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1
Falk, Anna. "Stem cells : proliferation, differentiation, migration /." Stockholm, 2005. http://diss.kib.ki.se/2006/91-7140-497-X/.
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Cheng, Wai. "The relationship between peroxisome proliferator-activated receptors (PPARs) and cell proliferation /." View the Table of Contents & Abstract, 2006. http://sunzi.lib.hku.hk/hkuto/record/B36433937.
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Cheng, Wai, and 鄭蔚. "The relationship between peroxisome proliferator-activated receptors (PPARs) and cell proliferation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B45010614.
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Ashagbley, Anthony J. "Ethanolamine requirement and cell proliferation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq23203.pdf.
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Hooper, Nigel I. "Methylglyoxal, glyoxalases and cell proliferation." Thesis, Aston University, 1987. http://publications.aston.ac.uk/12548/.
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The metabolic function of the glyoxalase system was investigated in (a) the differentiation and proliferation of human tumour cells in vitro, (b) the cell-free assembly of microtubules and (c) in the red blood cells during hyperglycaemia associated with Diabetes Mellitus. Chemically-induced differentiation of human promyelocytic HL60 leukaemia cells to neutrophils, and K562 erythroleukaemia cells, was accompanied by a decrease and an increase in the activity of glyoxalase I, respectively. Growth-arrest of Burkitt's lymphoma Raji cells and GM892 lymphoblastoid cells was accompanied by an increase and a decrease in the activity of glyoxalase I respectively. However, differentiation and growth arrest generally proceeded with an increase in the activity of glyoxalase II. Glyoxalase I activity did not consistently correlate with cell differentiation or proliferation status; hence, it is unlikely that glyoxalase I activity is either an indicator or a regulator of cell differentiation or proliferation. Conversely, glyoxalase II activity consistently increased during cell differentiation and growth-arrest and may be both an indicator and regulator of cell differentiation or proliferation. This may be related to the control of cellular microtubule assembly. S-D-Lactoylglutathione potentiated the cell-free, GTP-promoted assembly of microtubules. The effect was dose-related and was inhibited by glyoxalase II. During assembly, S-D-lactoylglutathione was consumed. This suggests that the glyoxalase system, through the influence of S-D-lactoylglutathione, may regulate the assembly of microtubules in cellular systems The whole blood concentrations of methylglyoxal and S-D-lactoylglutathione were increased in Diabetes Mellitus. There was no significant difference between red blood cell glyoxalase activities in diabetics, compared to healthy controls. However, insulin-dependent diabetic patients with retinopathy had a significantly higher glyoxalase I activity and a lower glyoxalase II activity, than patients without retinopathy. Diabetic retinopathy correlated with high glyoxalase I activity and low glyoxalase II activity and suggests the glyoxalase system may be involved in the development of diabetic complications.
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Ellison, David William. "Cell proliferation, cell death, and differentiation in gliomas." Thesis, University of Southampton, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295912.
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Petersen, Cecilia. "Paracrine regulation of Sertoli cell proliferation /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-443-7/.
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Zhang, Jiao, and 张姣. "Regulation of cell proliferation and modulation of differentiation in human induced pluripotent stem cell-derived mesenchumal stem cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B49617503.
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Functional mesenchymal stem cells (MSCs) derived from human induced pluripotent stem cells (iPSCs) may represent an unlimited cell source with superior therapeutic benefits for tissue regeneration to somatic tissue, such as bone marrow (BM)-derived MSC. In the first part of this project, I investigated whether the differential expression of ion channels in iPSC-MSCs was responsible for their higher proliferation capacity than that of BM-MSCs. The expression of ion channels for K+, Na+, Ca2+ and Cl- currents was assessed by reverse transcription-polymerase chain reaction (RT-PCR). The functional role of these ion channels were then verified by patch clamp experiments to compare the electrophysiological properties of iPSC-MSCs versus BM-MSCs. I detected significant mRNA expression of ion channel genes including KCa1.1, KCa3.1, KCNH1, Kir2.1, SCN9A, CACNA1C and Clcn3 in both human iPSC-MSCs and BM-MSCs; while Kir2.2 and Kir2.3 were only observed in human iPSC-MSCs. Furthermore, I identified five types of currents (BKCa, IKDR, IKir, IKCa and ICl) in iPSC-MSCs, while only four of them (BKCa, IKDR, IKir and IKCa) were observed in BM-MSCs. The rate of cell proliferation was 1.4 fold faster in iPSC-MSCs as compared to BM-MSCs. Interestingly, the proliferation rate of human iPSCMSCs was significantly reduced when inhibiting IKDR with shRNA and hEAG1 channel blockers, 4-AP and astemizole. Though to a lesser extent, the proliferation rate of human BM-MSCs also decreased by IKDR blockage. These results demonstrated that hEAG1 channel plays a crucial role in controlling the proliferation rate of human iPSC-MSCs but to a lesser extent in BM-MSCs.
Next, I examined whether forced expression of a transcription factor- myocardin in iPSC-MSC using viral vectors (adenovirus or lentivirus) can further enhance their trans-differentiation to cardiomyocytes and improve their electrophysiological properties for cardiac regeneration. My results on RT-PCR and immunofluorescent staining revealed that myocardin induced the expression of several cardiac and smooth muscle cell markers, including α-MHC, cTnT, GATA4, α-actinin, and cardiac MHC, smooth muscle cell markers MYH11, calponin, and SM α-actin, but not the more mature cardiac markers such as β-MHC and MLC2v in iPSC-MSCs. These findings indicate that forced expression of myocardin in iPSC-MSC resulted in partial trans-differentiation into cardiomyocytes phenotype. Furthermore, I also discovered that myocardin altered the electrophysiological properties of iPSC-MSCs when examined by RT-PCR and patch clamp experiments. Forced expression of myocardin in iPSC-MSC enhanced the expression of Kv4.3, SCN9A and CACNA1C, but reduced that of KCa3.1 and Kir 2.2 in iPSC-MSCs. Moreover, BKCa, IKir, ICl, Ito and INa.TTX were detected in iPSC-MSC with ectopic expression of myocardin; while only BKCa, IKir, ICl, IKDR and IKCa were noted in iPSC-MSC transfected with green florescence protein. Furthermore, as measured by multi-electrode arrays recording plate, the conduction velocity of the neonatal rat ventricular cardiomyocytes cocultured iPSC-MSC monolayer was significantly increased after ectopic expression of myocardin. Taken together, I have demonstrated that hEAG1 channel is important in the regulation of iPSC-MSC proliferation and forced expression of myocardin in iPSC-MSC resulted in their partial transdifferentiation into cardiomyocytes phenotype and improved the electrical conduction during integration with mature cardiomyocytes.<br>published_or_final_version<br>Medicine<br>Doctoral<br>Doctor of Philosophy
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Yamak, Fatimah Abir. "GATA4 Partners in Cardiac Cell Proliferation." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/23802.
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Cardiovascular diseases are the leading cause of death in humans throughout the world and “congenital heart defects” (CHDs) are the major cause of infant mortality and morbidity. GATA4 is one of the most critical and intensely studied cardiac transcription factor. It is important for proliferation of cardiomyocytes as well as their survival and adaptive response. The focus of the following thesis was to identify GATA4 mediators and cofactors in cardiac growth. The first part focused on cyclin D2 (CycD2), a growth inducible cell cycle protein. We identified Ccnd2 (gene encoding CycD2) as a direct transcriptional target of GATA4 in postnatal cardiomyocytes and Ccnd2 cardiomyocyte specific overexpression in Gata4 heterozygote mice was able to rescue their heart size and function. We further uncovered a novel regulatory loop between GATA4 and CycD2. CycD2 enhanced GATA4 activation of its target promoters. GATA4 was able to physically interact with CycD2 and its cyclin dependent kinase CDK4 suggesting that GATA4 recruits CycD2/CDK4 to its target promoters. Together, our data uncover a role of CycD2 in the developing and postnatal heart and provide novel insight for the potential of targeting the cell cycle in cardiac therapy. The second part of the project focused on KLF13, a cell specific cofactor of GATA4. KLF13 is a member of the Krϋppel-like transcription factors that are important regulators of cell proliferation and differentiation. Klf13 is highly enriched in the developing heart where it is found in both myocardial and endocardial cells. To determine its role in the mammalian heart, we deleted the Klf13 gene in transgenic mice. Klf13-/- mice were born at 50% reduced frequency and presented with variable cardiac phenotypes. Epithelial-mesenchymal transformation (EMT) was affected in these mice and reduced cell proliferation was evident in the AV cushion. These data uncover a role for a new class of transcription factors in heart formation and point to KLF13 as a regulator of endocardial cell proliferation and a potential CHD causing gene. Future discovery of more cardiac regulators and understanding the molecular basis of CHDs is essential for preventions of these defects and possible development of therapeutic approaches for myocardial repair.
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Cheung, Man-keung, and 張文強. "FBI-1 and choriocarcinoma cell proliferation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193565.
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Gestational trophoblastic disease (GTD) includes a spectrum of diseases that involve abnormal growth of trophoblastic cells inside the uterus. It can range from benign hydatidiform moles (HM) to frankly malignant choriocarcinoma, placental site trophoblastic tumor (PSTT) or epithelioid trophoblastic tumour (ETT).GTD are considered curable if the patient is correctly diagnosed and receive appropriate treatment during the early stage of the disease.
About 15% -30% of hydatidiform moles will develop persistent GTD, but majority of them can usually resolved by surgical intervention and post-operation weekly serial serum β-hCG level monitoring. In contrast, choriocarcinoma is a frankly malignant gestational trophoblastic neoplasm (GTN). Most choriocarcinoma arise from HM but can develop from any pregnancy related events such as ectopic pregnancy, live-birth or stillbirth. Being the most aggressive neoplasm in GTD, choriocarcinoma can develop widespread metastasis and can be fatal.
FBI-1 (Pokemon) is a transcription factor that is often overexpressed in various types of human cancer. We have reported overexpression of FBI-1 in ovarian cancer in association with cell proliferation and invasiveness. Our recent study also suggested that overexpression of FBI-1 in HM was related to subsequent development of gestational trophoblastic neoplasms(GTN).
In this study, we evaluated the role of FBI-1 inchoriocarcinoma cell proliferation. By MTT assay, the proliferation rates of two choriocarcinoma cell lines (JAR and JEG-3) was found to decrease when FBI-1 was downregulated by shRNA approach with statistical significance reached in JEG-3 (p < 0.05). By quantitative real time PCR, the relative levels of a panel of hedgehog pathway related genes, including SHH, SMO, GLI1, GLI2, GLI3, and KIF7 were assessed after knockdown of FBI-1 gene. Sonic hedgehog (SHH) was found to be consistently downregulated in JEG-3 and JAR transfected with FBI-1 shRNA constructs.
In conclusion, FBI-1 may play a role in choriocarcinoma cell proliferation and FBI-1 may be explored as a potential therapeutic target for GTD in the future.<br>published_or_final_version<br>Pathology<br>Master<br>Master of Medical Sciences
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Dunphy, Elizabeth Louise. "TAF1 HAT activity in cell proliferation /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/6250.
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Roshan, Amit. "Stochasticity and order : studies of keratinocyte proliferation." Thesis, University of Cambridge, 2014. https://www.repository.cam.ac.uk/handle/1810/252966.
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A central tenet of stem cell biology has been that proliferating tissues are maintained through a cellular hierarchy comprising of self-renewing stem cells at the apex, multiple lineage-restricted short-lived progenitor cells, and post-mitotic differentiated cells. The wide range of colony sizes in cultured human keratinocytes has been taken to support this hypothesis. Contrary to this model, researchers using genetic lineage tracing in mouse epidermis have inferred a single progenitor population for homeostasis, and a quiescent stem cell population activated upon wounding or genetic mutation. To study the proliferative behaviour of human keratinocytes, I used live imaging in vitro at single cell resolution. This shows two modes of proliferation: Type 1 cell division is stochastic with equal odds of generating dividing or non-dividing progeny, while Type 2 cell division predominantly produces two dividing daughters. These two modes are sufficient to explain the entire range of colony sizes seen after 7-12 days of culture and does not require a spectrum of proliferative ability. This insight provides a simple way to study the effects of external factors on cell fate. To exemplify this, I observed the effects of epidermal growth factor (EGF) and the Wnt agonist R-spondin on proliferation. Here I find proliferation in type 2 colonies changes by changing the proportion of cells dividing. This has implications for the limited success of EGF therapies in clinical trials following burns. To examine clonal contributions to wound repair, I used the mouse oesophageal epithelium which is exclusively composed of, and maintained by, a single progenitor population. I developed a micro-endoscopic wounding technique that produced localised superficial wounds. Here, I found that these wounds healed by uniform contribution from surrounding keratinocytes, demonstrating that reserve stem cells are not obligatory for wound repair. In summary, my work shows that human keratinocytes in vitro have two, and only two, modes of proliferation: a stochastic mode that is insensitive to external EGF signalling, and a EGF-sensitive exponential mode. Additionally, proliferation during wound repair can occur with stochastically dividing progenitors, and does not obligate stem cell recruitment in vivo.
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Kinoshita, Naoko. "REGULATION OF CELL PROLIFERATION USING TISSUE ENGINEERING IN MIN6 CELLS." Kyoto University, 2001. http://hdl.handle.net/2433/150577.
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Ryan, John Joseph. "Stem Cell Factor in Mast Cell and Schwann Cell Proliferation and Hyperplasia." VCU Scholars Compass, 1992. https://scholarscompass.vcu.edu/etd/5273.
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Stem cell factor (SCF) is a recently characterized hematopoietic growth factor capable of stimulating the proliferation and differentiation of many hematopoietic cells, including the mast cell. We have cloned the gene encoding SCF from a cDNA library prepared from NIH 3T3 fibroblasts, and have characterized the ability of recombinant SCF to induce the development of mast cell-committed progenitors (MCCP), found in the mesenteric lymph nodes of mice infected with Nippostrongylus brasiliensis (Nb-MLN), but not naive mice. We have also examined Schwann cells, mast cells, and reproductive tissues for their ability to produce SCF.
We have found that recombinant SCF alone can promote the formation of mast cell colonies from MCCP in methylcellulose. SCF affected not only MCCP proliferation, but could also induce their differentiation to connective tissue phenotype mast cells. SCF was also capable of generating mast cell colonies from precursors found in the peritoneal cavity of naive mice. Unexpectedly, infection of mice with Nippostrongylus caused a loss of the precursors from the peritoneal cavity by 14 days after infection.
Mast cells are found near Schwann cells, and increases in mast cells have been noted concomitant with Schwann cell neoplasia, and nerve damage and repair. Schwann cells from several sources were shown to produce mRNA for SCF, and the protein was also detected on the cell surface by immunofluorescent staining, or as a secretable product in cell-conditioned supernatant. Schwann cells were also analyzed for the ability to produce the receptor for SCF, c-kit. Immunofluorescent staining and polymerase chain reaction (PCR) analysis has shown that a human malignant schwannoma expresses c-kit, while normal human Schwann cells as well as SV-40 transfected, primary neonatal and primary adult rat Schwann cells do not. Thus normal production of SCF could form an autocrine growth loop in some Schwann cell neoplasias which aberrantly express c-kit.
Lastly, rat and human reproductive tissues were examined for expression of the SCF gene, using PCR and northern analysis. We found that SCF is expressed in a differential manner by various maternal and fetal tissues during pregnancy and the menstrual cycle. While rat tissues contained easily detectable SCF mRNA, human tissues appeared to express this gene in a lower quantity.
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Vanhee, Christine. "Influence of shear stress on cell proliferation and on protein kinase C localization in an anchorage-dependent mammalian cell line." Thesis, Georgia Institute of Technology, 1991. http://hdl.handle.net/1853/18866.
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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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Keith, Brooks. "IgE Enhances B Cell-Derived Exosomal Induced T Cell Proliferation." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2909.
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For many years it has been known that the injection of antigen bound to an antibody leads to more than a 1000-fold increase in antigen specific antibody response. This observation holds true for IgE, which is dependent upon CD23 expression, as this enhancement is not present in mice deficient in CD23. It also has been shown that when mice are injected with IgE-antigen complexes also display an increase in antigen specific T cell proliferation. While there are published studies that demonstrate a role for B cell derived exosomes in the activation and proliferation of T cells, none have focused upon the potential role of CD23 as a molecular basis for this phenomenon, at least in the context of allergy and asthma. This thesis provides direct evidence that B cell-derived exosomes possess co-stimulatory molecules, including CD80 and CD86, which act in concert with CD23 to induce T cell proliferation, at least in vitro. This is due to, or enhanced by, the exosomal transfer of the antigen or peptide to T cells. Importantly, the antigen transfer is dependent upon the availability of IgE and the expression of CD23.
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Gan, Lisha. "Corneal cellular proliferation and wound healing /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4505-5/.
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Apperly, James A. "The relationship between proliferation and differentiation during oligodendrocyte development." Thesis, University College London (University of London), 2001. http://discovery.ucl.ac.uk/1349376/.
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How do precursor cells know when it is time to stop dividing and differentiate? The phenomenon of lineage-specific progenitor cells undergoing a limited period of proliferation prior to terminal differentiation is a common theme in multicellular development. Despite this, little is understood about how these two events are co-ordinated during the normal schedule of development. I have studied the question of how proliferation and differentiation are co-regulated in the oligodendrocyte lineage in the rodent optic nerve. Oligodendrocytes are post-mitotic cells that myelinate axons in the vertebrate central nervous system. They develop from precursor cells whose maturation is controlled by a timer, which is an intrinsic property of the cells, that limits proliferation. The timer seems not to control the number of divisions the cell can undergo but rather the length of time during which divisions can occur. Significant effort has been devoted to understanding how the intracellular timer regulates oligodendrocyte development. The timer consists of two components that are modulated by distinct kinds of extracellular signals. Mitogens drive a timing component whose value increases as precursor cells continue to divide. Once this value exceeds a critical threshold, it signals that the proliferative period has elapsed, and hydrophobic signalling molecules trigger an effector component that elicits cell-cycle arrest and differentiation. The value of the timing component is determined by several intracellular molecules whose activities change as the timer runs. One of these molecules is the cell-cycle inhibitor p27: it accumulates in oligodendrocyte precursor cells as they proliferate in culture. When p27 expression is high the precursor cells are more likely to stop dividing and differentiate than when it is low. In oligodendrocyte precursor cells derived from mice that lack p27, the timer runs aberrantly and cell-cycle arrest and terminal differentiation are delayed. It is not understood how the molecular mechanics of the timer control oligodendrocyte development. Does the timer serve to arrest the cell-cycle, with differentiation following by default, or is cell-cycle arrest subordinate to the programme of terminal differentiation? These questions remain unanswered, largely because of a persistent inability to experimentally manipulate the genome of oligodendrocyte precursor cells. The present study was an attempt to overcome these problems and had two aims - first, to devise a reliable system for transfecting oligodendrocyte precursor cells and second, to determine whether the timer primarily controls the timing of cell-cycle arrest. I developed a new retroviral vector that co-expresses p27 and green fluorescent protein (GFP) in precursor cells. The use of GFP allows the identification of living precursor cells that over-express p27, which can then be followed over many days in culture. My findings support previous work showing that p27 plays a role in governing the timing of oligodendrocyte differentiation. They show that over-expression of p27 promotes oligodendrocyte differentiation by advancing the value of the timing component, although it does not promote differentiation if the effector component is inoperative. The cell-cycle time of precursor cells that over-express p27 is dramatically extended, but not stopped. It appears that a firm cell-cycle arrest and entry into a quiescent state may be required to elicit terminal differentiation.
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Miess, H. "Identification of metabolic genes essential for proliferation of clear cell Renal Cell Carcinoma (ccRCC) cells." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1462468/.
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Kidney cancer accounts for 2-3% of adult malignancies with clear cell renal cell carcinoma (ccRCC) being the most common histological subtype (70-80% of cases). Interestingly, ccRCCs show a highly distinct metabolic phenotype making this disease stand out amongst other cancer types. The underlying causes of the aberrant metabolism in ccRCC are not fully understood, but metabolic transformation could provide novel strategies for targeted therapies in this disease. The pVHL tumour suppressor is located on chromosome 3p21, which is frequently lost in ccRCC. pVHL is a negative regulator of the Hypoxia-inducible factor (HIF), which orchestrates the cellular response to oxygen deprivation and might contribute to the aberrant metabolic phenotype of ccRCC cells. In order to reveal metabolic weaknesses in ccRCC, a customised RNAi screen targeting 230 different metabolic enzymes, regulators and nutrient transporters was performed. The screen was performed in a panel of 5 ccRCC pVHL-null cell lines and included their counterparts with reconstituted pVHL, in order to also identify potential vulnerabilities that depend on VHL function. With this approach, several genes that are essential for ccRCC cell viability but dispensable for the survival of non-malignant renal epithelial cells were identified. It was found that ccRCC cell lines are highly sensitive to ablation of components of the glutathione-dependent reactive oxygen species (ROS) detoxification system. Silencing of enzymes of the glutathione biosynthesis pathway or different glutathione peroxidases (GPXs) severely impaired cell viability. One of the precursors of glutathione biosynthesis is glutamate, which is generated from glutamine by glutaminase (GLS). Interestingly, there is evidence that ccRCCs are highly dependent on the MYC oncogene, which induces many enzymes within the glutaminolysis pathway. Indeed, we found that glutamine starvation or chemical inhibition of GLS reduced proliferation and viability of ccRCC cells, confirming the importance of this pathway in ccRCC. In conclusion, the study reported in this thesis provides insight into the metabolic dependencies of ccRCC cells and emphasises the need for a solid anti-oxidant system for ccRCC cell survival and proliferation. Concomitantly, the reliance of ccRCC cells on glutamine and glutathione is a vulnerability that could potentially be exploited for diagnostic and/or therapeutical applications.
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Sutton, Selina Kaye. "How does mitochondrial heteroplasmy affect cell proliferation?" Thesis, University of Canterbury. Biological Sciences, 2006. http://hdl.handle.net/10092/1306.
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Mitochondrial mutations and heteroplasmy have been associated with disease states that result from inadequate cellular energy production. As mitochondrial DNA (mtDNA) encodes many of the polypeptides involved in oxidative phosphorylation (OXPHOS), mtDNA mutations may lower energy production which is required for cell division and sustained ATP synthesis. In order to test the relationship between mtDNA mutations and the rate of cell division, a mammary epithelial cancer cell line, MCF-7, is used as a model. Nine proliferate single cell clones have been isolated from MCF-7. Population doubling times of six single cell clones and the MCF-7 stock have been determined. Clones with distinctly different growth rates were selected for mutational analysis. Growth rates of these clones appeared to be different from each other. Using polymerase chain reaction (PCR) and DNA sequencing, three cases of heteroplasmy have been identified in the mitochondrial genes of the MCF-7 stock and four single cell clones (ATPase C9119T, ND6 T14300G, Cytb G15807A). Heteroplasmy present in the Cytb gene is differs between single cell clones. Differences between the growth rates may be indicative of metabolic variations in these single cell clones. The OXPHOS enzymes encoded by the mutated genes were quantified by standard enzymatic assays. The assays demonstrated significant differences in specific activity between the clones, but were not correlated with mitochondrial heteroplasmy. This thesis determines that the differences in specific activity observed between clones is of nuclear origin.
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Wang, Yanling. "cAMP-Regulated Cell Proliferation in Brown Preadipocytes." Doctoral thesis, Stockholms universitet, Institutionen för molekylär biovetenskap, Wenner-Grens institut, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-88393.
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As a prototypical second messenger, cAMP is involved in the regulation of multiple cell functions. cAMP has a well established inhibitory effect on cell proliferation in smooth muscle and epithelial cell types. However, there is accumulating evidence also for stimulatory effect on proliferation, mainly in endocrine cell types. Mechanisms mediating the cAMP stimulatory effect are not well studied. cAMP, produced via β1-adrenoceptor activation, promotes cell proliferation in brown preadipocytes. Due to the importance of brown adipose tissue in energy metabolism and its implication in the treatment of obesity and type II diabetes, understanding the mechanisms of tissue recruitment has clinical implication for the treatment of these metabolic syndromes. We found that the Erk1/2 family of MAPK, often involved in regulation of cell proliferation, can be activated in response to the stimulation of G protein-coupled receptors, including adrenergic receptors (α1-, α2-, β1- and β3-Adrenoceptors) and mitogenic lysophosphatidic acid (LPA) in primary cultured brown adipocytes. In contrast to the case e.g. in many immortalized cell lines and various primary cultured cells, EGF receptor transactivation is not employed in Erk1/2 activation by any G protein-coupled receptor tested in brown adipocytes. This suggests that EGF receptor transactivation is not an universal mediation process for GPCR activation of MAPK. cAMP-activated cell proliferation in brown preadipocytes is mediated through PKA rather than Epac under serum-free conditions. This effect is independent of PI3K/Akt, mTOR or Erk1/2 MAPK pathways. Differential responses to two different MEK inhibitors PD98059 and U0126 suggested the involvement of a pathway sensitive to PD98059, but independent of the Erk1/2 family of MAPK. At the transcriptional level, by combining microarray and RT-qPCR, we have identified eight genes, under the regulation of cAMP, that may be involved in the further mediation of the cAMP effect on cell proliferation. An understanding of cAMP-induced cell proliferation may be of importance both in metabolic and cancer research.<br><p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Manuscript. Paper 4: Manuscript.</p>
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Sohi, Jasloveleen. "Investigation of factors regulating parathyroid cell proliferation." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=55530.
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Parathyroid glands are responsible for maintaining normal extracellular calcium concentrations through their release of PTH. Calcium and 1,25-(OH)$ rm sb2D sb3$ have been demonstrated to be potent regulators of PTH and CgA synthesis and release. Primary cultures of quiescent bovine parathyroid cells proliferate in response to high concentrations of serum. Next, I examined the role of c-myc in the proliferation of the PT-r cell line, which was cloned from rat parathyroid cells. In order to study the role of c-myc in PT-r cell proliferation more precisely, I used antisense RNA technology to inhibit c-myc mRNA.<br>In summary, my studies have shown that parathyroid cells respond to selected growth factors. This proliferative response involves increased expression of c-myc, c-fos, c-jun and PTHrP. 1,25-(OH)$ rm sb2D sb3$ inhibits the expression or c-myc, and cell proliferation is inhited. The differentiated parathyroid cell expresses high levels of CgA and PTH. However, during proliferation these high levels are not sustained.
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Livingstone, D. "Modelling cell proliferation in a structured tissue." Thesis, University of Reading, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379764.
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Goodlad, J. R. "Germinal centre cell proliferation in murine spleens." Thesis, University of Aberdeen, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241447.
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Germinal centres are dynamic structures in which a number of kinetic processes take place. This thesis was designed to investigate mechanisms whereby one of these kinetic events, germinal centre cell proliferation, is regulated <I>in vivo</I>. In order to achieve this, the proliferative rate of germinal centre cells was measured in C3H/HeN mice under a variety of experimental conditions. In particular, the effect on germinal centre cell proliferation of different classes of antigen and of variously timed doses of the immunosuppressant drug cyclosporin A, was examined. In some experiments, an immunohistochemical technique was employed to demonstrate the distribution of antigen within murine spleens and to correlate the presence of antigen within germinal centres with the germinal centre cell birth rate. The results showed that the type of antigen to which an animal is exposed does determine the subsequent rate of germinal centre cell proliferation. In addition it became apparent that specific regulatory mechanisms were at work within murine germinal centres which either stimulated or inhibited germinal centre cell proliferation depending on the stage of the germinal centre reaction. The proliferative response to antigen was also significantly affected by treatment of the animals with cyclosporin A. The effect of the drug varied depending on the timing of its administration in relation to antigen. These results indicated that T cell derived cytokines play a central role in regulating both stimulation and inhibition of germinal centre cell proliferation. It is proposed that interleukin-4 and interleukin-5 are involved in driving the former, while interferon-γ is a candidate for mediating the latter.
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Noordin, Liza. "Molecular mechanisms of cell proliferation in endometriosis." Thesis, University of Strathclyde, 2011. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=16808.
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Li, Zhaoqi Ph D. Massachusetts Institute of Technology. "Bioenergetics and metabolism of eukaryotic cell proliferation." Thesis, Massachusetts Institute of Technology, 2020. https://hdl.handle.net/1721.1/130658.
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Thesis: Ph. D. in Biochemistry, Massachusetts Institute of Technology, Department of Biology, February, 2021<br>Cataloged from the official PDF of thesis. "February 2021." Vita. Page 179 blank.<br>Includes bibliographical references.<br>Cellular growth and proliferation necessitates the transformation of cell-external nutrients into biomass. Strategies of biomass accumulation across the kingdoms of life are diverse and range from carbon fixation by autotrophic organisms to direct biomass incorporation of consumed nutrients by heterotrophic organisms. The goal of this dissertation is to better understand the divergent and convergent modes of metabolism that support biomass accumulation and proliferation in eukaryotic cells. We first determined that the underlying mechanism behind why rapidly proliferating cells preferentially ferment the terminal glycolytic product pyruvate is due to an intrinsic deficiency of respiration to regenerate electron acceptors. We tested this model across an assorted array of proliferating cells and organisms ranging from human cancer cells to the baker's yeast Saccharomyces cerevesiae. We next determined that a major metabolic pathway of avid electron acceptor consumption in the context of biomass accumulation is the synthesis of lipids. Insights from this work has led to the realization that net-reductive pathways such as lipid synthesis may be rate-limited by oxidative reactions. Lastly, we established the green algae Chlorella vulgaris as a model system to study the comparative metabolism of photoautotrophic and heterotrophic growth. We determined that heterotrophic growth of plant cells is associated with aerobic glycolysis in a mechanism that may be suppressed by light. Collectively, these studies contribute to a more holistic understanding of the bioenergetics and metabolic pathways employed by eukaryotic cells to accumulate biomass and lay the foundation for future studies to understand proliferative metabolism.<br>by Zhaoqi Li.<br>Ph. D. in Biochemistry<br>Ph.D.inBiochemistry Massachusetts Institute of Technology, Department of Biology
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Jarboe, Daniel Lee. "Proliferation and Differentiation of Mast Cell Progenitors." VCU Scholars Compass, 1988. http://scholarscompass.vcu.edu/etd/4940.
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We have identified a late, committed stage in the differentiation of the mast cell progenitor just prior to granulation. This mast cell-committed progenitor (MCCP) differs from the more primitive bone marrow mast cell progenitor in that it is able to proliferate and differentiate in the absence of interleukin-3 (IL-3) when cultured on a monolayer of embryonic skin or 3T3 fibroblasts. The MCCP can be harvested from the mesenteric lymph nodes of mice in their fourteenth day of infection with the rodent hookworm Nippostrongylus brasiliensis and can be cloned in a methylcellulose culture system by supplementing the cultures with fibroblast-conditioned medium from monolayers of embryonic skin or 3T3 fibroblasts. The mesenteric lymph node was virtually uncontaminated with hematopoietic progenitors other than the MCCP.
The MCCP acquires a mucosa! mast cell phenotype when cloned in the presence of IL-3, but begins to take on a connective tissue mast cell phenotype when cloned in the presence of fibroblast conditioned medium. Upon fractionation by size exclusion chromatography, fibroblast conditioned medium contained a novel protein which supported proliferation of the MCCP and a separate granulation factor; thereby, proliferation and granulation can be uncoupled in vitro. These data demonstrate that IL-3 independent proliferation and differentiation of the MCCP does not require cell contact with fibroblasts. T cell-depleted cultures consistently produced higher numbers of mast cells than did nondepleted cultures. IL-3 production in the mesenteric lymph node peaked at day 11 and may instrumental in the transition of the IL-3 dependent progenitor into the MCCP.
When mast cell-deficient SI/SId or W/Wv mice were infected with Nippostrongylus, SI/SId mice, but not W/Wv' mice, produced the MCCP. To determine if these mice make the fibroblast derived factors that support development of the MCCP, monolayers were prepared from skin connective tissues of SI/SId and W/Wv mice, and MCCP from normal mice were cloned in the presence of conditioned medium from these monolayers. Fibroblast conditioned mediurn from monolayers prepared from W/Wv mice, but not SI/SId mice, was able to support the development of mast cell colonies from MCCP.
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Perez, Madrigal Diana. "The role of ERK5 in cell proliferation." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-erk5-in-cell-proliferation(ee569cda-581d-4698-80c0-84f15fe88f53).html.
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The extracellular signal-regulated protein kinase 5 (ERK5), also known as big mitogen-activated protein (MAP) kinase 1 (BMK1), is a non-redundant mitogen-activated protein kinase (MAPK) implicated in mediating the response of cells to mitogens, oxidative and osmotic stresses. The molecular complexity of the ERK5 cascade has been mostly delineated by over-expression studies. For example, like other MAPKs, ERK5 activity increases upon phosphorylation by a MAPK/ERK kinase, namely MEK5. However, the physiological role of ERK5 is not rigorously established by these data. Furthermore, in comparison to the other members of the family, little is known about the downstream targets of ERK5. This constitutes an obstacle for the molecular understanding of the signalling mechanisms that account for the effect of ERK5 activation in vivo. To clarify these issues, I have tested the effect of the conditional loss of ERK5 in primary mouse embryonic fibroblasts (MEFs). My results indicate that ERK5 is required for the proliferation of MEFs, at least in part, by promoting the entry into S phase of the cell cycle. ERK5 suppressed the expression of the cyclin-dependent protein kinase (CDK) inhibitors, p21 and p27. As a result, low-level CDK2 activity detected in ERK5-deficient MEFs correlated with hypo-phosphorylation of the retinoblastoma (Rb) protein and with a defect in G1 to S phase transition of the cell cycle. ERK5 blocks p21 expression by decreasing the stability of the p21 transcript. This process might, at least partially, involve a mechanism implicating c-Myc-induced transcriptional up-regulation of the miR-17-92 cluster. Concerning p27, ERK5 decreases p27 protein stability. The stabilisation of p27 in the absence of ERK5 resulted in the accumulation of the protein in the nucleus. To examine the relevance of my findings in cancer, I tested the effect of pharmacological inhibition of ERK5 in two human breast cancer cell lines, MCF7 and MDA- MB-231, using XMD8-92, a novel potent and selective inhibitor of ERK5. My results show that these cells are dependent on ERK5 to proliferate. Furthermore, I found that incubation of MDA- MB-231 cells with XMD8-92 compromised their ability to invade. In both breast cancer cell lines, ERK5 down-regulates p21 and p27 expression. Together with evidence that cancer patients with poor prognosis display a high-level of expression of components of the ERK5 signalling pathway, these findings support the hypothesis that ERK5 can be a potential target for cancer therapy.
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Cavanagh, Brenton. "Investigating Cell Proliferation in the Nervous System." Thesis, Griffith University, 2017. http://hdl.handle.net/10072/370820.
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Cell proliferation is a strictly regulated process which is preceded by DNA synthesis and results in an increase in the number of new cells. It is essential for the development, regeneration and is upregulated in tumours. Whilst the study of cell proliferation is fundamental for many arms of biomedical investigation, the techniques used in its study have remained unchanged for decades. Neuroscience is one such field where cell proliferation in the adult can be a rare event and where molecular biology techniques are accelerating discoveries. Unfortunately, the limitations of studying cell proliferation have become a constraint in the field. This thesis examines the development of techniques to identify, characterise, quantify and profile proliferative cells in neural tissue. The techniques are provided in the context of a collection of studies that applied the techniques to secure data in a testable framework. The nervous system of the brain and olfactory mucosa were used to develop techniques to investigate cells on a histological and molecular scale. Initial investigation developed and improved tissue processing workflow and techniques to provide the optimal samples for histological analysis. The optical properties of the sample were improved, allowing deeper imaging in thick tissue sections. The embedding of frozen samples was altered to make use of gradients of OCT embedding media that minimised cell lysis. Embedment in the wax polyethelene glycol was used for sectioning at room temperature. Both techniques preserved tissue cytoarchitecture and antigenicity, allowing fluorescent labelling with multiple markers simultaneously in tissues with well conserved ultrastructure. These optimally prepared thick tissue samples provided a means of imaging multiple phenotypes and cell states in a single specimen (multiplexed), rather than multiple replicates of tissue sections, with different markers. The high optical clarity of the section facilitated high resolution 3D image acquisition, using optimised imaging techniques, further increasing the amount of information obtained from a sample set. These histological techniques were applied to the olfactory mucosa and substantia nigra to quantify cell proliferation and neurogenesis. EdU a thymidine analogue was used to label cells during the S-phase of the cell cycle, identifying cells that had undergone proliferation during exposure. It was shown that although neurogenesis was present in the olfactory mucosa, cell proliferation that occurred in the substantia nigra rarely gave rise to cells of a neural lineage. These techniques enabled the development of novel cell quantification methods, using stereology principles. Due to the ease and significantly less fragile nature, the substantia nigra as opposed to the olfactory system, was chosen to develop this technique. By quantifying subtypes of dopaminergic neurons in the substantia nira pars compacta of both the mouse and rat, an unbiased and accurate method of cell estimation was developed. The embedding method, multiple labelling immunofluorescence and serial optical sections obtained from thick specimens enabled significant improvements to stereological assessment. Thus, multiplexed cellular data was accurately quantified in brain tissue. These techniques were used to label multiple cell phenotypes during a defined period of exposure to EdU. This provided a powerful tool to investigate tissue where data on cell division and development was required together with cell – cell interaction of specific cell phenotypes that were labelled fluorescently. Specific tissue regions were quantified accurately and unbiasedly employing the advanced cell estimation technique. Expanding on the ability to effectively label and analyse cellular structures in tissue sections, in-situ, the capability to isolate and extract biomolecules from proliferating cells for analysis was developed. Thus, providing insight into the cellular differences that occur in proliferating cells. The basis of the technique involved the dissociation and fluorescent labelling of samples pre-labelled with EdU. These labelled cells were then isolated using FACS and RNA was then extracted for assessment of quality and analysis. The optimisation of each step was required to conserve the cell integrity and RNA quality. An enzyme cocktail that provided a gentle dissociation of neuronal tissue, decreased copper in the EdU labelling reaction, and minimising cell disruption during FACS was developed. Thereby, single proliferating cells and their RNA content was effectively extracted from neural tissues. The RNA extracted from the dividing cells showed significant expression differences of several key RNA products when compared to the non-dividing cells of the same tissue. These techniques provide a powerful tool kit to investigate proliferating cells of neural origin. Their use is not limited to the tissues and applications outlined in this thesis but are translatable to other tissue and biomolecules.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>School of Natural Sciences<br>Science, Environment, Engineering and Technology<br>Full Text
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TUBITA, ALESSANDRO. "ERK5-dependent mechanisms regulate melanoma cell proliferation." Doctoral thesis, Università di Siena, 2019. http://hdl.handle.net/11365/1072181.
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Melanoma is the deadliest skin cancer, with a very poor prognosis in advanced stages. Available treatments for melanoma, especially in its intermediate or advanced stages, are unsatisfactory. ERK5 is a member of the Mitogen-Activated Protein kinase family and regulates cell functions critical for tumor development, such as proliferation, invasion and angiogenesis. In silico data analysis indicated that ERK5 pathway components are upregulated in 47% of human melanomas. On this basis, we hypothesized that ERK5 could play a relevant role in melanoma. To study the possible role of ERK5 in the biology of melanoma, we employed a number of human melanoma cell lines. During my PhD, we found that ERK5 is required for the growth of melanoma cells and xenografts harboring wild type (wt) or mutated BRAF (V600E). We later identified a new interplay between ERK5 and the mutated form of B-RAF (V600E) frequently present in melanoma patients. Indeed, using melanoma cells harboring wt BRAF (M26c) and HEK293T cells we found that B-RAFV600E positively regulates ERK5 expression and phosphorylation and increases ERK5 nuclear localization, including that in the chromatin-bound fraction. Accordingly, combined pharmacological inhibition of BRAFV600E and MEK5 is required to decrease nuclear ERK5, that is critical for the regulation of cell proliferation. Furthermore, the combination of MEK5 or ERK5 inhibitors with Vemurafenib is more effective than single treatments in reducing 2D colony formation and growth of BRAFV600E melanoma cells and xenografts.
To deepen the knowledge of the molecular mechanisms by which ERK5 controls the growth of melanoma cells, we performed microarray analysis to quantify mRNAs following genetic silencing of ERK5, using two different ERK5-targeting shRNAs (shERK5-275 and shERK5-262), in two different BRAF-mutated melanoma cell lines (A375 and SKMel-5).
In particular, by meta-analysis of microarray data, we identified 34 differentially expressed genes (DEGs) (logFC > 1.5) shared by A375 and SKMel-5 cells. Among the above-mentioned genes we further identified 16 upregulated and 18 downregulated DEGs. The idea is to use the upregulated genes in order to identify possible compensative pathways upon ERK5 genetic silencing and to use the downregulated genes to identify new functions of ERK5 in melanoma.
The results of the present study shed light on the fact that ERK5 is involved in several mechanisms including, surely, mechanisms involved in melanoma proliferation.
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Browning, Alexander P. "Stochastic mathematical models of cell proliferation assays." Thesis, Queensland University of Technology, 2017. https://eprints.qut.edu.au/110808/1/Alexander_Browning_Thesis.pdf.
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Cell proliferation assays are routinely used to study collective cell behaviour, and can be interpreted with mathematical models. In this thesis, we apply a computational Bayesian technique to calibrate stochastic discrete mathematical models of cell migration and cell proliferation in the context of a cell proliferation assay. Initially, we use a lattice-based model to explore the optimal duration of a cell proliferation assay. Next, we estimate the parameters in a lattice-free model using three independent experimental data sets. Our model is able to both describe and predict the evolution of the population and spatial structure in a cell proliferation assay.
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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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Li, Jing. "Effects of intrinsic & extrinsic factors on the growth and differentiation of human mesenchymal stem cells." View the Table of Contents & Abstract, 2006. http://sunzi.lib.hku.hk/hkuto/record/B36434450.
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Wiklund, Sofia. "Effects on immune cell viability, morphology and proliferation in a sub-microliter cell sampler system." Thesis, Linköpings universitet, Institutionen för fysik, kemi och biologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-89982.
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Today, most traditional method used in the research of immune cells, such as flow cytometry and microscopy, are based on average values of cell responses. However, immune cells are heterogeneous and respond differently to a given stimuli. There is also a risk that important, but rare, behaviors of individual cells are missed when a larger population of immune cells is analyzed. Also, flow cytometry and microscopy do not allow long-term survival of cells; these methods lack the ability to do dynamic long-term analysis of motile immune cells, i.e. studies of cell-cell interactions, morphology and proliferation. In a patient who is affected by cancer, the cell heterogeneity contributes to the ability to battle various types of cancer or virus infections. In an outbreak, immune cells recognize and kill tumor cells. However, the number of specific immune cells is sometimes too few to kill all the tumor cells in a successful way. One way to help these patients is to isolate, select out and cultivate the active immune cells with capacity to kill tumor cells. The Cell Physic Laboratory (a part of the department of Applied Physics) at the Royal Institute of Technology (KTH) has developed a method for single-cell analysis where the immune cells are trapped in microwells in a silicon chip. The immune cells are then studied by using fluorescence microscopy in an inverted setup. The method enables high-throughput experiments due to the parallelization. Furthermore, since the immune cells survive long periods in the chip, the cells can be analyzed over several days up to weeks. The research group has also developed a semi-automatic ‘cell-picker’. The cell-picker will be used in combination with the developed method for single-cell analysis, which enables picking of cells of interest. In this report, experiments for the characterization and evaluation of the biocompatibility of two generations of the cell-picker will be presented. The experiments include development of a protocol for the cell-picking process, studies of the survival time of transferred cells for both generation of the cell-picker and studies of surface coating in the chip in order to increase the biocompatibility. The preliminary results indicate that the cell-picker has potential to be used as a selection tool for immune cells of interest.
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Harrington, Elizabeth Anne. "Analysis of the molecular regulation of cell proliferation and cell death." Thesis, Imperial College London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283286.
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Herbert, Shane Paul. "Endothelial cell phospholipase Aâ‚‚ : roles in prostaglandin production and cell proliferation." Thesis, University of Leeds, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432387.
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Salinas, Daniel Cirera. "miR-33 regulates cell proliferation, cell cycle progression and liver regeneration." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2013. http://dx.doi.org/10.18452/16721.
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Der Cholesterin-Stoffwechsel ist sehr streng auf zellulärer Ebene reguliert und ist essentiell für das Zellwachstum. MicroRNAs (miRNAs), eine Klasse nicht-kodierender RNAs, wurden als kritische Regulatoren der Genexpression identifiziert und entfalten ihre Wirkung vorwiegend auf posttranskriptioneller Ebene. Aktuelle Arbeiten aus der Gruppe um Fernández-Hernando haben gezeigt, dass hsa-miR-33a und hsa-miR-33b, miRNAs die in den Intronsequenzen der Gene für die Sterol-regulatorischen Element- Bindungsproteine (SREBP-2 und SREBP -1) lokalisiert sind, den Cholesterin-Stoffwechsel im Einklang mit ihren Wirtsgenen regulieren. Gleichermaßen inhibiert miR-33 Schlüsselenzyme in der Regulation der Fettsäureoxidation, einschließlich CROT, CPT1A, HADHB, SIRT6, AMPKα, genauso wie IRS2, eine wesentliche Komponente des Insulin-Signalwegs in der Leber. Diese Studie zeigt, dass hsa-miR-33 Familienmitglieder nicht nur Gene in Cholesterin- und Fettsäure-Stoffwechsel sowie Insulin-Signalwege regulieren, sondern zusätzlich die Expression von Genen des Zellzyklus und der Zellproliferation modulieren. miR-33 inhibiert die Expression der CDK6 und CCND1, wodurch sowohol die Zellproliferation als auch die Zellzyklusprogression verringert wird. Die Überexpression von miR-33 induziert einen signifikanten G1 Zellzyklusarrest. Durch eine Inhibierung der miR-33 Expression mittels 2''F/MOE-modifiziert Phosphorothioat-Backbone Antisense-Oligonukleotiden, wird die Leberregeneration nach partieller Hepatektomie (PH) in Mäusen verbessert, was auf eine wichtige Rolle für miR-33 in der Regulation der Hepatozytenproliferation während der Leberregeneration hinweist. Zusammengefasst zeigen diese Daten, dass Srebf/miR-33 Locus kooperieren, um Zellproliferation und Zellzyklusprogression zu regulieren, und könnte somit auch relevant für die menschliche Leberregeneration sein.<br>Cholesterol metabolism is tightly regulated at the cellular level and is essential for cellular growth. Cellular imbalances of cholesterol and fatty acid metabolism lead to pathological processes, including atherosclerosis and metabolic syndrome. MicroRNAs (miRNAs), a class of noncoding RNAs, have emerged as critical regulators of gene expression acting predominantly at posttranscriptional level. Recent work from Fernández-Hernando´s group and others has shown that hsa-miR-33a and hsa-miR-33b, miRNAs located within intronic sequences of the sterol regulatory element-binding protein (SREBP-2 and SREBP-1) genes, respectively, regulate cholesterol metabolism in concert with their host genes. Similarly, miR-33 targets key enzymes involved in the regulation of fatty acid oxidation including CROT, CPT1A, HADHB, SIRT6 and AMPKα, likewise, IRS2, an essential component of the insulin- signaling pathway in the liver. This study shows that hsa-miR-33 family members not only regulate genes involved in cholesterol and fatty acid metabolism and insulin signaling, but in addition modulate the expression of genes involved in cell cycle regulation and cell proliferation. Thus, miR-33 inhibited the expression of CDK6 and CCND1, thereby reducing cell proliferation and cell cycle progression. Over-expression of miR-33 induced a significant G1 cell cycle arrest and most importantly, inhibition of miR-33 expression using 2’F/MOE-modified phosphorothioate backbone antisense oligonucleotides improved liver regeneration after partial hepatectomy (PH) in mice, suggesting an important role for miR-33 in regulating hepatocyte proliferation during liver regeneration. Altogether, these data establish that Srebf/miR-33 locus may co-operate to regulate cell proliferation, cell cycle progression and may also be relevant to human liver regeneration.
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Chen, Jingbo, and 陳靜波. "Calcium signaling pathways and cell proliferation in human cardiac fibroblast." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41290434.
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Chen, Jingbo. "Calcium signaling pathways and cell proliferation in human cardiac fibroblast." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41290434.
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Gustincich, Stefano. "Positive and Negative Pathways in Cell Proliferation Control." Doctoral thesis, SISSA, 1992. http://hdl.handle.net/20.500.11767/4206.
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Belsey, Mark James. "Osmosensitive taurine release and cell proliferation in neural cells : a pharmacological study." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424410.
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Camplejohn, Richard Stephen. "Cell kinetics and cancer." Thesis, University of Newcastle Upon Tyne, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327272.
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Beith, Jennifer Lynn. "The role of insulin on beta-cell proliferation." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/32143.
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A relative decrease in β-cell mass is key in the pathogenesis of type 1 diabetes, type 2
diabetes and in the failure of transplanted islet grafts. It is now clear that β-cell duplication plays
a dominant role in the regulation of adult β-cell mass. Knowledge of the endogenous regulators
of β-cell replication is therefore critical for understanding the physiological control of β-cell
mass and for harnessing this process therapeutically. We have shown that physiological
concentrations of insulin act directly on β-cells to promote survival. Whether insulin stimulates
adult β-cell proliferation remains unclear. We tested this hypothesis using dispersed primary
mouse islet cells double-labeled with BrdU and insulin antisera. Treating cells with 200 pM
insulin significantly increased proliferation from a baseline rate of 0.15% per day. Elevating
glucose from 5 mM to 15 mM did not significantly increase β-cell replication. β-cell
proliferation was inhibited by somatostatin, as well as inhibitors of insulin signalling.
Interestingly, inhibiting Raf-1 kinase blocked proliferation stimulated by physiological, but not
super-physiological insulin doses. Insulin-stimulated MIN6 cell proliferation was dependent on
both PI3-kinase/Akt and the Raf-l/MEK pathways. Examination of the effects of insulin and its
receptor pathway on cell cycle molecules was inconclusive. Together, these results demonstrate
for the first time that insulin, at physiological levels, can directly stimulate β-cell proliferation
and that Raf-l kinase is involved in this process. These findings have significant implications for
the understanding of the regulation of β-cell mass in both the hyperinsulinemic and insulindeficient
states that occur in the various forms of diabetes.<br>Medicine, Faculty of<br>Cellular and Physiological Sciences, Department of<br>Graduate
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Fiorini, Federica. "Soft hybrid materials for cell growth and proliferation." Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAF027/document.
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Le travail de recherche consiste à développer des hydrogels pour la prolifération et la migration cellulaires in vitro et in vivo en trois dimensions (3D). Des hydrogels à base de polyamidoamines avec d'intéressantes propriétés physicochimiques et une remarquable biocompatibilité ont été développés pour différentes applications biomédicales. Un hydrogel avec des sondes luminescentes d’iridium(III) incorporés de manière covalente, a été conçue comme plate-forme 3D de culture cellulaire, pour la visualisation directe des cellules vivantes en temps réel, et a démontré être un puissant outil de bioimagerie in vitro. En outre, un hydrogel nanocomposite, capable d'induire la chimiotaxie des cellules souches, a été développé et testé in vivo, en confirmant son potentiel en tant qu’implant pour l’ingénierie tissulaire. Finalement, un hydrogel injectable et biodégradable a été réalisé comme un nouvel agent pour la dissection sous-muqueuse endoscopique des lésions néoplasiques digestives<br>The research work focuses on the development of hydrogels to investigate three-dimensional (3D) cell proliferation and migration in vitro and in vivo. Polyamidoamines-based hydrogels with interesting physicochemical properties and high biocompatibility have been developed for different biomedical applications. An hydrogel with covalently incorporated iridium(III) fluorescent probes, has been conceived as a 3D cell culture platform for the direct visualization of living cells in real-time, demonstrating to be a powerful tool for in vitro bio-imaging. Moreover, a nanocomposite hydrogel, able to induce chemotaxis of stem cells, was developed andtested in vivo, confirming its potential as a tissue engineering implant. Finally, an injectable biodegradable nanocomposite hydrogel was realized as a novel agent for endoscopic submucosal dissection of large neoplastic lesions of the gastro-intestinal tract
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Schutte, Berend. "Cancer cell ploidy and proliferation in colorectal carcinoma." Maastricht : Maastricht : Rijksuniversiteit Limburg ; University Library, Maastricht University [Host], 1987. http://arno.unimaas.nl/show.cgi?fid=5360.
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Simon, Charles. "Novel resveratrol analogues : synthesis, metabolism and cell proliferation." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/9289.
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Resveratrol or trans-3,4’,5-trihydroxystilbene is a naturally occurring phytochemical contained in red grapes skin, nuts and berries. It has been shown over the years to have different biological properties particularly in the chemoprevention of cancer. However, it is metabolised in vivo to sulfates and glucuronides within 1h and is active against different targets in a dose dependant manner. A library of new analogues of resveratrol has been synthesised with the aim of stopping or at least slowing down the metabolism whilst keeping its activity on the inhibition of cancer cell proliferation. Seven new analogues of resveratrol were synthesised in which the phenol substituents were systematically replaced by benzylic alcohols and/or methoxy groups. The library was then assessed in in vitro enzymatic metabolism with mouse and human liver fractions in the presence of a cofactor. The compounds were also evaluated as inhibitors of HCA-7 colorectal cancer cell proliferation.
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Penglong, Tipparat. "Molecular Basis of Erythroid Cell Proliferation and Differentiation." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA11T022.
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Pour assurer la production de milliards de globules rouges, l’érythropoièse doit parfaitement contrôler les processus de prolifération et de différenciation. Ces deux processus sont régulés par l’expression de gènes spécifiques dépendant d’une coordination entre l’activité des facteurs de transcription (FT) et les fonctions épigénétiques portées par exemple par les protéines à bromodomaine. Cette étude se concentre sur les conséquences de l’association ou la dissociation du FT clef de l’érythropoièse GATA-1 avec les FT déterminant pour le cycle cellulaire, pRb et E2F. Dans la première partie de ma thèse, j’ai participé à l’étude du rôle de l’association/dissociation de GATA-1 et FOG-2 avec pRb/E2F dans le contrôle la balance prolifération/différenciation cellulaire. Nos résultats montrent que les souris exprimant une mutation de GATA-1 sur la sérine 310 (GATA-1S310A), qui a la capacité accrue à séquestrer E2F-2, présentent une anémie létale lorsqu’un mécanisme de compensation de production de E2F-2 induit par l’IGF-1 est inhibé. Puis, nous avons trouvé que les propriétés décrites pour GATA-1 sont partagées par le FT FOG-2 et montré que l’abrogation de sa fixation avec pRb induit une perturbation de l’adiposité dans des souris FOG-2pRb-. Dans la deuxième partie, l’expression de c-Myc étant régulé différentiellement par GATA-1 et E2F, j’ai testé si la drogue « JQ1 », premier inhibiteur épigenétique chimique de l’expression de c-Myc, pouvait contrôler l’érythropoièse. Pour cela, j’ai utilisé la ligné érythroleucémique UT7 qui prolifère sans se différencier en présence d’érythropoiétine (stade proérythroblaste). Les résultats montrent que le traitement par JQ1 bloque la prolifération des cellules UT7 et permet de réinitier le programme de différentiation érythroide terminale. J’ai alors recherché les mécanismes moléculaires impliqués dans cette régulation et trouvé que l’inhibition transcriptionnelle de c-Myc par JQ1 est associée à l’inhibition de l’activité transcriptionnelle de STAT5 sans modification de son état de phosphorylation. Enfin, j’ai montré que JQ1 pouvait avoir une activité comparable à celle du TGF-b mais sans implication les voies Smad. Des études in vivo montre que JQ1 augmente la viabilité cellulaire et accélère la maturation des cellules érythroides à la fois chez les souris sauvages et thalassémiques. Cette différence d’action de JQ1 sur l’érythropoièse normale et pathologique implique des modifications épigénétiques différentielles entre ces deux types cellulaires et sont à la base de nouvelles stratégies du traitement du cancer. Le rôle clef de la régulation de l’association/dissociation de GATA-1 ou FOG-2 avec pRb/E2F dans l’érythropoièse et l’adipogénèse, nous a conduit, dans une troisième partie, à déterminer in vivo, les conséquences physiologiques de la séquestration de E2F par pRb. Pour cela nous avons crée une souris transgénique exprimant de façon conditionnelle un peptide contenant la partie N terminale de GATA-1 qui se fixe à pRb (GATA-1Nter). In vitro, ce peptide séquestre E2F dans le complexe GATA-1Nter/pRb et inhibe la prolifération cellulaire de façon irréversible. In vivo, aucune souris transgéniques exprimant le peptide GATA-1Nter n’a pu être sélectionnée et une mortalité au stade embryonnaire est observée. Une expression induite de ce peptide au stade adulte ne produit que des souris chimériques avec une fréquence de recombinaison du transgène GATA-1Nter importante. L’établissement de lignées stables de souris exprimant le peptide GATA-1Nter permettra de déterminer les conséquences physiologiques de la séquestration de E2F dans le complexe GATA-1Nter/pRb<br>To ensure the generation of billions of erythrocytes daily, erythropoiesis must be well controlled by proliferation and differentiation processes. These two processes are regulated by expressions of specific genes, coordinated by transcription factors (TFs) and epigenetic factors, such as bromodomain proteins. This study focused on the effects of the binding and dissociation of a key erythroid TF, GATA-1, to the crucial cell cycle TFs, pRb and E2F. In the first part of this thesis, the role of GATA-1 and FOG-2 binding to pRb/E2F in a control balances between cell proliferation and differentiation was studied. Mice bearing a GATA-1 mutation (GATA-1S310A) displayed higher levels of E2F2 sequestration and suffered from fatal anemia when the compensatory pathway of E2F2 production via IGF-1 signaling was also inhibited. The properties described for GATA-1 were found to be common to FOG-2, and the abolition of FOG-2 binding to pRb led to obesity resistance in FOG-2pRb- mice. In the second part of this work, as c-Myc is regulated by GATA-1 and E2F, the first chemical epigenetic inhibitor repressing c-Myc expression to be described, JQ1, was investigated to see if it could control erythropoiesis. The UT7 erythroleukemia cell line, which proliferates without differentiating was used. This cell line stops differentiation at the proerythroblast stage, in response to erythropoietin. JQ1 treatment inhibited UT7 proliferation and restored terminal erythroid differentiation. The molecular mechanism underlying this regulation by JQ1 was shown that the inhibition of c-Myc expression was associated with the inhibition of STAT5 transcription, with no change in the phosphorylation of this protein. It was found that JQ1 had a putative TGF--like activity, which did not involve the Smad pathway. It was shown in the ex vivo studies that JQ1 increased the viability of erythroid cells and accelerated the maturation of these cells in both WT and thalassemic mice. The observed differences between leukemic and normal erythropoiesis involved differential epigenetic modifications that could be at the basis of new strategies regarding cancer treatment.The key role of the association of GATA-1 or FOG-2 had with pRb/E2F, and the dissociation of these factors, in erythropoiesis and adipogenesis, respectively, led us to investigate, in vivo, the physiological consequences of E2F sequestration by pRb. As a result, transgenic mice displaying conditional expression of a peptide containing the N-terminal part of GATA-1 that binds to pRb (GATA-1Nter) were developed. In vitro, this peptide traps E2F in a GATA-1Nter/pRb complex, resulting in the irreversible inhibition of cell proliferation. The yield of transgenic mice expressing the GATA-1Nter peptide in vivo was unsuccessful, as this expression lead to lethality at the embryonic stage. Using an alternative approach, based on the inducible expression of the peptide in adults, chimeric mice with a high frequency of recombination of the GATA-1Nter transgene were obtained for this study. The establishment of a stable mouse line expressing the GATA-1Nter peptide should make it possible to determine the pathophysiological consequences of E2F sequestration in the GATA-1Nter/pRb complex
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Gui, Dan Y. (Dan Yi). "The role of respiration in supporting cell proliferation." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/115451.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, June 2017.<br>Cataloged from PDF version of thesis. "May 2017." Page 163 blank. Vita.<br>Includes bibliographical references.<br>Compared to non-proliferating cells, proliferating cells such as cancer cells have additional metabolic requirements for generating biomass. However, despite these additional requirements the components of the mammalian metabolic network in both proliferating and non-proliferating cells are largely the same. Thus, in order to balance the competing anabolic and catabolic needs of a proliferating cell, the same metabolic networks components must take on distinct roles. Understanding how the various network components support proliferation may lead to improvements in cancer therapy. It has long been known that mitochondrial respiration is essential for proliferation. However, the precise metabolic role that is filled by respiration is not well defined. This thesis focuses on understanding the role of respiration in supporting mammalian proliferation. In non-proliferating cells respiration is considered to be primarily an ATP-producing catabolic process. We find that in proliferating cells, respiration serves a crucial anabolic role by providing access to an electron acceptor in the form of molecular oxygen. Electron acceptor availability is required for maintaining NAD+/NADH homeostasis and supporting aspartate synthesis. In conditions where alternative electron acceptors are provided such that cells can maintain NAD+/NADH homeostasis through alternative pathways, or when exogenous aspartate is provided, respiration is dispensable for proliferation. These findings highlight that metabolic dependencies can be modified by environmental conditions. Consistent with this, we find that altering NAD+/NADH homeostasis through alternative pathways or providing exogenous aspartate can modulate cellular sensitivity to respiration inhibitors such as metformin. Collectively, these studies contribute to an understanding of how metabolism supports biomass generation for proliferation and offers insight to how metabolism could be targeted for cancer therapy.<br>by Dan Y. Gui.<br>Ph. D.
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Stöber, Kai. "Pre-replicative complex proteins and human cell proliferation." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621319.
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