functions rather than just for simple sequestration from its nuclear targets.
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Jelić, Marko. "The function of Toc34 and its regulation." [S.l.] : [s.n.], 2003. http://edoc.ub.uni-muenchen.de/archive/00001421.
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Wu, Qun Garris Paul A. "Function and regulation of the dopamine transporter." Normal, Ill. Illinois State University, 1999. http://wwwlib.umi.com/cr/ilstu/fullcit?p9960430.
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Thesis (Ph. D.)--Illinois State University, 1999.Title from title page screen, viewed July 31, 2006. Dissertation Committee: Paul A. Garris (chair), Maarten E.A. Reith, Anthony J. Otsuka, Robert L. Preston, David L. Williams. Includes bibliographical references (leaves 221-242) and abstract. Also available in print.
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Wang, Chunbo. "Structure, function and regulation of TRP channels." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1148676549.
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Pyszniak, Andrew M. "Regulation of LFA-1 (CD11a/CD18) function." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq25139.pdf.
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Lindebro, Maria. "Mechanisms of regulation of dioxin receptor function /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-231-0/.
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Bahram, Fuad. "Post-translational regulation of Myc oncoprotein function /." Uppsala : Dept. of Plant Biology and Forest Genetics, Swedish Univ. of Agricultural Sciences, 2004. http://epsilon.slu.se/a467.pdf.
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Lundgren, Josefin. "Studies of metazoan proteasome function and regulation." Doctoral thesis, Stockholm : Department of molecular biology and functional genomics, Stockholm university, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-496.
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Burnett, Amanda. "Regulation of Neutrophil Function by the Angiopoietins." Thesis, University of Sheffield, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522497.
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Savage, Joshua S. "Protein kinase-dependent regulation of platelet function." Thesis, University of Bristol, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.559232.
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Platelets are essential in the initiation, growth and stabilisation of thrombi in normal haemostasis upon injury to the vasculature, or in cardiovascular disease upon rupture of an atherosclerotic plaque. Protein kinases are a crucial component in platelet signalling pathways, playing a combination of positive and negative regulatory roles. The AGC kinase family contains several known key regulatory kinases in platelet signalling, most notably PKC. PKC is largely considered a positive regulator of platelet function, although recent data suggests that some PKC isoforms play minor negative regulatory roles. Secretion of pro-aggregatory and pro-inflammatory mediators from platelet granules, a process previously shown to be PKC-dependent, is necessary for propagation of activation and for thrombus growth and stability. For this reason, in this study a clinically relevant PKCP inhibitor ruboxistaurin, used in the treatment of diabetic retinopathy, has been demonstrated to be an effective anti-platelet compound acting primarily through the inhibition of secretion. Ruboxistaurin ablated platelet aggregation which could be restored by exogenous ADP, unlike secretion which remained strongly inhibited. Additionally, thrombus formation under flow was significantly reduced in the presence of ruboxistaurin. This promising data suggests there may be potential clinical uses of ruboxistaurin as an anti-thrombotic agent. The mechanism by which PKC regulates granule secretion is yet to be elucidated. Unc13d'inx mice lack Munc13-4, a protein responsible for coordinating components of the secretory complex, possibly directly regulated by or downstream of PKC. Munc13-4 was shown to be absolutely essential for dense granule secretion, and knockdown of the gene caused a reduction in aggregation and thrombus formation, both of which were rescued by exogenous ADP. However, this study also reveals the existence of a Munc13-4 independent pathway, and a novel positive feedback mechanism for u granule release via ADP and P2Y12. The role of another AGC kinase, PKN, had not previously been studied in platelets. It was , hypothesised that, like PKC, PKNl and PKN3, the isoforms identified in platelets, would act as regulatory proteins via secretion and cytoskeletal reorganisation. Using PKNl/3-I- mice, PKN was revealed to be a negative regulator of aggregation, integrin UlIbP3 activation and spreading. The work presented here demonstrates the varied positive and negative roles that protein kinases play in platelet function, including, but by no means exclusively, in secretion. It also reveals a novel ADP-dependent pathway in platelet secretion and demonstrates that a clinically tested PKC inhibitor has potential as a novel anti-thrombotic therapy.
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Witzel, Ini-Isabee. "Investigating the function and regulation of SNIP1." Thesis, University of Bristol, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.529875.
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Janas, Maja. "Novel Regulation of MicroRNA Biogenesis and Function." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10121.
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MicroRNAs are small noncoding RNAs that post-transcriptionally reduce protein output from most human mRNAs by mechanisms that are still obscure. This thesis provides insights into three aspects of microRNA biogenesis and function described below. MicroRNA precursors are excised from primary transcripts by the Microprocessor complex containing Drosha and DGCR8. Although most microRNAs are located in introns of protein-coding and noncoding genes, the mechanisms coordinating microprocessing and splicing are unclear. MiR-211 is a microRNA expressed from intron 6 of melastatin, a suspected melanoma tumor suppressor. We demonstrate that miR-211, and not melastatin, is responsible for the tumor suppressive function of this locus, that Drosha-mediated processing of the miR-211 precursor promotes splicing of melastatin exon 6-exon 7 junctions, and that perturbing 5' splice site recognition by the U1 snRNP reduces Drosha recruitment to intron 6 specifically and intronic microRNA levels globally. Thus we identify a novel physical and functional coupling between microprocessing and splicing. Typically, Agos stabilize mature microRNAs and as a complex stoichiometrically bind to complementary mRNAs. We demonstrate an alternative order of events in which Agos bind and repress pre-formed imperfect microRNA-mRNA duplexes in processing bodies of live cells, and cleave pre-formed perfect microRNA-mRNA duplexes in vitro. Our data support a novel catalytic model whereby Agos first deposit microRNAs onto mRNAs and dissociate, thus priming multiple microRNA-mRNA duplexes for concurrent repression by a single Ago. Despite key roles in development and pathogenesis, effectors and regulators of microRNA-mediated repression are still poorly characterized. An RNAi screen revealed that depletion of ribosomal proteins of either small or large ribosomal subunit dissociates microRNA-containing complexes from mRNAs repressed at translation initiation, increasing their polysome association, translation, and stability relative to untargeted mRNAs. Thus ribosomal proteins globally regulate microRNA function. Another RNAi screen revealed that Akt3 phosphorylates Ago2, which negatively regulates cleavage and positively regulates translational repression of microRNA-targeted mRNAs. Thus Ago2 phosphorylation is a molecular switch between its mRNA cleavage and translational repression activities. The following pages will place these novel insights into biological and disease-relevant context, will describe what was known prior to these studies, and will provide perspectives for future studies.
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Cadman, Chris. "Regulation of the helicase function of PriA." Thesis, University of Nottingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428956.
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Clemett, Delyth A. "5-HTâ†7 receptor regulation and function." Thesis, University of Nottingham, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262781.
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McMullan, Rachel Jane. "Regulation of keratinocyte function by Rho kinase." Thesis, University of Birmingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275126.
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Higham, Andrew Damian. "Neuroendocrine regulation of gastric endocrine cell function." Thesis, University of Liverpool, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266054.
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Finkelstein, Erik I. "Regulation of neutrophil function by toxic aldehydes /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2002. http://uclibs.org/PID/11984.
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Hillwig, Melissa S. "Regulation, function, and evolution of T2 RNases." [Ames, Iowa : Iowa State University], 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3389103.
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Meng, Meng. "Plant UDP-glucose Pyrophosphorylase : Function and Regulation." Doctoral thesis, Umeå : Department of Plant Physiology, Umeå University, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1796.
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Glanz, Anna Nicole. "Regulation of the Antiviral Function of IRF3." University of Toledo Health Science Campus / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=mco1596792904962609.
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Lovewell, Thomas. "A study into the regulation and function of the Autoimmune Regulator (AIRE) Gene." Thesis, University of Sheffield, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500224.
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Lindås, Ann-Christin. "Tripeptidyl-Peptidase II : Structure, Function and Gene Regulation." Doctoral thesis, Uppsala University, Department of Biochemistry, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7345.
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The protein degradation process is of vital importance for the cell to maintain cellular functions. An important enzyme in this process is the multimeric tripeptidyl-peptidase II (TPP II). It removes tripeptides from a free N-terminus of the substrates. TPP II has broad substrate specificity and wide-spread distribution, suggesting that the TPP II gene is a house-keeping gene. However, the levels of both mRNA and TPP II protein varies during different conditions and the TPP II gene promoter was therefore identified and characterized. It is a 215 bp fragment just upstream of the coding sequence. This fragment lacks a TATA-box but contains an initiator, two inverted CCAAT-boxes and an E-box. The CCAAT-boxes and the E-box were found to bind the nuclear factor Y (NF-Y) and upstream stimulatory factor-1 (USF-1) respectively. The CCAAT-boxes appear to be most important for the transcriptional activation. Furthermore, several silencer element were identified further upstream of the 215 bp promoter and the octamer binding factor Oct-1 was found to bind one of these fragments. If Oct-1 is responsible for the inhibition of the transcription of the TPP II gene remains to be investigated. In addition, the substrate specificity was investigated. For this purpose an expression system using Pichia pastoris was developed. The purified recombinant TPP II was found to have the same enzymatic properties as the native enzyme. In order to identify the amino acids involved in the binding of the N-terminus of the substrate, wild-type murine TPP II and four mutants E305Q, E305K, E331Q and E331K were purified. Steady-state kinetic analysis clearly demonstrated that both Glu-305 and Glu-331 are important for this binding as the KMapp is more than 102 higher for the mutants than wild-type. Finally, the pH-dependence for cleavage of two chromogenic substrates was compared for TPP II from different species.
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Holmqvist, Marie. "The Cyanobacterial Uptake Hydrogenase : Regulation, Maturation and Function." Doctoral thesis, Uppsala universitet, Mikrobiell Kemi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-129223.
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With accellerating global warming and pollution problems a change of energy regime is necessary. Solar energy offers a clean and unlimited energy source of enormous potential. Due to it’s intermittenet nature solar energy must be stored - ideally in the chemical bond of a carrier molecule. Hydrogen gas, H2, an energy carrier with water as only emission when used in a fuel cell, is considered to be the choise for the future. In this context cyanobacteria show promising potential as future H2 factories since they can produce H2 from solar energy and water. The main enzymes directly involved in cyanobacterial hydrogen metabolism are nitrogenases and hydrogenases. Cyanobacterial hydrogenases are either uptake hydrogenases or bidirectional hydrogenases and their maturation requires assistance of six maturation proteins and two hydrogenase specific proteases. In this thesis the transcriptional regulation, maturation and function of the cyanobacterial uptake hydrogenases were investigated in the filamentous, heterocyst forming strains Nostoc punctiforme ATCC 29133 and Nostoc sp. strain PCC 7120. Five genes, encoding proteins putatively involved in the maturation of the uptake hydrogenase were identified upstream the known maturation genes. Two transcription factors, CalA and CalB, were found interacting with the stretch of DNA forming the upstream regions of the uptake hydrogenase structural genes and the novel maturation genes. The expression of the uptake hydrogenase were heterocysts specific and the specificity mapped to a short promoter region starting -57 bp upstream the transcription start point. In addition, the function of the uptake hydrogenase was inserted in a metabolic context. Among the proteases, a conserved region was discovered possibly involved in determining the hydrogenase specificity. This thesis has given valuable information about the transcriptional regulation, maturation and function of the uptake hydrogenase in filamentous, heterocystous cyanobacteria and identified new targets for bioengineering of mutant strains with higher H2 production rates.
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Eriksson, Anna S. "Syndecan - Regulation and Function of its Glycosaminoglycan Chains." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-197691.
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The cell surface is an active area where extracellular molecules meet their receptors and affect the cellular fate by inducing for example cell proliferation and adhesion. Syndecans and integrins are two transmembrane molecules that have been suggested to fine-tune these activities, possibly in cooperation. Syndecans are proteoglycans, i.e. proteins with specific types of carbohydrate chains attached. These chains are glycosaminoglycans and either heparan sulfate (HS) or chondroitin sulfate (CS). Syndecans are known to influence cell adhesion and signaling. Integrins in turn, are important adhesion molecules that connect the extracellular matrix with the cytoskeleton, and hence can regulate cell motility. In an attempt to study how the two types of glycosaminoglycans attached to syndecan-1 can interact with integrins, a cell based model system was used and functional motility assays were performed. The results showed that HS, but not CS, on the cell surface was capable of regulating integrin-mediated cell motility. Regulation of intracellular signaling is crucial to prevent abnormal cellular behavior. In the second part of this thesis, the aim was to see how the presentation of glycosaminoglycan chains to the FGF signaling complex could affect the cellular response. When attached to the plasma membrane via syndecan-1, CS chains could support the intracellular signaling, although not promoting as strong signals as HS. When glycosaminoglycans were attached to free ectodomains of syndecan-1, both types of chains sequestered FGF2 from the receptors to the same extent, pointing towards functional overlap between CS and HS. To further study the interplay between HS and CS, their roles in the formation of pharyngeal cartilage in zebrafish were established. HS was important during chondrocyte intercalation and CS in the formation of the surrounding extracellular matrix. Further, the balance between the biosynthetic enzymes determined the ratio of HS and CS, and HS biosynthesis was prioritized over CS biosynthesis. The results presented in this thesis provide further insight into the regulation of HS biosynthesis, as well as the roles of both HS and CS on the cell surface. It is evident, that in certain situations there is a strict requirement for a certain HS structure, albeit in other situations there is a functional overlap between HS and CS.
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Afar, Ronith. "Regulation and function of neuronal nicotinic acetylcholine receptors." Thesis, McGill University, 1993. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=41288.
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Two major subtypes of nicotinic acetylcholine receptors (nAChRs) have been identified in the nervous system. One site is bound by $ alpha$-bungarotoxin ($ alpha$-BGT), while the other has a higher affinity for agonists and does not bind the $ alpha$-toxin. Muscle nAChRs, which also bind $ alpha$-BGT, had been reported to be sensitive to a thymus-derived polypeptide, thymopoietin (TPO). The present work was therefore done to determine whether this agent might also interact with the different nAChR populations in neuronal cells.Initial studies involved thymopentin (TP-5), a 5 amino-acid peptide which may represent the active site of TPO. TP-5 inhibited nicotinic receptor-induced release of catecholamines in bovine adrenal medullary cells in culture, a function mediated through the $ alpha$-BGT-insensitive nAChR. On the other hand, TP-5 did not inhibit either ($ sp3$H) (-)nicotine or ($ sp{125}$I) $ alpha$-BGT binding to rat brain membranes. These results suggested that TP-5 interacted in a non-competitive manner with the $ alpha$-BGT-insensitive neuronal nAChR.
Studies were subsequently done with thymic preparations presumed to be purified TPO ('TPO'), the native polypeptide containing the TP-5 amino acid sequence. In contrast to the effect of TP-5, 'TPO' preparations did not alter nicotinic receptor mediated catecholamine release from neuronal cells in culture. However, 'TPO' preparations selectively decreased ($ sp{125}$I) $ alpha$-BGT binding to brain membranes suggesting an interaction between this polypeptide and $ alpha$-BGT receptors. Quantitative autoradiography revealed that 'TPO' inhibited specific ($ sp{125}$I) $ alpha$-BGT binding uniformly and with similar potency in different brain regions. As $ alpha$-BGT binding sites are highly expressed in the hippocampal formation, primary cultures of fetal rat hippocampal cells were used next to investigate regulation of the $ alpha$-BGT receptor by 'TPO'. 'TPO' caused a dose-dependent and slowly reversible decrease in the density of $ alpha$-BGT receptors. After completion of this work with 'TPO', studies by Quik and coworkers (1993) showed that $ alpha$-Naja toxin (or $ alpha$-cobratoxin) from Naja naja siamensis snake venom was present in the 'TPO' preparations; furthermore, this toxin component appeared to be responsible for the reported effects of 'TPO' on $ alpha$-BGT receptors. Therefore, the above results which had initially been interpreted to occur as a consequence of the interaction of the thymic polypeptide TPO at the nicotinic $ alpha$-BGT site, must now be attributed to the presence of $ alpha$-Naja toxin contaminant in the 'TPO' preparations.
Studies were also undertaken to identify a nicotinic function for $ alpha$-BGT receptors in neuronal cells. Intracellular calcium levels were measured in response to nicotine as recent work using parasympathetic neurons showed that this may represent an $ alpha$-BGT-sensitive response. In contrast to earlier findings, the present work indicates that nAChR-mediated calcium fluxes in cultured chromaffin cells do not reveal an $ alpha$-BGT-sensitive component. These results thus suggest that nicotinic $ alpha$-BGT receptors mediate their response by altering intracellular calcium levels in some but not all neuronal preparations.
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Unterberger, Alexander. "The role of DNMT1 regulation in cellular function." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=92154.
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Disruption of the epigenome and its components is a hallmark of all forms of cancer. Typically observed in cancer is an alteration of the DNA methylation pattern, with silencing of tumour suppressor genes, as well as an increase in DNA methyltransferase 1 (activity or expression). However it has yet to be determined exactly how DNMT1 increases in cancer and how this increase might serve as therapeutic target. This thesis focuses on the regulation of DNMT1 in the cell cycle and the consequences of depleting DNMT1 in cancer cells.During the cell cycle DNMT1 levels increase as the cell enters into S-phase. It has previously been shown that this cyclical regulation of DNMT1 occurs by destabilization of DNMT1 mRNA in G0/G1 through the action of a protein, identified to be the mRNA binding protein AUF1. AUF1 binds a regulator element located in the 3'UTR of DNMT1 mRNA and recruits the exosome, the RNA degradation complex, to degrade it.
When AUF1 is depleted in these cells, DNMT1 mRNA is stabilized which leads to increased DNMT1 protein levels, methyltransferase activity and genomic methylation. The changes of DNMT1 mRNA levels in the cell cycle were determined to occur as an inverse function of AUF1 protein levels. AUF1 levels were observed to decrease in S-phase which lead to increased stability in DNMT1 mRNA. This cell cycle regulation of AUF1 was determined to occur as a function of Rb. Rb actively stabilizes AUF1 protein. Indeed, upon elimination of Rb, AUF1 is degraded through the function of Hsp70 and the proteasome. This consequently leads to an elevation in DNMT1 protein levels which in turn increases genomic methylation levels. Elevated DNMT1 levels resulted in greater association with EZH2, which in turn leads to increased methylation of EZH2 targeted promoters, including p16 and CNR1. This promoter hypermethylation occurred as a function of DNMT1 and EZH2.These observations indicate that regulation of DNMT1 is tied into the cell cycle function of Rb and upon disruption of this system, a characteristic of cancer, site-specific methylation occurs at tumour suppressors, another characteristic of cancer.
Furthermore, we examined the effect of depleting DNMT1 in cancer cells. Upon depletion of DNMT1, a signaling pathway known as the replication arrest/DNA damage checkpoint was induced. Activation of this pathway results in arrest of cell growth and cell cycle blockage and occurred independently of the catalytic activity of DNMT1 and instead responded to the absence of DNMT1. This supports a role for DMNT1 as a negative regulator of the replication arrest/DNA damage checkpoint through the action of interaction with an unknown protein. Moreover, suppression of the replication arrest/DNA damage checkpoint has been determined to be a necessary step in the proliferation of cancer cells. Taken together, the data from this thesis determined that common events in cancer, such as inactivation of Rb, lead to deregulation of DNMT1 mRNA, through AUF1, leading to site-specific methylation of tumour suppressors and could potentially serve to block growth arresting checkpoints like the replication arrest/DNA damage checkpoint. The novel functions of DNMT1, such as cell cycle regulation, site-specific methylation and role in the replication arrest/DNA damage checkpoint discovered in this thesis could serve to help better understand how cancer develops. The results of this thesis could serve to develop novel strategies to target these events and better treat cancer.
L'altération de l'épigénome et de ses composants est une marque caractéristique de tous types de cancer. Une altération des profils de méthylation de l'ADN, associée à une inactivation de gènes suppresseurs de tumeurs ainsi qu'une augmentation de l'(activité/expression) de la méthyltransférase de l'ADN (DNMT1) sont largement observés dans les cancers. Cependant, les causes de cette augmentation de DNMT1 (expression/activité) dans le cancer et l'utilisation potentielle de cette augmentation comme cible thérapeutique n'ont pas encore été déterminées.
Au cours du cycle cellulaire, le niveau de DNMT1 augmente dès lors que la cellule entre en phase S. Il a été montré précédemment qu'une régulation cyclique de DNMT1 se met en place grâce à une déstabilisation de son ARN messager en phase G0/G1 sous l'action d'une protéine non identifiée. Cette protéine a été identifié comme AUF1. AUF1 interagit avec un élément régulateur situé dans la partie 3'-UTR de l'ARNm de DNMT1 et entraîne la dégradation de cet ARNm en recrutant l'exosome, un complexe de dégradation de l'ARN. La déplétion d'AUF1 stabilise l'ARNm de DNMT1 ce qui conduit à une augmentation de l'expression de cette protéine, de son activité méthyltransférase ainsi que de la méthylation du génome. Il a été également montré que le niveau d'expression de l'ARNm de DNMT1 au cours du cycle cellulaire est inversement corrélé à celui de la protéine AUF1. Ce niveau d'AUF1 est diminué en phase S ce qui traduit par une stabilité accrue de l'ARNm de DNMT1. Il a été montré que cette régulation d'AUF1 au cours du cycle cellulaire est fonction de la protéine Rb. Rb stabilise activement la protéine AUF1. En effet, AUF1 est dégradée par l'intermédiaire de la protéine Hsp70 et du protéasome. Cette dégradation a pour conséquence une augmentation du niveau d'expression de DNMT1 lequel conduit à une augmentation du niveau de méthylation du génome. De plus, cette augmentation de DNMT1 résulte en une plus grande association avec la protéine EZH2 entraînant une hyperméthylation de promoteurs de gènes ciblés par EZH2 (ex : p16, CNR1 et PCNA). Ces observations démontrent que la régulation de DNMT1 est étroitement liée aux fonctions de Rb dans le cycle cellulaire. Caractéristique dans les cancers, une rupture de cette relation DNMT1-Rb, entraîne ainsi une méthylation site-spécifique de gènes suppresseurs de tumeurs, une autre caractéristique des cancers.
En parallèle, nous avons étudié l'effet d'une déplétion de DNMT1 dans des cellules cancéreuses. Suite à une déplétion de DNMT1, une voie de signalisation connue comme un point de contrôle de l'arrêt de la réplication/lésions de l'ADN est induite. L'activation de cette voie de signalisation entraîne l'arrêt de la croissance cellulaire et le blocage du cycle cellulaire. L'activation de cette voie répond à l'absence de DNMT1 et de façon indépendante de son activité catalytique. Ceci est en faveur d'un rôle pour DNMT1 de régulateur négatif du contrôle de l'arrêt de la réplication/lésions de l'ADN via l'interaction avec une protéine qui reste encore à identifier. De plus, la suppression des points de contrôle de l'arrêt de la réplication/lésion de l'ADN a été montré comme étant une étape nécessaire à la prolifération des cellules cancéreuses. L'ensemble des données de cette thèse démontre que des événements communs aux cancers, telle que l'inactivation de Rb, peuvent conduire à la dérégulation, via AUF1, de l'ARNm de DNMT1, laquelle entraîne la méthylation site-spécifique de gènes suppresseurs de tumeurs. Cette dérégulation de DNMT1 pourrait potentiellement servir à bloquer les points de contrôle d'arrêt du cycle cellulaire/lésions de l'ADN.
Les nouvelles fonctions de DNMT1, telles que la régulation du cycle cellulaire, la méthylation site-spécifique et le contrôle de la réplication/lésions de l'ADN découverts dans cette thèse devraient permettre de mieux comprendre le développement cancéreux et de développer de nouvelles stratégies thérapeutiques.
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Martin, Richard. "Regulation of SCL expression and function in hematopoiesis." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85582.
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The development of the hematopoietic system occurs in two waves: a first wave of primitive erythropoiesis, which consists in the production of a single lineage, primitive erythrocytes, and a second wave of definitive hematopoiesis, which describes the generation of many specialized blood cell types from common hematopoietic stem cells. Whereas definitive hematopoiesis is fairly well understood, involves signals from the environment and the expression of lineage-specific transcription factors, the molecular mechanisms regulating primitive erythropoiesis remain to be defined. The aim of this thesis was to clarify the roles of the Stem Cell Leukemia (SCL) gene and Vascular Endothelial Growth Factor (VEGF) during primitive and definitive hematopoiesis. Although gene targeting experiments indicate essential roles for VEGF/Flk-1 signaling and SCL at the onset of hematopoiesis, their exact functions remain elusive. This work has revealed that different thresholds of VEGF are required for the migration of hematopoietic precursors from mesoderm to sites of hematopoiesis and for their subsequent expansion. Furthermore, it shows that SCL, a basic helix-loop-helix transcription factor, acts downstream of VEGF signaling to ensure the survival of primitive erythrocytes. During definitive hematopoiesis, conditional knock-out experiments establish a non-redundant role for SCL during erythroid and megakaryocytic differentiation. Yet, it remains unclear whether SCL is essential for commitment to these lineages. Results presented in this thesis suggest that SCL is not involved in commitment to these pathways, but rather acts to consolidate and expand the erythroid and megakaryocytic compartments, following lineage choice. Finally, despite the central role for SCL during hematopoietic development, the mechanisms regulating its tissue specific expression remain unknown. This work provides molecular and functional evidence that demonstrate that the homeodomain-Taken together, this work has elucidated molecular mechanisms which underlie cell fate decisions. It describes how the activity of a master regulator of erythroid differentiation, SCL, is regulated both by signals from the environment and at the transcriptional level, through combinatorial interactions between lineage-specific transcription factors.
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Djakovic, Stevan Nicholas. "Dynamic regulation of proteasome function by neuronal activity." Diss., [La Jolla] : University of California, San Diego, 2010. http://wwwlib.umi.com/cr/ucsd/fullcit?p3398601.
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Thesis (Ph. D.)--University of California, San Diego, 2010.Title from first page of PDF file (viewed May 5, 2010). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 104-122).
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Bassagañas, i. Puigdemont Sònia. "Regulation and function of silayltransferases in pancreatic cancer." Doctoral thesis, Universitat de Girona, 2014. http://hdl.handle.net/10803/285783.
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Changes in the expression of Lewis-type glycan antigens, especially a predominance of sialyl-Lewis x (SLex) structure, and the glycosyltransferases involved in its synthesis, correlate with pancreatic cancer invasive and metastatic capacities. This Doctoral Thesis has focused on the involvement of sialylated determinants on key stages of pancreatic cancer tumourigenesis, such as cell-extracellular matrix adhesion and cell-cell adhesion, and invasion; and also on the influence of glycosylation on the function of membrane glycoproteins involved in these processes, such as α2β1 integrin and E-cadherin.In addition, this study also describes that pancreatic tumour cells take advantage of the inflammatory environment that accompanies the tumour.It shows that proinflammatory cytokines regulate the cell expression of specific sialyltransferase and fucosyltransferase genes that contribute to the biosynthesis of Lewis-type and sialylated determinants, and thus may contribute to accelerate the tumour progression.S’ha descrit que canvis en l’expressió d’antígens glucídics tipus Lewis, especialment un predomini de l’estructura sialil-Lewis x (SLex), així com de les glicosiltransferases implicades en la seva síntesi, correlacionen amb la seva capacitat invasiva i metastàtica. En aquesta Tesi Doctoral s’ha aprofundit en l’estudi de la implicació dels determinants sialilats en etapes clau del procés tumorogènic del càncer de pàncrees, com són els processos d’adhesió cèl·lula-matriu extracel·lular i cèl·lula-cèl·lula, i la invasió, estudiant també la influència de la glicosilació en la funció de glicoproteïnes de membrana involucrades en aquests processos, com la integrina α2β1 i la E-cadherina. Alhora es posa de manifest que les cèl·lules tumorals de càncer de pàncrees treuen profit de les característiques de l’ambient inflamatori que acompanya el tumor, ja que les citoquines presents en l’estroma regulen l’expressió cel·lular dels gens involucrats en la biosíntesi dels antígens tipus Lewis i sialilats.
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Lu, Dan. "ATF3, a stress-inducible gene function and regulation /." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1155740569.
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Van, Kampen Corinne. "Expression, regulation and function of bovine adhesion molecules." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0006/NQ43276.pdf.
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Lindås, Ann-Christin. "Tripeptidyl-peptidase II : structure, function and gene regulation /." Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7345.
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Wånggren, Kjell. "Regulation and function of the human fallopian tube /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-159-3/.
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Van, der Hoek Kylie. "Ovarian macrophages and the regulation of ovarian function /." Title page, table of contents and abstract only Title page, table of contents and abstract only, 2004. http://web4.library.adelaide.edu.au/theses/09PH/09phv2282.pdf.
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Cho, Jun-Hyeong. "Acid-Sensing Ion Channels: Regulation And Physiologic Function." Columbus, Ohio : Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1204658790.
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Port, Martha D. "Regulation of expression and function of neurokine receptors /." Thesis, Connect to this title online; UW restricted, 2008. http://hdl.handle.net/1773/6283.
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Kühnle, Simone [Verfasser]. "Insights into E6AP regulation and function / Simone Kühnle." Konstanz : Bibliothek der Universität Konstanz, 2011. http://d-nb.info/1045840483/34.
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Beliakoff, Jason Allyn. "Regulation of estrogen receptor function by molecular chaperones." Diss., The University of Arizona, 2003. http://hdl.handle.net/10150/289969.
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The estrogen receptor (ER) plays a major role in breast cancer progression, and ER+ tumors respond favorably to hormonal manipulation. The selective estrogen receptor modulator (SERM) tamoxifen (Tam) induces remissions in most ER+ patients. However, acquired resistance is often observed. Tam-resistant breast cancer is sensitive to other antiestrogenic compounds, but resistance to these agents has also been described, illustrating a major limitation to antiestrogen therapy. Therefore, we investigated a ligand-independent approach for treating Tam-resistant breast cancer by targeting the molecular chaperone Hsp90. The ER exists in a multi-protein complex containing Hsp90, which regulates the activity and stability of the receptor. Hsp90 regulates the stability of other proteins relevant to breast cancer, including Akt and Raf-1. The benzoquinone ansamycin antibiotic geldanamycin (GA) and its clinically relevant analog, 17-demethoxy-17-allylaminogeldanamycin (17AAG), bind to Hsp90 and induce the degradation of Hsp90 clients. In these studies, we show that GA depletes ER levels in Tam-resistant cell lines, and the Hsp90 clients Akt and Raf-1. Unexpectedly, Tam inhibited GA-induced degradation of the ER, but not Akt and Raf-1. This effect was consistent in vivo, where ER levels were measured in tumor xenografts growing in Tam-supplemented mice. However, Tam-stimulated tumor growth was inhibited by 17AAG, and tumor Akt and Raf-1 levels were downregulated. Immunoprecipitation experiments showed that Tam does not inhibit GA-induced changes in the ER-chaperone complex, suggesting an alternate mechanism for the inhibition of GA-mediatied ER degradation. Through cell fractionation, immunostaining, and chromatin immunoprecipitation experiments, we have found that the mechanism involves prolonged association of the ER with the DNA in the presence of Tam, which leads to nuclear accumulation of the ER and sequestration from the proteasome. Furthermore, inhibition of GA-induced ER degradation was inhibited by another SERM, Raloxifene, indicating that the effect is not Tam-specific. Based on its ability to downregulate critical signaling proteins involved in breast cancer, including the ER, 17AAG may provide a useful alternative for patients that have failed hormonal therapy. Because SERMs inhibit the degradation of ER protein induced by GA, they may compromise the efficacy of GA on ER activity, and combined therapy should be approached with caution.