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Chauhan, Anuradha. "Cell cycle." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2011. http://dx.doi.org/10.18452/16301.
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Die Zellreplikation ein kontrollierter Prozess aus sequentieller und zeitlich koordinierter Aktivierung und Abbau von Zyklinen, die einen schnellen Übergang zwischen den Zyklusphasen ermöglichen. Dabei ist der Erfolg bei der Ermittlung der wichtigsten Komponenten und Aufgliederung der Schaltmechanismen im Wesentlichen auf die gleichzeitige Anwendung von Modellsystemen wie Hefe, Frosch und Fliege zurückzuführen. Das heutige Verständnis des Zellzyklus muss erweitert werden, um zu überprüfen ob die Erkenntnisse auch auf in-vivo Modelle von Säugetieren wie der Maus zutreffen. Es existieren solche Modelle, die sich auf spezifische Kontrollpunkte oder Übergänge konzentrieren, allerdings noch kein integriertes Modell, in dem der Zellzyklus durch eine Verletzung im Säugetier induziert wird. Das Modellsystem der Leberregeneration bei Nagern wurde gewählt, da es sich durch das am höchsten verbreitete Phänomen der Synchronisation der Zellproliferation auszeichnet. Mit dem Fokus auf die Frage, wie die Zellen durch pro-inflammatorische Signale nach Verletzungen ins Priming in der G1/S Phase eintreten, gingen wir in einen durch Zytokine und Wachstumsfaktoren induzierten Säugetier-Zellzyklus über. Weiterhin wurden mitotische Ereignisse modelliert, die zum Alles-oder-Nichts G2/M Übergang und dem mitotischen Ausgang führen. Wir konzentrieren uns auf die vielversprechende Funktion von Cdh1 in der Zellzykluskontrolle, welches bekanntlich eine Schlüsselrolle in der G1 Phase spielt. Weiterhin haben wir dessen Rolle bei der Verzögerung der G2 Phase untersucht. Wir vermuten eine zentrale Rolle von Cdh1 im Zellzyklus durch die Kontrolle der Dynamik der Zykline. Das Modell ist ein Versuch, die Kernmechanismen der Zellzykluskontrolle bei Säugetieren zu verstehen. Besseres Verständnis der Mechanismen in der Säugetierzelle würde das Studium der Zellphysiologie im Hinblick auf Störungen der humanen Zellzyklusmaschinerie, welche zu Krankheiten wie Krebs führen.Cell replication is a controlled process with sequential and timely activation and degradation of cyclins leading to swift transitions between the phases of the cell cycle. The essential achievement in identifying the key components and in dissecting the mechanisms of the cell cycle circuitry has been attributed to the simultaneous use of model systems like yeast, frogs, and flies. Present understanding of the cell cycle needs to be extended to investigate whether those findings also apply to mammalian in-vivo models like mice. We chose liver regeneration in mammals as the model system because it is the most synchronised cell proliferation phenomenon, where 95\% of the cells simultaneously enter cell cycle. The G1-S phase transition was modelled, focusing on how injury induced pro-inflammatory signals \textit{prime} the cells in G1 phase and consequently both cytokine and growth factor induced pathways lead to further cell cycle progression. The model was further extended to mitotic events leading to the all-or-none G2-M transition and mitotic exit. I focussed on the emerging role of Cdh1 in the mammalian cell cycle. Cdh1 known for its role in G1 phase was further investigated for its role G2 delay. Cdh1 was suggested to be at the core of the cell cycle machinery controlling cyclin dynamics. This model is an attempt in understanding core machinery of the mammalian cell cycle. Better understanding of the cell cycle control system in mammalian cells would enable understanding perturbations of the human cell cycle machinery which lead to diseases like cancers.
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Radmaneshfar, Elahe. "Mathematical modelling of the cell cycle stress response." Thesis, University of Aberdeen, 2012. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=192232.
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Thanky, Niren Rasik. "The mycobacterial cell cycle." Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405727.
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Chaffey, Gary S. "Modelling the cell cycle." Thesis, University of Surrey, 2015. http://epubs.surrey.ac.uk/807189/.
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This thesis may be divided into two related parts. The first of which considers a population balance approach to modelling a population of cells, with particular emphasis on how the cells pass between the G1 and S phases of the cell cycle. In the second part of the thesis a model is described which combines a cell cycle model with a simple Pharmacokinetic/Pharmacodynamic (PKPD) drug model. This model is then discussed in detail. Knowledge of how a population of cancerous cells progress through the cell cycle is vital if the population is to be treated effectively, as treatment outcome is dependent on the phase distributions of the population. Estimates on the phase distribution may be obtained experimentally however the errors present in these estimates may effect treatment efficacy and planning. In this thesis mathematical models are used to explore the factors that effect the phase distributions of the population. In this thesis it is shown that two different transition rates at the G1-S checkpoint provide a good fit to a growth curve obtained experimentally. However, the different transition functions predict a different phase distribution for the population, but both lying within the bounds of experimental error. Since treatment outcome is effected by the phase distribution of the population this difference may be critical in treatment planning. Using an age-structured population balance approach the cell cycle is modelled with particular emphasis on the G1-S checkpoint. By considering the probability of cells transitioning at the G1-S checkpoint, different transition functions are obtained. A suitable finite difference scheme for the numerical simulation of the model is derived and shown to be stable. The model is then fitted using the different probability transition functions to experimental data and the effects of the different probability transition functions on the model's results are discussed. In contrast to the population balance approach a more simplistic compartmental model is also considered. This model results in a system of linear ordinary differential equations which, under specific circumstances may be solved analytically. It is shown that whilst not as accurate as the population balance model this model provides an adequate fit to experimental data with the results for the total cell population lying within the bounds of experimental error. The ODE compartment model is combined with a simple PKPD model to allow a detailed analysis of the equations for this combined model to be undertaken for different drug-cell interactions. These results are then discussed. As a tumour grows many of the cells receive oxygen and nutrients from blood vessels formed within the tumour, these provide a less than ideal supply, resulting in areas that are well perfused, hypoxic and necrotic. In hypoxic regions the lack of oxygen and nutrients limit the cells' growth by increasing their cycle time and also reducing the effects of radiation and chemotherapy. In the conclusion of this thesis the idea of separating a tumour into three regions, normoxic, hypoxic and necrotic is discussed. Each of these regions may then be modelled using three coupled compartments, each of which contain a cell cycle model, modelled using a set of ordinary differential equations. Additionally, the interaction of a simple (PKPD) drug model with these populations of cells may be considered.
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Li, Victor Chun. "The Cell Cycle and Differentiation in Stem Cells." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10536.
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The relationship between cellular proliferation and differentiation is a major topic in cell biology. What we know comes from models of somatic cell differentiation, where it is widely viewed that cycling and differentiation are coupled, antagonistic phenomena linked at the G1 phase. The extension of this view to stem cells, however, is unclear. One potential possibility is that stem cells also tightly link their G1 phase with their differentiation, indicating a similarity between the differentiation of stem cells and the differentiation of more mature somatic cells. On the other hand, stem cells may utilize different mechanisms or adaptations that confer on them some aspect of uniqueness or "stemness." In this case, stem cells will not exhibit the same coupling with the cell cycle as in many somatic cell models. In this thesis, we examined mouse embryonic stem cells (mESCs), a stem cell that is pluripotent and rapidly cycling with a highly condensed G1 phase. Direct extension of the somatic view posits that elongation of their G1 phase to somatic lengths by cyclin-dependent kinase (CDK) activity inhibition should induce or increase differentiation of these stem cells. Evidence supporting this claim has been contradictory. We show that elongation of the cell cycle and elongation of G1 to somatic lengths is fully compatible with the pluripotent state of mESCs. Multiple methods that lengthen the cell cycle and that target CDK activity or that trigger putative downstream mechanisms (i.e. Rb and E2F activity) all fail to induce differentiation on their own or even to facilitate differentiation. These results indicates that the model of linkage between the G1 phase and differentiation in mESCs is incorrect and leads us to propose that "stemness" may have a physiological basis in the decoupling of cell cycling and differentiation. In summary, we provide evidence that there is a resistance of mESCs to differentiation induced by lengthening G1 and/or the cell cycle. This could allow for separate control of these events and provide new opportunities for investigation and application.
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Gauger, Michele Ann Sancar Aziz. "Cryptochrome, circadian cycle, cell cycle checkpoints, and cancer." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,971.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.Title from electronic title page (viewed Dec. 18, 2007). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biochemistry and Biophysics." Discipline: Biochemistry and Biophysics; Department/School: Medicine.
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Gad, Annica. "Cell cycle control by components of cell anchorage /." Stockholm : Division of Pathology, Karolinska institutet, 2005. http://diss.kib.ki.se/2005/91-7140-359-0/.
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Cadart, Clotilde. "Cell size homeostasis in animal cells." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS103/document.
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Le mécanisme d’homéostasie de taille chez les cellules animales est très peu compris actuellement. Cette question est pourtant d’un intérêt majeur car le maintien de l’homéostasie de taille dans une population de cellules prolifératives doit se faire par une coordination entre la croissance et la division. Chez la levure S. pombe, il a ainsi été montré que la taille est une information cruciale pour déclencher l’entrée en mitose (Fantes, 1977). Chez plusieurs bactéries et les cellules filles de la levure S. cerevisiae au contraire, de récentes études ont au contraire montré que l’homéostasie de taille était le résultat d’une addition constante de volume, indépendamment de la taille initiale des cellules (Campos et al., 2014; Soifer et al., 2016; Taheri-Araghi et al., 2015). Ce mécanisme est appelé « adder » et génère une régression des tailles à la moyenne, génération après génération. Ces résultats ont été possibles grâce au développement de techniques permettant la mesure dynamique du volume à l’échelle de la cellule unique et sur plusieurs générations. Une telle mesure est cependant très difficile chez les cellules de mammifère dont le volume fluctue constamment et qui cyclent sur des temps plus longs (environ 20 heures). Pour cette raison, la plupart des approches proposées sont indirectes (Kafri et al., 2013; Sung et al., 2013; Tzur et al., 2009) ou reposent sur une mesure de la masse plutôt que du volume (Mir et al. 2014; Son et al., 2012). Ensemble, ces études ont montré que les cellules de mammifère croissaient de manière exponentielle. Elles ont aussi remis en cause le modèle traditionnel qui proposait que l’homéostasie de taille reposait sur l’adaptation de la durée du cycle et mis en avant un rôle de la régulation de la vitesse de croissance. Cependant, aucun modèle n’a réellement été proposé ou démontré. La nature et l’existence même d’un mécanisme maintenant l’homéostasie de taille des cellules de mammifère est en fait discutée (Lloyd, 2013).Pour caractériser l’homéostasie de taille des cellules de mammifères, nous avons développé une technique permettant pour la première fois la mesure du volume de ces cellules sur des cycles complets (Cadart et al., 2017; Zlotek-Zlotkiewicz et al. 2015). Nous montrons que plusieurs types cellulaires (HT29, MDCK et HeLa) se comportent d’une manière similaire à celle d’un « adder ». Pour tester davantage cette observation, nous induisons artificiellement des divisions asymétriques en confinant les cellules dans des micro-canaux. Nous observons que les asymétries de tailles sont réduites mais pas complètement corrigées au cours du cycle suivant, à la manière d’un « adder ». Pour comprendre comment la croissance et la progression dans le cycle sont coordonnées et génère cet « adder », nous combinons notre méthode de mesure de volume avec un suivi de la progression dans les différentes phases du cycle. Nous montrons que la durée de la phase G1 est inversement corrélée au volume initial des cellules. Cependant, cette corrélation semble contrainte par une durée minimale de G1 mise en évidence lors de l’étude de cellules artificiellement poussées à atteindre de grandes tailles. Néanmoins, même dans cette condition où la modulation de la durée du cycle est perdue, l’observation du « adder » est maintenue. Ceci suggère un rôle complémentaire de la régulation de la vitesse de croissance des cellules. Nous proposons donc une méthode pour estimer théoriquement la contribution relative de l’adaptation de la vitesse de croissance et de la durée du cycle dans le contrôle de la taille. Nous utilisons cette méthode pour proposer un cadre général où comparer le processus homéostatique des bactéries et de nos cellules. En conclusion, notre travail apporte pour la première fois la démonstration que les cellules de mammifères maintiennent l’homéostasie grâce à un mécanisme similaire au « adder ». Ce mécanisme semble impliquer à la fois une modulation de la durée du cycle et du taux de croissanceThe way proliferating mammalian cells maintain a constant size through generations is still unknown. This question is however central because size homeostasis is thought to occur through the coordination of growth and cell cycle progression. In the yeast S. pombe for example, the trigger for cell division is the reach of a target size (Fantes, 1977). This mechanism is referred to as ‘sizer’. The homeostatic behavior of bacteria and daughter cells of the yeast S. cerevisiae on the contrary was recently characterized as an ‘adder’ where all cells grow by the same absolute amount of volume at each cell cycle. This leads to a passive regression towards the mean generation after generation (Campos et al., 2014; Soifer et al., 2016; Taheri-Araghi et al., 2015). These findings were made possible by the development of new technologies enabling direct and dynamic measurement of volume over full cell cycle trajectories. Such measurement is extremely challenging in mammalian cells whose shape constantly fluctuate over time and cycle over 20 hours long periods. Studies therefore privileged indirect approaches (Kafri et al., 2013; Sung et al., 2013; Tzur et al., 2009) or indirect measurement of cell mass rather than cell volume (Mir et al. 2014; Son et al., 2012). These studies showed that cells overall grew exponentially and challenged the classical view that cell cycle duration was adapted to size and instead proposed a role for growth rate regulation. To date however, no clear model was reached. In fact, the nature and even the existence of the size homeostasis behavior of mammalian cells is still debated (Lloyd, 2013).In order to characterize the homeostatic process of mammalian cells, we developed a technique that enable measuring, for the first time, single cell volume over full cell cycle trajectories (Cadart et al., 2017; Zlotek-Zlotkiewicz et al. 2015). We found that several cell types, HT29, HeLa and MDCK cells behaved in an adder-like manner. To further test the existence of homeostasis, we artificially induced asymmetrical divisions through confinement in micro-channels. We observed that asymmetries of sizes were reduced within the following cell cycle through an ‘adder’-like behavior. To then understand how growth and cell cycle progression were coordinated in way that generates the ‘adder’, we combined our volume measurement method with cell cycle tracking. We showed that G1 phase duration is negatively correlated with initial size. This adaptation is however limited by a minimum duration of G1, unraveled by the study of artificially-induced very large cells. Nevertheless, the adder behavior is maintained even in the absence of time modulation, thus suggesting a complementary growth regulatory mechanism. Finally, we propose a method to estimate theoretically the relative contribution of growth and timing modulation in the overall size control and use this framework to compare our results with that of bacteria. Overall, our work provides the first evidence that proliferating mammalian cells behave in an adder-like manner and suggests that both growth and cell cycle duration are involved in size control
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Poplawski, Andrzej. "Cell cycle analysis of archaea." Doctoral thesis, Uppsala University, Department of Cell and Molecular Biology, 2000. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1078.
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In my thesis, the cell cycle analysis of archaea and hyperthermophilic organisms is presented for the first time. Crenarchaea from the genus Sulfolobus were used as a model system. Plow cytometry and light microscopy were applied to investigate the timing and coordination of different cell cycle events. Furthermore, DNA content, nucleoid structure, and nucleoid distribution at different stages during the cell cycle were studied. The Sulfolobus cell cycle was characterized as having a short pre-replication and a long post-replication period. The presence of a low proportion of cells with segregated genomes in the exponentially growing population suggested 3 considerable time delay between termination of chromosome replication and completion of nucleoid partition, reminiscent of the G2 period in eukaryotic cells.
The first available collection of conditional-lethal mutants of any archaeon or hyperthemophile was used to elucidate the coordination of cell cycle events. The studies showed that chromosome replication, nucleoid partition and cell division in Sulfolobus acidocaldarius, which are normally tightly coordinated during cellular growth, could be separately inhibited or uncoupled by mutation.
The ftsZ gene, which is involved in cell division in bacteria and euryarchaea, was isolated from the halophilic archaeon Haloferax mediterranei. Transcriptional start sites were mapped, and putative translation initiation elements were identified. In both the upstream and downstream regions of the ftsZ gene, open reading frames were found to be conserved within the genus Haloferax. Furthermore, at the 3' end of the ftsZ gene, the homologs of the bacterial secE and nusG genes are conserved in almost all euryarchaea analyzed so far. The studies also demonstrated the functional conservation of the FtsZ protein in different archaeal species, as well as between euryarchaea and bacteria.
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Shirazi, Fard Shahrzad. "The Heterogenic Final Cell Cycle of Retinal Horizontal Cells." Doctoral thesis, Uppsala universitet, Medicinsk utvecklingsbiologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-222559.
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The cell cycle is a highly complex process that is under the control of several pathways. Failure to regulate and/or complete the cell cycle often leads to cell cycle arrest, which may be followed by programmed cell death (apoptosis). One cell type that has a variety of unique cell cycle properties is the horizontal cell of the chicken retina. In this thesis we aimed to characterize the final cell cycle of retinal horizontal cells. In addition, the regulation of the cell cycle and the resistance to apoptosis of retinal horizontal cells are investigated. Our results show that the final cell cycle of Lim1-expressing horizontal progenitor cells is heterogenic and three different cell cycle behaviors can be distinguished. The horizontal cells are generated by: (i) an interkinetic nuclear migration with an apical mitosis; (ii) a final cell cycle with an S-phase that is not followed by mitosis, such cells remain with a fully or partially replicated genome; or (iii) non-apical (basal) mitoses. Furthermore, we show that the DNA damage response pathway is not triggered during the heterogenic final cell cycle of horizontal progenitor cells. However, chemically induced DNA damage activated the DNA damage response pathway without leading to cell cycle arrest, and the horizontal progenitor cells entered mitosis in the presence of DNA damage. This was not followed by apoptosis, despite the horizontal cells being able to functionally activate p53, p21CIP1/waf1, and caspase-3. Finally, we show that FoxN4 is expressed in horizontal progenitor cells and is required for their generation. Over-expression of FoxN4 causes cell death in several neuronal retinal cell types, except horizontal cells, where it results in an overproduction. In conclusion, in this thesis, a novel cell cycle behavior, which includes endoreplication not caused by DNA damage and a basal mitosis that can proceed in the presence of DNA damage, is described. The cell cycle and cell survival processes are of particular interest since retinal horizontal cells are suggested to be the cell-of-origin for retinoblastoma.
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Lomazzi, Marina. "Regulation of cell cycle by E2F1 in primary cells." Thesis, Open University, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.397894.
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Giraddi, Rajashekharagouda. "Cell cycle kinetics of mammary stem and progenitor cells." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607789.
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Wang, Li. "CELL CYCLE REGULATION IN THE POST-MITOTIC NEURONAL CELLS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1184254319.
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France, Stephen Andrew. "Transcription and cell cycle control." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340264.
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Sheppard, Catherine Louise. "Phosphodiesterases in the cell cycle." Thesis, University of Glasgow, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392426.
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Zuo, Yuting. "Trichomonas vaginalis cell cycle studies /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/9301.
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Lantela, Daniel. "CUX1 and the Cell Cycle." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=119509.
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CUX1 is a transcription factor implicated in the control of cell proliferation. Over-expression of CUX1 is observed in many human tumors and cancer cell lines. Cells constitutively over-expressing the p110 isoform of CUX1 proliferate faster and spend less time in G1 following quiescence. We studied three aspects of CUX1 function and regulation during the cell cycle. In the first part of this study we investigated how over-expression of p110 CUX1 results in a shortened G1. Using quantitative PCR we showed that over-expression of p110 CUX1 caused an increase in the transcription of DDK genes (cdc7 and Dbf4) upon exit from quiescence. Western blot analysis revealed that p110 CUX1 cells display elevated phosphorylation of MCM2 serine 5 (pS5-MCM2) during quiescence, indicating an increased activity of DDK. This was associated with a faster loading of MCM2 onto the chromatin after re-entry into the cell cycle and a shortening of G1 as shown by FACS. In a set of experiments, we investigated how the phosphorylation of CUX1 by cyclinD1-CDK4 contributes to cell cycle regulation. Electrophoretic mobility shift assay (EMSA) analysis revealed that phosphorylation of a recombinant CUX1 protein (1125-1505) by cyclinD1-CDK4 inhibited its DNA binding while PKA activated it. Another recombinant CUX1 protein (1125-1308), missing the C-terminal repression domains, is activated by cyclinD1-CDK4 and inhibited by PKA. Autoradiography and western blot analysis revealed that cyclinD1-CDK4 phosphorylates CUX1 on S1216 while PKA phosphorylates S1215 and S1216. FACS analyses showed that cells expressing mutant p110 CUX1S1215/1216A decrease in size with extended passages in culture and eventually die by apoptosis, indicating the importance of cyclinD1-CDK4 regulation in maintaining cell size. Thirdly, during mitosis CUX1 appears ~15kDa larger when observed by SDS-PAGE. We wanted to search for any large post translational modifications such as ubiquitin. No such modifications were identified, however, using mass spectrometry we demonstrated that during mitosis CUX1 is phosphorylated on at least twelve residues compared to six during G2.CUX1 est un facteur de transcription impliqué dans la régulation de la prolifération cellulaire. La surexpression de CUX1 est observée dans de nombreuses tumeurs humaines et lignées de cellules cancéreuses. Les cellules qui surexpriment constitutivement l'isoforme p110 de CUX1 prolifèrent plus rapidement et passent moins de temps en G1 après quiescence. Nous avons étudié trois aspects de la régulation de CUX1 au cours du cycle cellulaire. Dans la première partie de cette étude, nous avons analysé le mécanisme par lequel la surexpression de p110 CUX1 conduit à une réduction dans la durée de la phase G1. En utilisant la méthode de PCR quantitative, nous avons montré que la surexpression de p110 CUX1 a augmenté la transcription de gènes DDK (Cdc7 et Dbf4) à la sortie de quiescence. L'analyse par immuno-buvardagea révélé que les cellules p110 CUX1 montrent une phosphorylation élevée de pS5-MCM2 pendant la quiescence, ce qui indique une augmentation de l'activité de DDK. Cette phosphorylation élevée est associée à un chargement plus rapide de MCM2 sur la chromatine après entrée dans le cycle cellulaire et un raccourcissement de la phase G1 tel que mesuré par FACS. Dans un deuxième projet, nous avons étudié l'effet de la phosphorylation de CUX1 par le complexe cyclin D1/CDK4 sur la régulation du cycle cellulaire. Des test de liaison à l'AND ont révélé que la phosphorylation d'une protéine recombinante CUX1 (1125-1505) par cyclinD1-CDK4 inhibeé sa liaison à l'ADN tandis que la PKA l'active. À l'inverse, une autre protéine recombinante CUX1 (1125-1308), qui ne contient pas les domaines répression en C-terminaux, est activée par cyclinD1-CDK4 et inhibée par la PKA. L'autoradiographie et l'analyse par immuno-buvardage ont révélé que cyclinD1-CDK4 phosphoryle la sérine 1216, alors que PKA phosphoryle sur les sérines 1215 et 1216. Les analyses par FACS ont montré que les cellules exprimant un mutant p110 CUX1S1215/1216A passent moins de temps en G1, deviennent progressivement plus petites et finissent par mourir par apoptose. Ces résultats suggèrent que la phosphorylation de CUX1 par le complexe cyclinD1-CDK4 sert à contrôler la taille des cellules. Finalement, au cours de la mitose, CUX1 semble ~ 15 kDa plus grands quand on l'observe par SDS-PAGE. Nous avons vérifié si cette différence de poids moléculaire résultait de modifications post-traductionnelles telles que l'ajout d'un peptide de la famille des ubiquitines. Aucune de ces modifications n'a été identifiée, mais en utilisant la spectrométrie de masse, nous avons démontré que, durant la mitose, CUX1 est phosphorylé sur au moins douze résidus par rapport à six au cours de G2.
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Batsivari, Antoniana. "Studying the cell cycle status during haematopoietic stem cell development." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25802.
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In adults blood stem cells, called haematopoietic stem cells (HSC), give rise to all blood cells throughout life. The origin and biology of HSCs during embryo development has been an intensely studied topic. Definitive HSCs are generated intra-embryonically in the aorta-gonad-mesonephros (AGM) region of the mid-gestation embryo. Recent research revealed that HSCs emerge through multistep maturation of precursors: proHSC → preHSC I → preHSC II → definitive HSC (dHSC). A hallmark of the HSC emergence is the appearance of intra-aortic haematopoietic clusters that are considered to be sites of haematopoiesis. It was shown in vitro that the E11.5 HSCs are slowly cycling compared to progenitor cells. However, cell cycle status and its role during early HSC development remain unclear. Here I used Fucci transgenic mice that enable in vivo visualisation of the cell cycle. Functional and phenotypic analysis showed that in the early embryo the proHSC precursors cycle slowly, whereas committed progenitors are actively cycling. Meanwhile the preHSC I precursors arising in the E10.5 AGM region become more rapidly cycling. They are located closer to the luminal cavity of the dorsal aorta, while their ancestors, the proHSCs, are slowly cycling and are located at base of the clusters. Furthermore, in the mid-gestation embryo the preHSC I become slowly cycling and are closer to the endothelial lining of the aorta, while they give rise to the actively cycling preHSC II that are located to the luminal area of the artery. Finally, definitive HSCs are mainly slowly cycling at this stage like their foetal liver counterparts. As expected, HSCs in adult bone marrow are mainly dormant. The data suggest that transition from one precursor type to another is accompanied by distinct changes in cell cycle profile and that HSCs become progressively quiescent during development. To test the role of cell cycle in HSC maturation, we used inhibitors against signalling pathways known to play important roles in HSC development. Notch inhibitor affected the cell cycle status of haematopoietic precursors, by possibly promoting them to rapidly proliferate and potentially blocking the maturation from preHSC I to preHSC II precursors. Shh antagonist had the opposite effect and enhanced the HSC activity from the preHSC I precursors. Altogether these results suggest that the cell cycle status plays an important role in the HSC development. A better understanding of the molecules that control this process will allow us to optimize the culture condition for generation of functional HSCs in the laboratory.
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Lyman, Rachel C. "Cell cycle control and its modulation in HPV infected cells /." St Andrews, 2009. http://hdl.handle.net/10023/863.
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Ching, Ada Sik-Lun. "Cell cycle studies in Paramecium : effects of abrupt changes of nutritional state on cell cycle regulation." Thesis, University of British Columbia, 1985. http://hdl.handle.net/2429/24595.
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The controls over initiation of DNA synthesis, initiation of cell division, regulation of macronuclear DNA content, and the relationship between cell mass and growth rate were examined in cells growing under nutrient constraint, or in cells experiencing a change in growth conditions through nutritional enrichment (shift-up) or nutritional shift-down.
Reduction in both cell mass and DNA content was achieved by growing Paramecium cells under nutritional limitation in the chemostat. Under the extreme condition in the chemostat, the normally balanced relationship between DNA content and cell mass (Berger, 1984 Kimball, 1967) is uncoupled. The DNA content in these cells is maintained at about 50 units, but cell mass can be as little as 24% of normal. The generation time in these slow growing cells was increased 4 to 5 times that of rapidly growing cells; the growth rate was also reduced by about the same proportion. Nutritional shift-up was done by transferring the chemostat cells to medium of excess food. Similarly, nutritional shift-down was performed by transferring cells either to the chemostat or to exhausted medium.
The timing of DNA synthesis initiation is largely determined in the preceding cell cycle. Although growth rate (protein synthesis rate) responds quickly to the new conditions, the timing of DNA synthesis initiation is not readjusted immediately and reflects that of the parental cell cycle. The rate at which cells enter S phase however, is affected by a reduction in growth rate.
The criteria for DNA synthesis initiation are not determined by cell mass per se. First, cell mass increases to about 180% of the initial G1 value at the time of DNA synthesis initiation following a nutritional shift-up. This value is much greater than that of well-fed controls (118%). However, the increase in cell mass up to the mean time of DNA synthesis initiation and cell division are not significantly different than that observed in well-fed cells. This suggests a mass-related control over initiation of DNA synthesis. Second, cells initiate DNA synthesis even when there is a net decrease in cell mass following nutritional shift-down. Thus, an increase in cell mass per se is not necessary for DNA synthesis initiation. Unlike initiation of DNA synthesis, the regulatory mechanisms determining the macronuclear DNA synthesized reflects solely the current nutrient conditions. Cells in chemostat culture normally maintain about half the normal amount of DNA (about 50 units). Following nutritional shift-up cells synthesize 100 units of DNA instead. Similarly cells synthesize only 50 units of DNA following nutritional shift-down. The amount of DNA synthesized, therefore, is related to the growth rate, and as discussed later, is also related to the commitment point to cell division.
This study also reveals that the point of initiation of cell division is not time-dependent. It does not occur at a fixed duration following the previous fission or the initiation of DNA synthesis. The point of commitment to division occurs at about 95 minutes before fission regardless of growth rate. Analysis of the effects of macronuclear DNA synthesis inhibition in cc1 cells after the transition point for division indicate that cells synthesize 50 units of DNA before the point of commitment to division. This suggests that cells are committed to divide after synthesizing about 50 units of DNA. Following this point, rapidly growing cells will produce 50 units of DNA before fission; whereas slow growers will accumulate an amount proportional to their growth rate. There are reasons to believe that the threshold value of DNA for commitment to cell division may be 41 units instead of 50.Science, Faculty of
Zoology, Department of
Graduate
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Richardson, Deborah Susan. "Drug-induced apoptosis and cell cycle modulation in leukaemia cells." Thesis, Queen Mary, University of London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417928.
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Hosseini, Shirazi Seyed Farshad. "Cell cycle dependency of cisplatin cytotoxicity on ovarian cancer cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0028/NQ36776.pdf.
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Wade, Mark. "p53 independent apoptosis and cell cycle checkpoints in human cells." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251742.
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Lyman, Rachel C. "Cell cycle control and its modulation in HPV infected cells." Thesis, University of St Andrews, 2010. http://hdl.handle.net/10023/863.
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A key effect of human papillomavirus (HPV) infection is to disrupt the normal cell cycle in order to subvert the cellular DNA replication machinery. Morphologically, condylomata induced by high and low risk HPV types cannot be distinguished and many studies have shown that the pattern of viral gene expression is similar in condylomata caused by both high risk and low risk HPV types. Detailed morphological study of cell cycle protein expression has not previously been performed on condylomata infected with low risk HPV types. The findings presented suggest that the mechanisms employed by low risk HPV6 or HPV11 to subvert cellular functions in condylomata acuminata are similar to those employed by high risk HPVs, with the exception of cyclin D1 and p53 protein over-expression. The differences in p53 expression and cyclin D1 expression seen between high and low risk HPV infection, reflect the known differences between high and low risk types and are in agreement with the known differences between high risk and low risk E6 and E7 proteins. PHK transduction studies demonstrated HPV E6 and E7 induce changes in cell cycle protein expression and that there are differences in cell cycle abrogation between HPV6 and HPV16. Disruption of the p53-MDM2 interaction can lead to activation of the p53 pathway. HPV infected lesions almost always contain wild-type p53. The binding of HPV E6 to p53, and its subsequent targeting for degradation, prevents activation of the p53 pathway in HPV infected cells. Cells over expressing HPV genes were treated with Nutlin-3, a MDM2-small molecule antagonist. The findings presented suggest treatment with Nutlin-3 induces cell cycle arrest in cells expressing HPV16 E7 and HPV6 E6 and HPV6 E7. This suggests a potential role for Nutlin-3 in the treatment of HPV infected cells.
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Yildirim, Salih. "Cell cycle responses of glioma stem cells to ionizing radiation." Thesis, University of Sussex, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589993.
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The Cancer Stem Cell (CSC) hypothesis has provided a novel theory of tumorigenesis by suggesting that mechanisms of organogenesis in developmental processes may be aberrantly active in neoplasms. This hypothesis proposes that CSCS within a tumour play the role of stem cells in a tissue. This novel approach not only leads to new insights into the origination of cancer, but also suggests that CSCs may be responsible for the resistance of several cancer types to current therapies. Thus, CSCs may also be targets for novel therapies. This study interrogates the proposed role of Glioma Stem Cells (GSCs) in radioresistance of glioblastoma (GBM), and specifically addresses the cell cycle checkpoint responses of GSCs to ionising radiation (IR). The aims of this project are: to generate GSC cultures from primary and established GBM cell lines, to examine the radiosensitivity of GSCs, to investigate cell cycle and proliferation dynamics of GSCs and to investigate differential cell cycle checkpoint responses of GSCs to IR. In this study, a panel of glioblastoma cell lines was used, which included primary tumour cultures as well as established cell lines. Populations were enriched for GSCs by culturing as neurospheres in serum-free medium, or depleted of GSCs by culturing as adherent monolayers in serum- containing medium. Using flow cytometry, changes in the cell cycle progression of GSCs and non- stem glioma cells (NSGCs) after IR were compared. In contrast to previously published reports, GSCs did not show preferential activation of the G2-M checkpoint. However, in the 3 cell lines studied, GSCs exhibited earlier re-entry to mitosis than NSGCs. Results for G1-S arrest varied between the cell lines. To identify potential mechanisms for the early resumption of the cell cycle in GSCs, expression and phosphorylation of checkpoint proteins and the mitotic entry promoter Plk1 were investigated. The most likely explanation for the early G2/M checkpoint recovery in GSCs was reduced phosphorylation of Chk1. This hypothesis was validated by inhibiting Chk1, which led to an earlier release from IR-induced G2/M arrest in NSGCs, but did not change mitotic re-entry in GSCs. This study presents the first direct investigation of the effects of ionising radiation on cell cycle progression of CSCs. It also provides a detailed comparison of dynamic changes in radiation induced phosphorylation of checkpoint proteins in populations of GSCs and NSGCs. The novel observation that GSC show early release from the G2/M checkpoint is supported by reduced phosphorylation of Chk1 in these cells.
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Thompson, Christopher C. M. "Cell cycle-associated thymidine kinase regulation in friend erythroleukaemia cells." Thesis, University of Ulster, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260517.
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Yiangou, Loukia. "Investigating the role of cell cycle regulators in mesoderm specification." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/276182.
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Mesoderm is one of the three primary germ layers from which the cardiovascular system, muscle and bone originate and derivatives of the mesoderm lineage are affected in a number of pathologies. Therefore, understanding the mechanisms regulating formation of mesoderm is interesting for a diversity of diseases and clinical application. In vivo study of human development beyond gastrulation is technically challenging and the mechanisms controlling mesoderm specification are difficult to study since the maximum number of days allowed to grow human embryos is 14 days. Thus, in this dissertation I use human pluripotent stem cells (hPSCs) as a simplified model of human development. Studies have shown that the cell cycle machinery plays a direct role in the differentiation of endoderm and ectoderm lineages but its role in guiding mesoderm subtype formation remains elusive. In this dissertation, I provide new insights of the importance of the cell cycle regulators in mesoderm specification. I first developed tools such as the FUCCI2A reporter line to isolate cells in the different cell cycle phases and to investigate propensity of mesoderm differentiation. I have shown that the propensity of differentiation into the three mesoderm subtypes lateral plate mesoderm, cardiac mesoderm and presomitic mesoderm varies during the cell cycle phases, with differentiation being more efficient in the G1 and to a lesser extend in G2/M phase. Furthermore, I developed a protocol where cells can be efficiently synchronised in the different cell cycle phases using the G2/M inhibitor nocodazole. Using this tool, I showed that developmental signalling pathways such as BMP and WNT are active in all cell cycle phases indicating that alternative mechanisms are involved in the differentiation process. In order to further explore these mechanisms, I investigated the role of cell cycle regulators controlling the G1 and G2 checkpoint. I have shown that the cell cycle regulators CDK4/6, CDK2, Retinoblastoma phosphorylation and CDK1 are essential for mesoderm subtype formation. Furthermore, I have shown that CDK1 regulates the activity of ERK1/2 signalling, an important pathway for the differentiation process confirming the existence of complex interplays between cell cycle machinery, signalling pathways and transcription factors in mesoderm subtype formation. This knowledge will be useful to further improve protocols for generating mesoderm subtypes from hPSCs for clinical applications such as drug screening, disease modelling and cell based therapy.
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Lundgren, Magnus. "Exploring the Cell Cycle of Archaea." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7848.
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Zakeri, Ghazal. "Prioritization of cell cycle regulated genes." Thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for biologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-23242.
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The cell cycle is an important biological process in which a set of events occurs in a sequential manner progressing to the cell division. Cell cycle is regulated by periodic fluctuations in the expression levels of several genes referred to as cell cycle regulated genes. In this study, we apply machine learning techniques to prioritize a list of candidate genes with respect to being involved in the cell cycle regulation process. We focus on the data obtained from different expression experiments on which partial least squares regression (PLS) models have been previously developed to identify genes with cell cycle dependent expression profiles. The different expression experiments used different synchronization methods to halt the cell cultures, so that each experiment started to measure gene expression values at different cell cycle phases after synchronization. We are mainly interested in genes having cyclic expression profile which is consistent with respect to cell cycle phases within all experiments. Our goal is therefore to develop a method that can identify genes that have consistent cyclic expression profiles across multiple synchronization experiments.We solve the cell cycle related gene prioritization problem through a novelty detection approach using one-class support vector machine. The candidate genes are ranked according to their similarity to the genes with known cell cycle function. After checking the function of the top ranked genes, it is found that most of them are involved in biological processes related to the cell cycle, which is a good indication that our approach is able to prioritize genes with cell cycle function.Keywords: Cell cycle, Partial least squares (PLS), Gene prioritization, one-class support vector machine.
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Bolger, Brendan Stephen. "Cell cycle kinetics in cervical tumours." Thesis, Imperial College London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294984.
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Brown, N. R. "Structural studies of cell cycle proteins." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299526.
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Woollard, Alison. "Cell cycle control in fission yeast." Thesis, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318479.
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Wrighton, Katharine Helen. "TP53 mutation and cell cycle regulation." Thesis, King's College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405794.
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Firby, D. J. "Regulation of the sycamore cell cycle." Thesis, De Montfort University, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304219.
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Crossland, V. M. "Cell cycle specific recruitment of PKCε." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1352790/.
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Protein kinase C (PKC) comprises a family of serine/threonine kinases which play central roles in intracellular signal transduction typically triggered by recruitment to membraneous compartments. The epsilon isoform of PKC (PKCå) has been shown to localize to cell-cell contacts and to the cytokinetic furrow/midbody, indicative of a role in the cell cycle. Both recruitment patterns can be visualized under conditions of PKCå inhibition, which is selectively achieved using a gatekeeper mutant (PKCå-M486A) and the inhibitor NaPP1. Initial studies indicated that interphase and mitotic cells were not distinguished in their capacity for PKCå-M486A recruitment as evidenced by optical trapping experiments. I therefore assessed whether recruitment to the furrow/midbody is a general property reflecting the juxtaposition of two membranes and a cell-cell contact response. I have successfully used fluorescence recovery after photobleaching (FRAP) to distinguish between the localization at the furrow/midbody from that at cell-cell contacts by measuring PKCå-M486A turnover at these two compartments. It is demonstrated that PKCå-M486A has a slower turnover at the furrow/midbody. The distinct kinetic behaviour of PKCå M486A at the furrow/midbody is indicative of other factors contributing to recruitment and/or retention. Sites and domains within PKCå-M486A were therefore assessed for their involvement in this process using a combination of mutagenesis and confocal microscopy. Through these studies I have identified a short motif in the regulatory domain of PKCå-M486A, the inter C1 domain (IC1D), that is in part required for the accumulation of PKCå-M486A at the furrow/midbody. The deletion of this domain (PKCå-ÄIC1D-M486A) prevents the kinase being recruited to the furrow/midbody despite, the recruitment and furrow/midbody localization of the co-expressed PKCå-M486A. Given that the IC1D was previously identified as an actin-binding region, I have assessed the relationship between actin and PKCå-M486A recruitment by manipulating actin polymerization. Using latrunculinA, an inhibitor of F-actin assembly, I have shown that PKCå-M86A and RhoA colocalize and are stabilized in the same compartment in conditions where F-actin is depolymerized. Importantly, the behaviour is observed for both active and inactive PKCε-M486A. This condition may be analogous to a stage in midbody biogenesis and may be evidence of the requirement of F-actin for normal PKCε and RhoA behaviour in cytokinesis. These data show some progress towards understanding the unique behaviour of PKCε at the furrow/midbody and indicate a complex relationship between PKCε, actin and RhoA.
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He, Enuo. "Stochastic modelling of the cell cycle." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:04185cde-85af-4e24-8d06-94b865771cf1.
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Precise regulation of cell cycle events by the Cdk-control network is essential for cell proliferation and the perpetuation of life. The unidirectionality of cell cycle progression is governed by several critical irreversible transitions: the G1-to-S transition, the G2-to-M transition, and the M-to-G1 transition. Recent experimental and theoretical evidence has pulled into question the consensus view that irreversible protein degradation causes the irreversibility of those transitions. A new view has started to emerge, which explains the irreversibility of cell cycle transitions as a consequence of systems-level feedback rather than of proteolysis. This thesis applies mathematical modelling approaches to test this proposal for the Mto- G1 transition, which consists of two consecutive irreversible substeps: the metaphase-to-anaphase transition, and mitotic exit. The main objectives of the present work were: (i) to develop deterministic models to identify the essential molecular feedback loops and to examine their roles in the irreversibility of the M-to-G1 transition; (ii) to present a straightforward and reliable workflow to translate deterministic models of reaction networks into stochastic models; (iii) to explore the effects of noise on the cell cycle transitions using stochastic models, and to compare the deterministic and the stochastic approaches. In the first part of this thesis, I constructed a simplified deterministic model of the metaphase-to-anaphase transition, which is mainly regulated by the spindle assembly checkpoint (the SAC). Based on the essential feedback loops causing the bistability of the transition, this deterministic model provides explanations for three open questions regarding the SAC: Why is the SAC not reactivated when the kinetochore tension decreases to zero at anaphase onset? How can a single unattached kinetochore keep the SAC active? How is the synchronized and abrupt destruction of cohesin triggered? This deterministic model was then translated into a stochastic model of the SAC by treating the kinetochore microtubule attachment at prometaphase as a noisy process. The stochastic model was analyzed and simulation results were compared to the experimental data, with the aim of explaining the mitotic timing regulation by the SAC. Our model works remarkably well in qualitatively explaining experimental key findings and also makes testable predictions for different cell lines with very different number of chromosomes. The noise generated from the chemical interactions was found to only perturb the transit timing of the mitotic events, but not their ultimate outcomes: all cells eventually undergo anaphase, however, the time required to satisfy the SAC differs between cells due to stochastic effects. In the second part of the thesis, stochastic models of mitotic exit were created for two model organisms, budding yeast and mammalian cells. I analyzed the role of noise in mitotic exit at both the single-cell and the population level. Stochastic time series simulations of the models are able to explain the phenomenon of reversible mitotic exit, which is observed under specific experimental conditions in both model organisms. In spite of the fact that the detailed molecular networks of mitotic exit are very different in budding yeast and mammalian cells, their dynamic properties are similar. Importantly, bistability of the transitions is successfully captured also in the stochastic models. This work strongly supports the hypothesis that uni-directional cell cycle progression is a consequence of systems-level feedback in the cell cycle control system. Systems-level feedback creates alternative steady states, which allows cells to accomplish irreversible transitions, such as the M-to-G1 transition studied here. We demonstrate that stochastic models can serve as powerful tools to capture and study the heterogeneity of dynamical features among individual cells. In this way, stochastic simulations not only complement the deterministic approach, but also help to obtain a better understanding of mechanistic aspects. We argue that the effects of noise and the potential needs for stochastic simulations should not be overlooked in studying dynamic features of biological systems.
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Santos, Carlo Steven. "Circadian Control of Cell Cycle Progression." Thesis, Virginia Tech, 2009. http://hdl.handle.net/10919/76987.
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Tumorigenesis is the result of uncontrolled cell growth due to the deregulation of cell cycle checkpoints 1. Period 2 (Per2) is a tumor suppressor that oscillate in expression in a 24-hour cycle 2, 3. Here, we show that Per2 interacts with the tumor suppressor protein p53. Both G1 and G2 checkpoint pathways involve a p53 dependent pathway which can trigger the cell to go through cell arrest or programmed cell death4. Understanding all the mitigating factors involved in regulating cell cycle progression under DNA damage can offer a better idea in how cells become immortal.
Initially discovered through screening of a human liver cDNA library, the novel interaction between p53-Per2 was further documented using co-precipitation. Interestingly, under genotoxic stress conditions, p53 and Per2 were not found to bind which leads us to suspect that Per2 does not affect active p53 which may possibly be due to post translational modifications of its active state. Furthermore we investigated p53's ability to act as a transcription factor in the presence of Per2, showing that the Per2-p53 complex prevents p53 from binding to DNA. This implies that the tetramerization of p53 may also be another factor in Per2's ability to bind to p53. A truncated p53 lacking the last 30 amino acids that theoretically increase p53's ability to form a tetramer showed a drastic reduction in binding to Per2 5, 6. On the other hand, p53 lacking the tetramerization domain showed binding similar to wildtype. Consequently we speculate that the ability of Per2 to modulate p53 and act as a tumor suppressor protein may be dependent on either the post translational modifications of p53 or its oligomeric state.Master of Science
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Kuleszewicz, Katarzyna. "Cell cycle regulation in mammalian oocytes." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/26148.
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An unusual feature of mammalian female germ cells is that they are arrested in meiotic prophase, equivalent to mitotic G2-phase, for an extended period of time. In this thesis I have investigated two aspects of this arrest. First, I examined whether cohesin replenishment is required for the maintenance of chromosome cohesion during protracted meiotic prophase arrest. Nipbl, an evolutionarily conserved protein, is a component of protein complex called kollerin, whose activity in loading cohesin onto chromosomes is necessary for accurate chromosome segregation during mitosis. However, until now its function in mammalian meiosis was unknown. I have showed that Nipbl is present on meiotic chromosomes throughout meiotic prophase in mouse spermatocytes and oocytes and it accumulates at chromosomal axes where it co-localises with cohesin. I employed conditional knockout strategy to inactivate Nipbl gene in mouse oocytes arrested in meiotic prophase. Although functional Nipbl transcripts were efficiently depleted, these oocytes underwent meiotic maturation with unaffected chiasmata and cohesion. Surprisingly, Nipbl-deleted eggs were fertile and the loading of mitotic cohesin containing Rad21 was unaffected in fertilized eggs. Aditionally, these eggs could develop into blastocysts upon parthenogenetic activation, however harbouring a high proportion of cells with misaligned chromosomes. These results suggest that Nipbl is very stable in the oocyte. In the second project we conceived that the maintenance of the cell cycle arrest in primordial oocytes is an important aspect of follicular survival. Previously proposed involvement of the anaphase promoting complex/cyclosome (APC/C), a cell cycle ubiquitin ligase complex in down-regulating the cyclin-dependent kinase activity in fully-grown oocyte led me to inactivate APC/C in dormant oocytes using conditional knockout system. I found that upon APC/C inactivation, primordial follicles were completely depleted before adulthood, within 5 weeks of birth, suggesting that the APC/C activity is required for the survival of primordial oocytes. These results propose the presence of previously unknown mechanism involving APC/C, essential for primordial follicle survival.
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Holt, Liam J. "Combinatorial control of the cell cycle." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2008. 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:3330864.
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Delorme, Marilyne. "Downregulation of ATRX disrupts cell proliferation and cell cycle progression." Thesis, University of Ottawa (Canada), 2008. http://hdl.handle.net/10393/27627.
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ATRX is a chromatin remodelling protein of the SNF2 family of chromatin remodelling proteins. Mutations in the ATRX gene have been shown to cause the ATR-X syndrome, an X-linked mental retardation disorder. ATRX is part of a chromatin-remodelling complex with Daxx that localizes to PML nuclear bodies or pericentromeric heterochromatin and is thought to regulate gene expression. In mice, Atrx inactivation results in embryonic lethality whereas conditional forebrain specific Atrx ablation showed impaired development and disorganization of the cortex. Furthermore, ATRX phosphorylation was shown to be cell cycle dependant, suggesting an important role for ATRX in cell cycle regulation. In this study we investigated the effects of ATRX downregulation in cell culture models, using siRNA transient transfection, a clone expressing an shRNA targeted to ATRX, and Atrxnull MEFs. ATRX downregulated cells showed reduced growth rates and cell cycle defects at the G1 and S phases of the cell cycle. Moreover, ATRX ablation was associated with an altered Rb phosphorylation status and decreased expression of the cyclin A and E2F-1 proteins. Taken together our results suggest that ATRX may play a significant role in cell cycle progression that is pertinent for proper development.
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Jahnke, Ulrike. "Cell cycle de-regulation and cell death in leukaemia chemotherapy." Thesis, Queen Mary, University of London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439424.
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Anderson, Jon E. "Cell cycle regulation in the early porcine embryo /." free to MU campus, to others for purchase, 2000. http://wwwlib.umi.com/cr/mo/fullcit?p9974607.
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Caldon, Catherine Elizabeth Garvan Institute of Medical Research Faculty of Medicine UNSW. "Cell cycle control by ID1 and WT1 in breast cancer cells." Awarded by:University of New South Wales. Garvan Institute of Medical Research, 2007. http://handle.unsw.edu.au/1959.4/33125.
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Loss of proliferative control is a cornerstone of cancer development, induced by deregulation of mitogenic signalling, insensitivity to anti-proliferative signals and direct changes in cell cycle proteins. In breast cancer these alterations are frequently targeted through cyclins D1 and E, leading to defects in G1/S transition. I have investigated the role of two potential pro-proliferative oncogenes in breast cancer, id1 andwt1. Each protein promotes proliferation in distinct contexts, with unique consquences for breast cancer cells. Using a 3D culture model of non-transformed mammary epithelial cells, I identified that id1 undergoes downregulation via rapid proteosomal degradation and cytoplasmic relocalisation during mammary epithelial morphogenesis. Overexpression of Id1 led to an increase in acinar size via an increase in S phase, and wa dependent on the presence of an intact HLH domain in Id1. Co-expression with the proto-oncogene Bcl2 led to a more disorganised acinar structure, indicating that Id1 overexpression primed the cells for further oncogenic insult. Further, Id1 overexpression was unable to increase acinar size in cyclin D1-/- acini, indicating that Id1 is dependent on cyclin D1 for its proliferative effects. Overall these data identified Id1 as capable of altering the proliferation of normal mammary epithelial cells, a crucial step in early breast carcinogenesis. Wt1 was originally identified as a tumour suppressor, but our data lends support to Wt1 acting as an oncogene in breast cancer. Wt1 is expressed highly in a range of breast cancer cell lines, and is strongly regulated by progestins. Using siRNA, we identified that Wt1 is likely to be a molecular intermediary of progestin as the downregulation of Wt1 mimics a subset of progestin effects on cell proliferation and lipid synthesis. Conversely, the overexpression of the major Wt1 isoform, Wt1 (+/+), led to attenuation of progestin-induced differentiation and growth arrest via maintenance of cyclin D1 levels. The effects of Wt1 overexpression were specific to progestins, and did not affect the actions of anti-estrogens or androgens. Consequently the overexpression of Wt1 (+/+) may disrupt the endocrine response in mammary epithelial cells, and contribute to excess proliferation and failure to differentiate during breast oncogenesis.
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Blakemore, Louise Margaret. "Curcumin-induced G2/M cell cycle arrest in colorectal cancer cells." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/9809.
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Curcumin, a diet-derived chemopreventive and chemotherapeutic agent has been shown to induce G2/M cell cycle arrest, and previous studies suggested that microtubule depolymerisation may be linked to M-phase arrest. However, mechanisms involved have not been elucidated and often non-physiological concentrations of curcumin were used. The goal of this study was to characterise in more detail curcumin-induced cell cycle arrest using a panel of human colorectal cancer cell (CRC) lines, HT-29, SW480, HCT116 p53+/+, HCT116 p53-/- and HCT116 p21-/-. Using physiologically relevant concentrations of curcumin (5-10μM), achievable in the gut tissue following oral ingestion, cell cycle analysis showed that treatment for 12 hours results in significant G2/M arrest in all five cell lines. Curcumin treatment significantly increased the number of cells in M phase in 4 out of the 5 lines tested for this duration, and those with microsatellite instability (HCT116) were found to have a higher mitotic index than those with chromosomal instability. Pre-treatment with caffeine abrogated mitotic arrest in these cell lines, indicating the involvement of the ATM/ATR kinases. Activating phosphorylation of the Chk1 kinase was increased and total protein levels of CDC25C reduced, further implicating the DNA damage pathway in the induction of arrest. Higher levels of HSP70 were also found, indicating proteotoxic stress such as proteasomal inhibition. Image analysis revealed impaired mitotic progression, and significantly higher levels of mitotic spindle abnormalities following curcumin treatment. Aurora B mislocalisation and significantly lower levels of centrosomal separation were found in the HCT116 p53+/+ line. Furthermore, the high levels of pH2A.X staining seen in curcumin-treated mitotic but not interphase cells suggest that aberrant mitosis may result in DNA damage. This proteotoxic and genotoxic stress incurred following curcumin treatment may contribute to the upregulation of NKG2D ligands on the cell surface, leading to CRC lysis and enhancement of the anti-cancer immune response.
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Izzard, Tanya. "Extracellular matrix and the cell cycle in vascular smooth muscle cells." Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322616.
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Ouertani, A. "Determinants of cell cycle progression in human mammary epithelial MCF12 cells." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1362848/.
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Cancer of the mammary gland is the most common type of cancer in women worldwide, and the vast majority of breast cancers originate from a cluster of malignant cells in the epithelial tissue of the breast, which initially confines the ductal carcinoma in situ. Research has shown that the signalling pathways that increase differentiation and maintain proliferation in normal epithelial cells are of utmost importance for sustaining this barrier against malignant cells. As a model for normal mammary epithelial cells, the MCF-12A cell line was used to determine factors that are required for cell cycle progression of these cells. A discontinuous treatment assay was developed in which the MCF-12A cells were treated with epidermal growth factor (EGF) and insulin at two distinct times to induce cell cycle re-entry. The use of these chemically defined growth factors enabled us to determine that continuous stimulation with mitogenic factors is not required for these cells to re-enter the cell cycle. An initial activation of the MAP kinase pathway and an up-regulation of the transcription factor c-Myc, followed by activation of the PI3K pathway, resulted in full competence to progress into S phase. The order in which the growth factors were applied, and thus the sequence in which the subsequent proteins were triggered, was of great importance for successful S phase entry. We found that estradiol (E2) was unable to induce the factors necessary for cell cycle progression. Furthermore, we report for the first time that E2 did not affect estrogen-regulated genes which normally are under the control of a ligand-bound estrogen receptor (ER). We suggest that the mechanism by which the ligand-activated ER usually interferes with the estrogen responsive element in the promoter region of the target genes is defective in the MCF-12A cell line. The results presented here may contribute to new approaches in chemotherapy, taking advantage of the diverse molecular mechanism in place for cell cycle progression and proliferation in malignant cells compared to normal mammary epithelial cells.
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Calegari, Federico, and Julieta Aprea. "Bioelectric State and Cell Cycle Control of Mammalian Neural Stem Cells." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-185623.
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The concerted action of ion channels and pumps establishing a resting membrane potential has been most thoroughly studied in the context of excitable cells, most notably neurons, but emerging evidences indicate that they are also involved in controlling proliferation and differentiation of nonexcitable somatic stem cells. The importance of understanding stem cell contribution to tissue formation during embryonic development, adult homeostasis, and regeneration in disease has prompted many groups to study and manipulate the membrane potential of stem cells in a variety of systems. In this paper we aimed at summarizing the current knowledge on the role of ion channels and pumps in the context of mammalian corticogenesis with particular emphasis on their contribution to the switch of neural stem cells from proliferation to differentiation and generation of more committed progenitors and neurons, whose lineage during brain development has been recently elucidated.
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Calegari, Federico, and Julieta Aprea. "Bioelectric State and Cell Cycle Control of Mammalian Neural Stem Cells." Sage-Hindawi, 2012. https://tud.qucosa.de/id/qucosa%3A27972.
Full textAbstract:
The concerted action of ion channels and pumps establishing a resting membrane potential has been most thoroughly studied in the context of excitable cells, most notably neurons, but emerging evidences indicate that they are also involved in controlling proliferation and differentiation of nonexcitable somatic stem cells. The importance of understanding stem cell contribution to tissue formation during embryonic development, adult homeostasis, and regeneration in disease has prompted many groups to study and manipulate the membrane potential of stem cells in a variety of systems. In this paper we aimed at summarizing the current knowledge on the role of ion channels and pumps in the context of mammalian corticogenesis with particular emphasis on their contribution to the switch of neural stem cells from proliferation to differentiation and generation of more committed progenitors and neurons, whose lineage during brain development has been recently elucidated.
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Ashford, Anne Louise. "The role of the protein kinase DYRK1B in cancer cell survival and cell cycle control." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648671.
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Fredlund, Jan O. "The role of polyanimes in cell cycle progression." Lund : Lund University Dept. of Animal Physiology, 1996. http://catalog.hathitrust.org/api/volumes/oclc/38100686.html.
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