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Pat, Sze Wa. "Cell metabolism in cell death and cell growth." HKBU Institutional Repository, 2007. http://repository.hkbu.edu.hk/etd_ra/775.
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Crisby, Milita. "Cell death in atherosclerosis /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-3191-7/.
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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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Uppington, Kay Marie. "Cell death in prion disease." Thesis, University of Bath, 2008. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.488879.
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Prion diseases are a group of fatal neurodegenerative diseases, including CJD and scrapie, which are thought to be caused by a protein termed a prion (PrP). As manganese has previously been suggested to be involved in prion disease we have investigated manganese binding to PrP and its role in the toxicity of the protein. We have shown that manganese bound PrP (MnPrP) has several of the characteristics of the disease form of PrP, including protease resistance and toxicity that is dependent on cellular PrP expression. Further investigation into the mechanism of toxicity revealed that MnPrP is significantly more toxic to neuronal cells than nonmanganese bound PrP and that toxicity requires the presence of known metal binding residues within the protein. We have demonstrated that treatment of neuronal cells with MnPrP causes caspase 3 activation and apoptosis, as demonstrated by DNA laddering, and we hypothesise that caspase 3 is activated by a p38 pathway. Treatment of neurones with MnPrP also caused a significant increase in cellular ROS production, although this did not appear to be a major cause of cell death as antioxidants were unable to save cells from cell death. We also investigated mechanisms by which cells can survive scrapie infection and MnPrP toxicity. We have shown that cells infected with scrapie have increased ERK activation which was important for their survival. Cells that survived MnPrP treatment were also found to have increased ERK activation. This suggests that ERK may have a protective role in prion diseases and may be a potential therapeutic target.
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Beeharry, Neil. "Cell death in insulin-containing cells : induction and prevention." Thesis, University of Brighton, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401600.
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Gorak-Stolinska, Patricia. "Activation induced cell death in human T cell subsets." Thesis, King's College London (University of London), 2002. http://kclpure.kcl.ac.uk/portal/en/theses/activation-induced-cell-death-in-human-t-cell-subsets(eb708e24-eccb-42fc-8930-d62ddf6794c1).html.
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Cheng, Jade. "Regulation of cell division and cell death by GRASP65." Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.544414.
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RUNYAN, CHRISTOPHER MICHAEL. "The Role of Cell Death in Germ Cell Migration." University of Cincinnati / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1210732680.
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Courtois-Moreau, Charleen Laetitia. "Programmed Cell Death in Xylem Development." Doctoral thesis, Umeå universitet, Umeå Plant Science Centre, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1831.
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Concerns about climate changes and scarcity of fossil fuels are rising. Hence wood is becoming an attractive source of renewable energy and raw material and these new dimensions have prompted increasing interest in wood formation in trees, in both the scientific community and wider public. In this thesis, the focus is on a key process in wood development: programmed cell death (PCD) in the development of xylem elements. Since secondary cell wall formation is dependent, inter alia, upon the life time of xylem elements, the qualitative features of wood will be affected by PCD in xylem, about which there is little information. This thesis focuses on the anatomical, morphological and transcriptional features of PCD during xylem development in both the stem of hybrid aspen, Populus tremula (L.) x tremuloides (Michx.) and the hypocotyl of the herbaceous model system Arabidopsis thaliana (L. Heynh.). In Populus, the progressive removal of organelles from the cytoplasm before the time of death (vacuolar bursts) and the slowness of the cell death process, illustrated by DNA fragmentation assays (such as TUNEL and Comet assays), have been ascertained in the xylem fibres by microscopic analyses. Furthermore, candidate genes for the regulation of fibre cell death were identified either from a Populus EST library obtained from woody tissues undergoing fibre cell death or from microarray experiments in Populus stem, and further assessed in an in silico comparative transcriptomic analysis of Arabidopsis thaliana. These candidate genes were either putative novel regulators of fibre cell death or members of previously described families of cell death-related genes, such as autophagy-related genes. The induction of the latter and the previous microscopic observations suggest the importance of autophagy in the degradation of the cytoplasmic contents specifically in the xylem fibres. Vacuolar bursts in the vessels were the only previously described triggers of PCD in the xylem, which induce the very rapid degradation of the nuclei and surrounding cytoplasmic contents, therefore unravelling a unique previously unrecorded type of PCD in the xylem fibres, principally involving autophagy. Arabidopsis is an attractive alternative model plant for exploring some aspects of wood formation, such as the characterisation of negative regulators of PCD. Therefore, the anatomy of Arabidopsis hypocotyls was also investigated and the ACAULIS5 (ACL5) gene, encoding an enzyme involved in polyamine biosynthesis, was identified as a key regulator of xylem specification, specifically in the vessel elements, though its negative effect on the cell death process. Taken together, PCD in xylem development seems to be a highly specific process, involving unique cell death morphology and molecular machinery. In addition, the technical challenges posed by the complexity of the woody tissues examined highlighted the need for specific methods for assessing PCD and related phenomena in wood.Oron för klimatförändringar och brist på fossila bränslen har ökat påtagligt under de senaste åren. De enorma möjligheter som skogsråvaran erbjuder som alternativ källa för förnyelsebar energi och råmaterial har väckt ett stort intresse också för den biologiska processen bakom vedbildning i träd. Denna avhandling fokuserar på en viktig process i vedbildning: programmerad celldöd (PCD) i xylemet. Xylemcellernas livstid påverkar bildningen av sekundära cellväggar, vilket i sin tur påverkar vedens kvalitativa egenskaperna, så som veddensitet. Trots dess betydelse för viktiga egenskaper hos vedråvaran existerar fortfarande väldigt lite information om xylem PCD på cellulär eller molekylär nivå. I den här avhandlingen belyses de anatomiska, morfologiska och genetiska aspekterna av PCD i xylemutveckling i både stam av hybridasp, Populus tremula (L.) x tremuloides (Michx.) och hypokotyl av det örtartade modellsystemet Arabidopsis thaliana (L. Heynh.). Xylemet i både Populus och Arabidopsis består av två olika celltyper; de vattentransporterade kärlen och de stödjande fibrerna. Det är känt att celldöd i kärlen pågår mycket snabbt efter att den centrala vakuolen brister och de hydrolytiska enzymer släpps in i cytoplasman. I den här avhandlingen ligger fokus på fibrerna i Populus xylemet. Med hjälp av mikroskopianalyser av cellmorfologin (elektronmikroskopi) och DNA-fragmentering i cellkärnan (TUNEL- och Comet-analyser) kunde vi konstatera att till skillnad från kärlen så uppvisar fibrerna en långsam och progressiv nedbrytning av organellerna och cellkärnans DNA före vakuolbristning. Dessutom har kandidatgener för reglering av fibercelldöd identifierats antingen från ett Populus EST bibliotek från vedartade vävnader som genomgår fibercelldöd eller från mikroarray experiment i Populus stam. Dessa kandidatgener är antingen potentiella nya regulatorer av fibercelldöd eller medlemmar av tidigare beskrivna familjer av celldödsrelaterade gener. Bland de sistnämnda finns autofagi-relaterade gener, vilket stöder funktionen av autofagi i samband med autolys av cellinnehållet i xylemfibrerna. Dessa studier pekar därför på en typ av PCD som har inte tidigare beskrivits för xylemet. Arabidopsis är ett alternativt växtmodellsystem för studier av vissa aspekter av vedbildningen, såsom karakteriseringen av negativa regulatorer av PCD. Därför har också hypokotylanatomin analyserats, och ACAULIS5 (ACL5) genen, som kodar för ett enzym i biosyntesen av polyaminer, har visats vara en viktig regulator av xylemspecifikation genom dess negativa effekt på kärlens celldöd. Sammantaget visar denna avhandling att PCD i xylemutvecklingen verkar involvera unika morfologiska och molekylära mekanismer. Vi visar dessutom att komplexiteten hos de vedartade vävnaderna leder till ett behov av bättre anpassade verktyg för att djupare kunna bedöma PCD och liknande fenomen i veden.
Även med namnet Moreau-Courtois, Charleen L. samt Moreau, Charleen.
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Klassen, Shaun Scott. "Nitric oxide-induced cardiomyocyte cell death." Thesis, University of British Columbia, 2006. http://hdl.handle.net/2429/31539.
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Nitric oxide (NO), a regulator of diverse cardiovascular functions, modifies cardiac cell
viability through mechanisms that remain uncertain. Several pathways were studied to
understand these effects. The possibility that the protein p53 is involved in the cardiomyocyte
response to the NO donor s-nitrosoglutathione (GSNO) or the peroxynitrite donor 3-
morpholinosydnonimine (SIN-1) was explored. These donors induced a concentration-dependent
increase of cell death in cultured embryonic chick cardiomyocytes. Expression of p53
protein was increased in response to GSNO, specifically in the nucleus. GSNO also caused
DNA damage, but pifithrin, an inhibitor of p53 transactivation activity, did not alter the extent of
this damage or cell death. Therefore, the role of increased nuclear p53 in response to NO and
NO-induced DNA damage may not be specifically operative in NO-induced cell death. The
action of GSNO also appears independent of mitochondrial pathways in cell death, as there was
no association of p53 with the mitochondria. Neither GSNO- or SIN-1-induced cell death was
altered by cyclosporin A, suggesting that permeability transition pore opening is not operative in
these modes of induction of death. In contrast to SIN-1, GSNO did not reduce mitochondrial
transmembrane potential, implying separate mechanisms of cell death. Immunocytochemistry
demonstrated increased amounts of nitrotyrosine in response to GSNO or SIN-1, confirmed by
Western blot following SIN-1. FeTPPS, an isomerase that converts peroxynitrite into the less
toxic nitrate, produced a significant reduction of SIN-1-induced cell death and cellular protein
nitration. FeTPPS did not reduce cell death from GSNO alone, but did from the combination of
GSNO and hydrogen peroxide, a condition which promotes the generation of peroxynitrite. In
summary, NO-induced cardiomyocyte cell death is due in part to the disruption of normal
cellular functions by nitration of key proteins. Peroxynitrite decomposition reduces protein
nitration and cell death, while p53 appears functions independent of the mitochondria or gene
transactivation and may act in other pathways, such as cell repair.Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate
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Martinez, Bermudez Ana Katherine. "Isoprostanes in brain endothelial cell death." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0025/MQ50832.pdf.
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Maianski, Nikolai. "Neutrophil cell death: mechanisms and regulation." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2004. http://dare.uva.nl/document/88280.
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Martinez, Bermudez Ana Katherine. "Isoprostanes in brain endothelial cell death." Thesis, McGill University, 1998. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=21605.
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Oxygen free radicals have been implicated in several diseases including ischemic stroke, and myocardial infarction. They can trigger chain reactions like peroxidation of membrane phospholipids, leading to osmotic imbalance and cell death. Isoprostanes are stable products of lipid peroxidation that have a constrictor effect on the vasculature and bronchii. As isoprostanes are abundantly generated in tissues under oxidant stress, we have hypothesized that they could be related to endothelial dysfunction observed during ischemia/reperfasion by affecting endothelial cell survival. The effects of 8-iso-PGE2 and 8-iso-PGF2alpha, two abundantly produced isoprostanes, were studied on porcine endothelial cultures and isolated brain microvessels. Cell survival was evaluated by MTT reduction, double staining with DNA-binding fluorochromes and in situ DNA fragmentation labeling,8-Iso-PGF2alpha (1--10 nM) induced 20--25% cell death in endothelial cultures after 24 h coincident with similar increase in the number of cells that become permeable to PI. On the contrary, 8-iso-PGE 2 did not affect endothelial cell survival. Approximately 9% of the cells suffered apoptosis. This percentage remained unchanged regardless the treatment. Several observations indicate a role for thromboxane A2 to mediate 8-iso-PGF2alpha-induced death: (1) the levels of thromboxane A2 increased dramatically in endothelial cultures after 8-iso-PGF2alpha-treatment; (2) inhibitors of thromboxane synthase, CGS12970 and U6355A and Ibuprofen, a non-selective inhibitor of cyclooxygenases, reverted the effect of the isoprostane; (3) analogs of thromboxane A2 U46619 and IBOP, reproduce the effect of 8-iso-PGF 2alpha after 24 h. 8-Iso-PGF2alpha also decreased endothelial viability on isolated brain microvessels. These results suggest, that 8-iso-PGF2alpha, might be a direct contributor to ischemia/reperfusion injury.
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Spanos, Sophia. "Cell death during preimplantation embryo development." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398228.
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Świdziński, Jodi A. "Programmed cell death in Arabidopsis thaliana." Thesis, University of Oxford, 2003. http://ora.ox.ac.uk/objects/uuid:6e2580fc-8873-4722-89f7-b206d4be2a5f.
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Programmed Cell Death (PCD) describes an orderly cellular breakdown that occurs in both plants and animals throughout development and in response to biotic and abiotic stresses. The molecular machinery that functions in the induction and execution of animal PCD has been characterised in great detail. Conversely, few genes and proteins involved in plant PCD have been identified. While certain features of animal PCD may be conserved, the induction and execution of plant PCD is also likely to involve novel proteins and mechanisms. The aim of the work presented in this thesis was to investigate experimental approaches for studying plant PCD and to gain an understanding of the molecular mechanisms involved. To this end, an Arabidopsis thaliana cell suspension system was developed in which PCD could be induced by both a heat treatment (55°C, 10 min) and senescence (13 to 14 days-old). This system allowed for the molecular responses related to programmed cell death to be distinguished from those that were a specific response to the inducing stimulus. The Arabidopsis cell suspension system was utilised for an analysis of transcriptomic and proteomic changes that occur following the induction of PCD. A custom cDNA microarray analysis of ~100 putative cell death-related genes was used to measure the abundance of transcripts of these genes during PCD, and this work was extended to a whole-genome transcriptomic analysis of PCD. A number of candidate genes that may play a role in plant PCD were identified. These included those encoding antioxidant enzymes, cytosolic heat shock proteins, the mitochondrial adenine nucleotide translocase, ion transporters, a two-component response regulator (ARR4), several pathogenesis-related proteins, phospholipases and proteases, extracellular glycoproteins and enzymes (including a subtilisin-like protease, chitinases, and glucanases), and transcriptional regulators such as a homeobox leucine zipper and NAC-domain proteins. The induction and execution of plant PCD is also likely to involve mechanisms that are not transcriptionally regulated. A proteomic analysis of changes in the total cellular protein profile during heat- and senescence-induced PCD was therefore used to identify 12 proteins that are modulated in both systems and may play a PCD-specific role. These included the mitochondrial voltage-dependent anion channel (Athsr2), catalase, mitochondrial superoxide dismutase, an extracellular glycoprotein, and aconitase. Selected genes and proteins identified in the transcriptomic and proteomic analyses were further investigated in an attempt to define their role in plant PCD. Since PCD is difficult to quantitatively analyse at the whole-plant level, initially a strategy of transient expression of genes of interest in Arabidopsis protoplasts was adopted. However, it proved to be technically difficult to accurately quantify the number of dead cells in this system. As an alternative, Arabidopsis T-DNA insertional mutants within genes of interest were investigated for PCD-related phenotypes. Mutants in Senescence-Related Gene 3, the mitochondrial voltage-dependent anion channel (Athsr2), and cytosolic Heat shock protein 70-3 were isolated. The mutant lines were not visibly affected in their development, formation of xylem, onset and progression of senescence, or responses to abiotic and biotic stresses. This indicated that these genes are either not involved in the PCD pathway or that their functional role can be fulfilled by other gene products.
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Cox, Orla T. "Vascular cell death in diabetic retinopathy." Thesis, Queen's University Belfast, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343079.
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Sharma, Pundrique Radheyshyam. "Programmed cell death during heart development." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272255.
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Fitzgerald, Julia. "Monoamine oxidase in neuronal cell death." Thesis, Nottingham Trent University, 2008. http://irep.ntu.ac.uk/id/eprint/51/.
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Monoamine oxidase (MAO) is an oxidative enzyme that deaminates a variety of amine substrates, including the neurotransmitter dopamine. The enzymatic reaction requires molecular oxygen and produces hydrogen peroxide as a by-product. MAO is localised in the outer mitochondrial membrane and exists as two isoforms, MAO-A and MAO-B, which are differentially expressed in the body and differ in their substrate and inhibitor specificities. Previous studies have suggested that MAO-generated reactive oxygen species (ROS) contribute to oxidative stress in the cell and can directly inhibit electron transport, cause damage to mitochondrial DNA and enhance cell death signalling. In this study the role of MAO in cell death was investigated in dopaminergic neuroblastoma (SH-SY5Y) cells, in three diverse models of mitochondrially-mediated apoptosis. The relevance of MAO in cell death signalling was confirmed with the use of two unrelated MAO inhibitors and the creation of stable SH-SY5Y cell lines that either over express MAO-A or have reduced levels of MAO-A. The study is the first to over express MAO-A using recombinant technology and to use miRNA to stably knock-down MAO-A expression in human neuronal cells. Results confirm that MAO-A is involved in modulating cell death but the mechanism and extent of the involvement depends on the apoptotic inducer. In classical apoptosis induced by staurosporine (STS), cells undergo rapid morphological and biochemical changes indicative of mitochondrially-mediated apoptosis, which is partly dependent on ROS production by MAO-A and induction of mitogen-activated protein kinase (MAPK) signalling cascades. MAO-A protein and catalytic activity are increased in this model, however the mechanism by which this occurs is unknown and is not a result of increased gene transcription. In death induced by growth factor withdrawal, the MAO-A gene is up regulated via p38 and JNK MAPK pathways, which occurs downstream of caspase activation. In both the STS and growth factor withdrawal models, MAO inhibition reduced apoptosis. Most significantly reduced levels of MAO-A expression in 'knock down' cells protected against cell death induced by the complex I inhibitor rotenone, suggesting that MAO has an important role in mitochondrial function. Over expression of MAO-A resulted in stress and apoptosis, followed by a period of cellular senescence and eventually death by necrosis. These data compliment the effects of chronic exposure to oxidative stress in ageing and neurodegeneration. For the first time this work has shown that the MAO-A isoform is an important regulator of STS-induced apoptosis, that MAO-A gene expression is regulated by JNK signalling, and that MAO-A is significantly involved in mitochondrial dysfunction induced by complex I inhibition. These data raise important questions regarding predisposition to the development of neurodegenerative diseases such as Parkinson's disease and to approaches used for their treatment.
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Ramos, Paulina Joanna. "Fibronectin Enhances Carfilzomib Mediated Cell Death." Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/579327.
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Cell Adhesion Mediated Drug Resistance (CAM-DR) is a factor in Multiple Myeloma (MM) drug resistance. Despite advances in treatment, multiple myeloma remains incurable and often results in drug resistance. It is known that cell adhesion to fibronectin via integrin β1 confers survival in myeloma cells. We show here that adherence of the NCI-H929 and MM.1S myeloma cells to fibronectin, promotes cell death when treated with proteasome inhibitor Carfilzomib (Kyprolis). These data are in contrast to other cytotoxic drugs, such as melphalan or doxorubicin, and different myeloma cell lines in which the CAM-DR survival phenotype is expressed. We found a significant amount of death in myeloma cells adhered to fibronectin when exposed to carfilzomib. In addition, we demonstrate that pan-caspase inhibitor, Q-VD-OPH, inhibits cell death in myeloma cells in suspension. Carfilzomib cytotoxicity is caspase dependent in suspension. We propose that the increased cytotoxicity in cells adhered to fibronectin may be caspase independent, perhaps due to failed autophagy. These data support the hypothesis that β1 mediated adhesion to fibronectin induces an autophagic response in MM cells contributing to CAM-DR phenotype. We propose that further induction of autophagy by proteasome inhibitors exceeds the adaptive threshold survival response and initiates caspase independent cell death.
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Janson, Veronica. "Cisplatin-resistance and cell death in malignant pleural mesothelioma cells." Doctoral thesis, Umeå universitet, Medicinsk biovetenskap, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1680.
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Malignant pleural mesothelioma (MPM) is an aggressive, treatment-resistant tumour. Cisplatin (cis-diamminedichloroplatinum (II)) is the best single-agent chemotherapy for MPM, but platinum-based combination therapies give the best overall response rates. However, cisplatin use is limited by resistance and severe side effects. This thesis has increased the knowledge concerning cisplatin-induced cell death in MPM by describing a novel potential therapeutic target, and three novel phenotypes of cisplatin-resistance in a human MPM cell line (P31) and its cisplatin-resistant sub-line (P31res1.2). The novel potential therapeutic target, and one of the novel phenotypes, was cisplatin-resistant pro-apoptotic BH3-only proteins. In the P31 cells, cisplatin transiently increased pro-apoptotic BH3-only proteins during 6 h of exposure. This response was almost completely abrogated in the P31res1.2 cells. De-regulated caspase activity and activation was the second novel phenotype identified. The P31res1.2 cells had earlier, possibly mitochondria-independent, caspase-3 activation, increased basal caspase-3 activity and increased basal cleavage of caspase-8 and -9. Despite these differences, 6-h equitoxic cisplatin exposures rendered 50-60% of the cells apoptotic in both cell lines. The third novel phenotype was abrogated Na+K+2Cl--cotransporter (NKCC1) activity. Although NKCC1 activity was dispensable for cisplatin-induced apoptosis, balanced potassium transport activity was essential for P31 cell survival. Finally, the survival signalling protein Protein Kinase B (PKB or Akt) isoforms α and γ were constitutively activated in a PI3K-independent manner in P31 cells. In the P31res1.2 cells, PKBα and γ activities were increased, and there was PI3K-dependent activation of PKBβ. However, this increase in PKB isoform activity was not strongly associated to the cisplatin-resistance of the P31res1.2 cells.
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McComb, Scott. "The Paradoxical Roles of Cell Death Pathways in Immune Cells." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/24331.
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Cell death plays a vital role throughout the immune response, from the onset of inflammation to the elimination of primed T cells. Understanding the regulation of cell death within immune cells is of vital importance to understanding the immune system and developing therapies against various immune-disorders. In this thesis I have investigated the regulation of cell death and its functional role in of the innate and adaptive arms of the immune system.
The mechanisms that govern expansion and contraction of antigen stimulated CD8+ T cells are not well understood. In the first section of this thesis, I show that caspase-3 becomes activated in proliferating CD8+ proliferation, yet this does not result in cell death. I used both in vivo and in vitro models to demonstrate that caspase-3 activation is specifically driven by antigen presentation and not inflammation, and that it likely plays a role in promoting T cell proliferation.
Next, I present novel data regarding the regulation of a newly identified form of programmed cell death via necrosis, known as necroptosis. I show that the cellular inhibitor of apoptosis (cIAP) proteins act to limit activation of key necroptosis proteins in macrophage cells. Furthermore, I show that necroptosis can be exploited by intracellular bacterial pathogens to escape removal by the immune system. I also demonstrate that necroptosis is highly intertwined with the pathway of inflammation, and the autocrine production of type-I interferon constitutes a vital positive feedback loop in the induction of inflammatory cell death. In the final section of my thesis work, I delve into
the specific regulation of Rip1 kinase and demonstrate that in addition to previously demonstrated regulation by caspase-8, cathepsins are also able to cleave Rip1 kinase and limit necroptosis.
This thesis presents a wide variety of novel data regarding the regulation of cell death within immune cells. In total, the results reveal a picture of two divergent forms of programmed cell death, apoptosis and necroptosis. Through improving the understanding of the cross-regulation of these two key cell death pathways this work aims to improve the understanding of the immune function.
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Kaul, Aparna. "Mechanisms of Non-Conventional Cell Death in Brain Tumor Cells." University of Toledo Health Science Campus / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=mco1243364096.
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Koterba, Kristen L. "Regulation of Autophagy and Cell Death in Breast Carcinoma Cells." University of Toledo Health Science Campus / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=mco1276005638.
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Stuckey, Crystal Elaine. "Oxidative Stress and Cell Death in Osmotically Swollen Glial Cells." Wright State University / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=wright1208492663.
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Prise, Kevin M. "Cell death and DNA damage in methotrexate-treated HeLa cells." Thesis, University of Aberdeen, 1985. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU362655.
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The cancer chemotherapeutic agent methotrexate inhibits the enzyme dihydrofolate reductase leading to a depletion of cellular reduced folates and inhibition of thymidylate synthase. A predicted consequence of this depletion of cellular thymidylate residues is that the nucleotide dUMP may be incorporated into DNA in place of dTMP. The subsequent cycle of uracil removal and reincorporation by an excision-repair pathway may cause DNA damage, a possible contributory factor leading ultimately to cell death. DNA. damage, in the form of single- and double-strand breaks, was -5 detected in HeLa cells treated with high dose (>10 M) methotrexate using the sensitive nucleoid sedimentation technique and alkaline filter elution. The maximum level of DNA damage, in the form of single-strand breaks, was detected after only 1 hour of drug incubation, but breaks were not detectable after this time, presumably because they had been repaired. DNA double-strand breaks were detectable from 18 hours onwards, along with a small level of single-strand breaks. The presence of hypoxanthine together with the irethotrexate to overcome the inhibition of de novo purine biosynthesis led to a similar occurrence of strand breaks, although a greater number of double-strand breaks was detected. The early appearance of single-strand breaks coincided with a substantial decrease in cellular dTTP levels and loss in colony-forming ability of the cells. No significant changes in cell viability, as measured by a dye-exclusion assay, were detected until at least 12 hours drug incubation. The greater level of double-strand breaks in cells grown with methotrexate and hypoxanthine coincided with a greater loss in colony-forming ability in these cells. 6. Changes in chromatin structure in cells treated with drug for 24 hours or longer were detected as a faster sedimentation of nucleoids compared to control cells. These changes were not due to the supercoiled state of the DNA but were related to the protein component of the nucleoid cage structure. 7. The enzyme ADP-ribosyltransferase was found to be stimulated in response to the appearance of single-strand breaks, reaching a maximum stimulation of 2 - 3 fold after 3 hours incubation with methotrexate. With hypoxanthine present no activation was detected, even though single-strand breaks were present. In neither case was there a change in the degradation rate of ADP-ribose protein conjugates nor a significant change in intracellular NAD+ levels. 8. In methotrexate-treated cells, the activation of the transferase led to an increase in the ADP-ribosylation of three specific proteins, probably by the addition of mono (ADP-ribose) residues. 9. The complete inhibition of ADP-ribosyltransferase activity by 3-aminobenzamide, or the prevention by hypoxanthine of its activation by methotrexate, did not have any significant effect on changes in cell number, cell viability or colony-forming ability in cells incubated with methotrexate. Thus ADP-ribosylation of proteins is not an effective component during the cytotoxic action of methotrexate.
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Stuart, Lynda Maria. "Cell death, dendritic cells and downregulation of the immune response." Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/23214.
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Apoptotic cells are an important source of many autoantigens and the realization that dendritic cells (DCs), the main antigen presenting cell of the adaptive immune system, not only internalise such drying cells but present antigen derived from them had important implications for our understanding of autoimmunity, tumour immunology and anti-viral responses. The aim of this thesis was to explore the likely consequences of clearance of cells dying by constitutive apoptosis by myeloid phagocytes, with particular emphasis on the mechanism and outcome of DC clearance and the implications for autoimmunity. Firstly it will show that DCs generated from murine bone marrow demonstrated many characteristics attributed to DCs in vivo including endocytosis and phagocytosis and mature upon receipt of danger signals such as endotoxin. However, internalisation of apoptotic cells does not augment DC maturation but rather inhibits subsequent responses to LPS, rendering these DCs less efficient than their neighbours at stimulating naïve T cells. These effects do not appear to be due to secretion of inhibitory cytokines such as TGFβ or IL10 and are not dependent on CD36 or β3/5 integrins, receptors thought to be involved in DC internalisation of apoptotic cells. In addition apoptotic cells inhibit LPS driven IL12 production by ex vivo DCs and in mice immunised with apoptotic cells in vivo. Furthermore, macrophages, likely to be found in high numbers in the inflammatory site also inhibit DCs and these inhibitory effects could be further augmented by the presence of apoptotic cells. Taken together these data demonstrate that internalisation of apoptotic cells by myeloid phagocytes modulates the adaptive immune response and suggests that the likely outcome of internalisation of cells dying by constitutive apoptosis will be tolerance rather than autoimmunity.
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Ahmed, Yasser Abdel Galil. "Analysis of physiological death in equine chondrocytes /." Connect to thesis, 2007. http://eprints.unimelb.edu.au/archive/00003656.
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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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Watson, Andrea. "Heat shock proteins in leukaemia cell differentiation and cell death." Thesis, Aston University, 1990. http://publications.aston.ac.uk/12533/.
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When HL60 cells were induced to differentiate to granulocyte-like cells with the agents N-methylformamide and tunicamycin an concentrations marginally below those which were cytotoxic, there was a decrease in the synthesis of the glucose- regulated proteins which preceded the expression of markers of a differentiated phenotype. There was a transient increase in the amount of hsp70 after 36 hours in NMF treated cells but in differentiated cells negligible amounts were detected. Inducers which were known to modulate hsp70 such as azetadine carboxylic acid did not induce differentiation suggesting early changes in the endoplasmic reticulum may be involved in the commitment to terminal differentiation of HL60 cells. These changes in group synthesis were not observed when K562 human chronic myelogenous leukemia cells were induced to differentiate to erythroid-like cells but there was a comparable increase in amounts of hsp70. When cells were treated with concentrations of drugs which brought about a loss in cell viability there was an early increase in the amount of hsp70 protein in the absence of any increase in synthesis. HL60 cells were treated with NMF (225mM), Adriamycin (1 jiM), or CB3717 (5iM) and there was an increase in the amounts of hsp70, in the absence of any new synthesis, which preceded any loss of membrane integrity and any significant changes in cell cycle but was concomitant with a later loss in viability of > 50% and a loss in proliferative potential. The amounts of hsp70 in the cell after treatment with any of the drugs was comprable to that obtained after a heat shock. Following a heat shock hsp70 was translocated from the cytoplasm to the nucleus, but treatment with toxic concentrations of drug caused hsp70 to remain localised in the cytoplasm. Changes in hsp70 turn-over was observed after a heat shock compared to NMF-treated cells. Morphological studies suggested that cells that had been treated with NMF and CB3717 were undergoing necrosis whereas the Adriamycin cells showed characteristics that were indicative of apoptosis. The data supports the hypothesis that an increase in amounts of hsp70 is an early marker of cell death.
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Sciacovelli, Marco. "Cell death regulation by mitochondrial chaperones in tumor cell models." Doctoral thesis, Università degli studi di Padova, 2011. http://hdl.handle.net/11577/3421645.
Full textAbstract:
Cancer cells are endowed with the capability to evade normal apoptotic signaling, as they display a constitutive hyperactivation of kinase signaling pathways. Integration of survival and death stimuli occurs on mitochondria, where many of these signals converge in the regulation of a channel termed permeability transition pore (PTP). PTP opening commits cells to death, and it is regulated by a variety of factors, among which molecular chaperones play a pivotal role. Here I have studied how mitochondrial chaperones interact with signal transduction pathways, modulate the PTP and more in general mitochondrial bioenergetics, and how these regulatory networks control tumor cell viability. In a first part of my work, I have explored a functional connection between the Ras/ERK signaling axis, whose constitutive activation characterizes most tumors and prompts their growth and survival, and cyclophilin D (CyP-D), a mitochondrial chaperone that regulates the PTP. A fraction of active ERK was found to be located in mitochondria in RWPE-2 cells, obtained by v-Ki-Ras transformation of the epithelial prostate RWPE-1 cell line; in metastatic prostate cancer DU145 cells; and in osteosarcoma SAOS-2 cells. All these tumor cells displayed marked resistance to death caused by apoptotic stimuli like arachidonic acid and the BH3 mimetic EM20-25, which cause cell death through the mitochondrial PTP. PTP inhibition and the ensuing resistance to cell death induced by arachidonic acid or EM20-25 could be ablated by inhibiting ERK with the drug PD98059 or with a selective ERK activation inhibitor peptide. ERK inhibition enhanced GSK-3-dependent phosphorylation of CyP-D), whereas GSK-3 inhibition protected from PTP opening. Neither active ERK in mitochondria nor pore desensitization were observed in non-transformed RWPE-1 cells. Thus, in tumor cells mitochondrial ERK activation desensitizes the PTP through a signaling axis that involves GSK-3 and CyP-D. In a second part of my thesis work, I have investigated the activity of a second mitochondrial chaperone, TRAP1/HSP75, overexpressed in tumor cells and proposed to be involved in regulation of the pore. I have determined that TRAP1 interacts with CyP-D and characterized its survival function against a wide spectrum of death stimuli inducing oxidative stress, including diamide, exposure to TNFα, and glucose deprivation. Moreover, I have found that knocking-down TRAP1 expression level through RNA interference in SAOS-2 osteosarcoma cells facilitates PTP opening, thus lowering the threshold for committing cells to death. TRAP1 modulates cell metabolism and possibly the response to oxidative stress by reducing mitochondrial respiration and the activity of respiratory chain complex I, with which TRAP1 directly interacts, both in cells and in tumor samples. Notably, down-modulation of TRAP1 ablates the tumorigenic potential of SAOS-2 cells both in vitro and in-vivo. Altogether, these data indicate that mitochondrial chaperones such as CyP-D and TRAP1 play an important role in tumor progression and constitute a possible target for anti-neoplastic intervention.Le cellule tumorali sono caratterizzate dalla capacità di evadere il normale signale apoptotico, così come mostrano una iper-attivazione costitutiva delle vie di signale kinasico. L’integrazione degli stimoli di sopravvivenza e morte si concentra nei mitocondri, dove molti di questi segnali convergono nella regolazione di un canale chiamato poro della transizione di permeabilità (PTP). L’apertura del PTP porta le cellule alla morte ed è regolata da una varietà di fattori e fra questi gli chaperoni giocano un ruolo fondamentale. Nel mio lavoro di tesi ho studiato come gli chaperoni mitochondriali si integrano nelle vie di trasduzione del segnale , modulando il PTP e più in generale la bioenergetica mitocondriale e come questi network regolatori controllano la vitalità cellualre. Nella prima parte del mio lavoro ho studiato una possibile connessione fra la via del segnale Ras/ERK, la cui attivazione costitutiva caratterizza molti tumori favorendo la loro crescita e sopravvivenza, e la ciclofilina D (CyP-D), uno chaperone mitocondriale che regola il PTP. Una frazione di ERK attivo è stato trovato nei mitocondri delle cellule RWPE-2, ottenute tramite trasformazione con v-ki-Ras a partire da cellule dell’epitelio prostatico RWPE-1; in cellule metastatiche di tumore prostatico DU145; e in cellule di osteosarcoma SAOS-2. Tutte queste cellule tumorali mostrano una marcata resistenza alla morte indotta da stimoli pro-apoptotici come l’acido arachidonico e il BH3 mimetico EM20-25, i quali inducono la morte cellulare attraverso il PTP mitocondriale. L’inibizione del PTP e la conseguente resistenza alla morte cellulare indotta da acido arachidonico o EM-20-25 può essere abolita dall’inibizione di ERK con il farmaco PD98059 o con un peptide selettivo inibitorio di ERK. L’inibizione di ERK aumenta la fosforilazione GSK-3 dipendente della CyP-D, mentre l’inibizione di GSK3 protegge dall’apertura del poro. Ne ERK attivo nei mitocondri, ne desensibilizzazione del poro è stata osservata in cellule non trasformate RWPE-1. In conclusione, nelle cellule tumorali l’attivazione dell’ERK mitocondriale desensibilizza il PTP attraverso un asse di segnale che coinvolge GSK3 e Cyp-D. Nella seconda parte del mio lavoro di tesi, ho studiato l’attività di un secondo chaperone mitocondriale, TRAP1/HSP75, fortemente espresso nelle cellule tumorali e che è stato proposto essere coinvolto nella regolazione del poro. Ho dimostrato che TRAP1 interagisce con la CyP-D ed ho caratterizzato la sua funzione di pro-sopravvivenza nei confronti di un vasto spettro di stimoli di morte, incluso lo stress ossidativo, la diamide, il TNFα, e la deplezione di glucosio. Inoltre ho trovato che il knocking-down dei livelli di espressione di TRAP1 attraverso la tecnica dell’RNA interference in cellule di osteosarcoma SAOS-2 facilita l’apertura del PTP, abbassando la soglia per portare le cellule alla morte. TRAP1 modula inoltre il metabolismo cellulare probabilmente la risposta allo stress ossidativo e l’attività della del complesso I della catena respiratoria, con il quale TRAP1 interagisce direttamente sia in cellule che campioni tumorali. La down- regolazione di TRAP1 abolisce il potere tumori genico delle cellule SAOS-2 sia in vitro che in vivo. Tutti insieme questi dati indicano che gli chaperoni mitocondriali come CyP-D e TRAP! Giocano un ruolo importante nella progressione tumorale e costituiscono un possibile target di nuove terapie antineoplastiche.
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Tamm, Christoffer. "Apoptotic cell death in neural stem cells exposed to toxic stimuli /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-301-6/.
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Ajabnoor, Ghada. "Mechanism of cell death in drug resistant human breast cancer cells." Thesis, University of Surrey, 2010. http://epubs.surrey.ac.uk/842867/.
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Anticancer drug resistance occurs as a result of altered response to cytotoxic insult, via inhibition or inactivation of apoptosis (programmed cell death type I, PCDI), which plays a major role in tumour development and progression. An alternative form of cell death - non-apoptotic, or autophagic cell death (PCD II) has recently emerged as a factor contributing to the cytotoxic response of cancer cells. We studied in vitro cell death in a drug resistant model MCF-7 human breast cancer cells with acquired resistance (c. 10- 20 fold) to paclitaxel, termed MCF-7TaxR. It has been reported that the absence of caspase-3 in parental MCF-7 cells (due to chromosome deletion) may explain why they recruit apoptotic and autophagic cell death following cytotoxic insult. We investigated the induction of apoptosis response to staurosporine and Z-VAD (pan-caspase inhibitor) using the Annexin V-FITC/PI assay and studied the effect of anti-Fas on MCF-7TaxR. Results demonstrated the lack of apoptosis induction in paclitaxel resistant breast cancer cells. The oligo GEAiTayRTM human apoptosis microarray and qPCR analysis confirmed the absence of caspase-7 and caspase-9 genes and many other apoptosis genes in MCF-7TaxR cells and their presence in MCF-7 cells. Western blot analysis also confirmed these results. Therefore, we investigated the presence of autophagic cell death in our MCF-7TaxR model. Flow cytometry using Acridine Orange assay, Beclin 1 and LC-3 protein detection, confocal microscopy and detection of Akt/mTOR expression. Data showed evidence of autophagic cell death in MCF-7TaxR cells in the absence of an apoptotic response. Collectively, these findings indicate the lack of involvement of caspase mediated cell death in a paclitaxel drug-resistant cancer cell line MCF-7TaxR, and presence of autophagic cell death as an alternative cell death mechanism.
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Jaligam, Vanaja. "Developmental cell death in the midline glia cells of Drosophila embryo." College Park, Md. : University of Maryland, 2004. http://hdl.handle.net/1903/1467.
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Thesis (M.S.) -- University of Maryland, College Park, 2004.Thesis research directed by: Dept. of Cell Biology and Molecular Genetics. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Wilkie, Alexander David. "Evasion of Cell Death in Burkitt’s Lymphoma and Pancreatic Cancer Cells." Thesis, Griffith University, 2016. http://hdl.handle.net/10072/367897.
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This thesis examined exploitation of cell death to combat cancer from two angles:
investigating cell death signalling pathways to find new targets for treatment, and using the novel anti-austerity approach to combat the tolerance of cancer cells to nutrient deprivation.
Cancers often display high levels of genetic diversity, even within cancers of a particular organ. These genetic differences often make treatments which work with a particular cancer ineffective on another - even from the same origin, and lead to differences in outcomes to selective pressures such as nutrient deprivation. Current treatments are aimed at killing rapidly proliferating cells and often have severe side effects. Their efficacy is highly dependent on early diagnosis and many cancers are resistant to chemotherapeutic drugs. In addition, cancer cells on the inside of tumours have the ability to survive under adverse conditions such as nutrient deprivation due to intermittent blood supply, Therefore, alternative treatment strategies must be explored.
Defects in cell death play a large contributing factor to cancer progression and tumour growth and the evasion of cell death by cancers presents a major problem in its treatment Conventional cancer treatment relies on the activation of cell death in fast growing cancer cells while attempting to leave normal cells undamaged. Therefore, selective triggering of cell death in a cancer cell would be extremely useful. In order to achieve this goal a thorough understanding of the cell death response of a particular cell type to a particular stimulus must be known. Moreover, any novel or unusual cell death signalling pathways would provide more opportunities and targets for attempting to trigger selective cell death in cancers.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Natural Sciences
Science, Environment, Engineering and Technology
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Latif, Lubna Salah Eldin Abdel. "Assessment of Cell Death Parameters in Bovine Parvovirus-Infected EBTr Cells." BYU ScholarsArchive, 2005. https://scholarsarchive.byu.edu/etd/445.
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Bovine parvovirus (BPV) is a helper-independent parvovirus. It has a small icosahedral capsid with a single stranded DNA genome. It is a highly stable virus with a narrow host range. It causes acute gastroenteritis in calves. It is considered to be a cytolytic virus because it kills the host cells. However, the mechanism by which the virus causes cell death is not known. The work described in this thesis assessed different parameters of cell death in BPV infected embryonic bovine tracheal (EBTr) cells. There are several ways for viruses to induce cell death. Viruses can induce apoptosis in the infected cell. They can also kill the host cell by necrosis. Several approaches were used in this work to look for evidence of apoptosis and necrosis. Cells undergoing apoptosis exhibit cardinal signs that distinguish them from other dying cells. Among these signs are the exposure of phosphatidylserine to the outer surface of the plasma membrane, DNA fragmentation into non-random DNA sections that are multimers of 180bp, nuclear morphology changes and caspase activation. These signs were studied in this research and data collected from these experiments did not show any positive sign of apoptosis in infected cells due to virus infection. Cells undergoing a necrotic cell death have a different pattern. The cells swell then burst releasing their cytoplasmic contents. The DNA is fragmented in a random fashion. Cellular morphology was studied in this research and the data suggested that BPV infected cells swell, then shrink and detach from the surface of the culture vessel. Moreover, formation of apoptotic bodies was not detected in dying infected cells. Release of cytoplasmic contents was also assessed by looking at concentrations of LDH enzyme, viral haemagglutinin, and the number of infectious viral particles in the media of infected cells. Data from the different approaches employed in this study do not support the hypothesis that BPV kills the infected EBTr cell by apoptosis, rather, infected cells in culture become necrotic, swell, release their cytoplasmic contents, and detach.
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Mai, Thi Trang. "Cell death mechanisms of Marmycin A and Salinomycin in cancer cells." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS014.
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Le produit naturel salinomycine (SAL) est largement utilisé comme médicament anticoccidien et maintenant de plus en plus reconnu comme un agent destiné à réduire la proportion de population CD44⁺ / CD24⁻ cellules souches du cancer du sein. Ce facteur est important et intervient lors des rechutes des tumeurs du sein. Pour la première fois, nous avons décrit que l'action n’était pas ionophorique mais que le proton dit "éponge" de la salinomycine ciblait particulièrement la population des cellules souches du cancer. De plus, un analogue alcyne-amine synthétisé de la salinomycine a une action similaire à cette dernière sur la population CD44⁺ / CD24⁻ mais à une concentration inférieure : 30 nM pour 500 nM pour la salinomycine. En utilisant la méthode de clic-imagerie, nous avons observé le composé incolore dans les lysosomes et les auto-lysosomes. En augmentant le pH des vésicules acides, la salinomycine et ses analogues inhibent les activités des cathepsines B, L et D empêchant ainsi l'autophagie. Cette autophagie joue un rôle important dans la survie des cellules souches du cancer conduisant à une augmentation du facteur ROS et à une mort cellulaire par apoptose. Notre étude donne un aperçu du mécanisme par lequel la salinomycine élimine les cellules souches cancéreuses et propose des stratégies pour le traitement de cancers résistantsA natural product Salinomycin (SAL) is widely used as an anticoccidial drug now being increasingly recognized as an agent for reducing the proportion of CD44⁺/CD24⁻ breast cancer stem cell which is perceived as important factor for breast tumor relapse. We first time report that not ionophoric action but the proton “sponge” of SAL is responsible for distinguishingly targeting cancer stem cell population. In addition, one SAL-analog alkyne-amine performed the similar action with SAL on CD44⁺/CD24⁻ population but at much lower concentration than SAL, at 30 nM compare to 500 nM of SAL. Using click-imaging method we visually observed the colorless compound saturated in lysosomes and autolysosomes. By raising pH of acidic vesicles, SAL and its analogs inhibit cathepsin B, L, D activity preventing the autophagy which plays an important role in cancer stem cell maintain and survival thus lead to cell death via increasing ROS and apoptosis. Our study provides the insight mechanism how SAL actually eradicates cancer stem cells and suggests sharpened strategies for treating resistant cancers
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Giampazolias, Evangelos. "Investigating non-apoptotic cell death in cancer." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8056/.
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Rijal, Dikchha. "Cell Death Signaling Complexes During Macrophage Differentiation." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/36455.
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Monocytes migrate to various tissues and differentiate to macrophages and mediate early control of pathogens. Various alternative pathways of cell death have been discovered which have been shown to play a key role in host survival. Herein, we investigated the impact of differentiation of monocytes to macrophages on their susceptibility to two distinct cell death inducing complexes, ripoptosome and necrosome. Our results indicate that differentiation of macrophages results in resistance to ripoptosome- but not necrosome- induced cell death. Additional experiments indicated that the resistance to ripoptosome signaling correlated with reduced caspase activation and enhanced expression of anti-apoptotic mediators XIAP and cFLIPL. Our results also reveal the contradictory roles of p38 MAPK/MK2 in stimulating (phosphorylating RipK1) or inhibiting (reducing TNF-α expression and caspase 8 activation) ripoptosome signaling. These findings reveal novel mechanistic insights that can be exploited for development of therapeutics.
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O'Hare, Michael J. "Cell cycle related signaling in neuronal death." Thesis, University of Ottawa (Canada), 2006. http://hdl.handle.net/10393/29368.
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Evidence indicates that neuronal loss in the course of neurodegenerative disease often occurs through programmed death processes. The development of effective therapeutic treatments for such diseases requires detailed knowledge of the intracellular signaling pathways controlling these death processes. Previous work has identified cyclin-dependent kinases, a family of kinases normally involved in the control of cell division, as potential regulators of death in neurons. For instance, a number of events that occur during the G1 to S transition in proliferating cells, such as cyclin D/cdk4 activation and phosphorylation of its target, pRb, have been detected in dying neurons and appear to be essential for death. In the cell cycle, pRb phosphorylation is followed by activation of the transcription factor E2F1. It is not known if E2F1 is also involved in neuronal death. I found that E2F1 expression in neurons induced apoptotic death dependent on Bax but independent of p53. Also, E2F1 mRNA and protein levels increase in neurons induced to die by exposure to low concentrations of K+, and neurons from E2F1 null mice are resistant to this death. These results are consistent with participation of endogenous E2F1 in neuronal death signaling.
Cdk5 is a member of the cyclin-dependent kinase family which does not have a function in the cell cycle. Instead cdk5, together with its binding partners p35 and p39, is involved in a variety of neuronal functions. Cleavage of p35 into a smaller p25 form has been shown to convert cdk5 into a death promoting kinase. However, it is not yet clear under which circumstances cdk5 signals death, and there is also some contrasting evidence suggesting cdk5 is a pro-survival factor. By targeting dominant negative cdk5 expression to either the nuclear or cytoplasmic compartments I show that cdk5 performs a pro-death function within the nucleus but a pro-survival function within the cytoplasm. The nuclear pro-death signal is relevant only when p25 is produced early, as it is following glutamate induced death, and not when it is produced late as a result of caspase activation, as it is following DNA damage.
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Lai, Xin-He. "Francisella tularensis infection induces macrophage cell death." Doctoral thesis, Umeå : Univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-295.
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Robey, Thomas Edwin. "Reducing fibrosis and cell death in cardiomyoplasty /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8031.
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Ménard, Isabelle. "Exploring the many facets of cell death." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111878.
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This thesis summarises research performed with the intent of exploring the many facets of cell death. In the first part of the thesis, the fate of the formin-homology domain containing protein FHOD1 during apoptosis is examined (research performed in the laboratory of Dr. Sophie Roy) and evidence for the cleavage of FHOD1 by caspase-3 at the SVPD616 site is demonstrated. Moreover, the C-terminal FHOD1 cleavage product is shown to translocate to the nucleolus where it inactivates RNA polymerase I transcription.In the second part of the thesis, the role of the RNA-binding protein HuR in cancer cell migration and invasion, as well as in multidrug resistance is determined using RNA interference to knockdown the expression of HuR in HeLa and KB-V1 cells respectively (research performed in the laboratory of Dr. Imed Gallouzi). In this part of the thesis, HuR is shown to promote cancer cell migration and invasion by stabilizing the beta-actin mRNA in a U-rich-dependent manner. Moreover, evidence is shown for the potential involvement of HuR in the phenomenon of multidrug resistance possibly through the post-transcriptional regulation of the multidrug resistance 1 gene.
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Palazzo, Francesco Fausto. "Programmed cell death in autoimmune thyroid disease." Thesis, Queen Mary, University of London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270709.
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Edwards, Susan N. "Regulation of cell death in sympathetic neurons." Thesis, University of Oxford, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.316898.
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Atkin, Charlotte J. "Developmental cell death in the rat brain." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393568.
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Loughery, Jayne Eleanor Patricia. "Mismatch repair, DNA methylation and cell death." Thesis, University of Ulster, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.551565.
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Mismatch repair is a vital DNA repair mechanism whose absence leads to a tolerance towards mutations and a predisposition to colon cancer. MLHl is one of the main proteins involved and is highly conserved from E. coli to human. It not only plays a role in repair, but can signal the cell to die if damage levels become too high. The mechanism by which MLHl triggers cell death in response to damage is not entirely clear, and is likely to differ between normal and cancerous cells. Previous work in the Walsh lab had generated MLH1-depleted subclones of a telomerase- immortalised normal human fibroblast cell line. These had been generated by transfecting the parental line hTERT-1604 with an shRNA vector against MLHl and selecting subclones which had reduction in MLHl to various degrees. I further characterised these MLHl knockdown cell lines and revealed that they also exhibit resistance to the methylating agent N-Methyl-N-Nitrosourea. Through the use of various assays we were able to determine that the hTERT immortalised cells did not undergo cell cycle arrest, apoptosis or senescence in response to MNU as colon cancer cell do. Instead, they undergo an MLH1-dependant form of programmed cell death mediated by PARP, but independent of caspase, P53 and ATM/ATR. In 2004, DNMTl deficiency was also implicated in causing MMR defects in mouse embryonic stem cells without a causal mechanism being identified. The effects of DNMTl deficiency are not the same in stem cells and differentiated cells. To determine if depletion of DNMTl can also cause MMR defects in normal human cells, I created DNMT1-depleted hTERT-1604 cells using the same shRNA-mediated strategy as above. Subsequent characterisation of the DNMT1-depleted subclones established that they have a reduction in DNA methylation and the most severely reduced cells are arrested at the G2/M checkpoint. Subclones with significant reductions in DNMT1 also exhibited a decrease in MLH1 expression at the protein, but not the mRNA level. This reduction in MLH1 expression was reversed when a protease inhibitor was employed. The subclone with 31% DNMT1 expression exhibited microsatellite instability, providing further evidence for an interaction between mismatch repair and DNMT1 in human cells and suggesting a mechanism by which this may occur. In conclusion, the work presented here demonstrates a novel role for the mismatch repair protein MLH1 in triggering PARP-dependent cell death in response to damage by MNU. It also shows a link between DNMT1 depletion and MMR deficiency through destabilisation of MLH1.
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Parnaik, Rahul. "Cell death and clearance in young animals." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284799.
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Kreuzaler, Peter Anton. "Cell death modalities in mammary gland involution." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609378.
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Wilkinson, Derek. "Proteases and programmed cell death in fungi." Thesis, University of Exeter, 2011. http://hdl.handle.net/10036/3629.
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Programmed cell death in animals, plants and protists is in part regulated by a variety of proteases, including cysteine aspartyl proteases, (caspases, paracaspases and metacaspases), cathepsins, subtilisin-like serine proteases, vacuolar processing enzymes and the proteasome. The role of different proteases in the cell death responses of the fungi is however largely unknown. A greater understanding of the fungal cell death machinery may provide new insights into the mechanisms and evolution of PCD and potentially reveal novel targets for a new generation of antifungal drugs. The role of a metacaspase encoding gene, MCA1, in the cell death response of the human pathogen Candida albicans pathogen has been investigated by functional analysis. MCA1 deletion not only alters the sensitivity of cells to a number of cell death stimuli, it also enhances virulence in an insect model. C. albicans shows altered cell and colony morphology on Lee’s medium. Evidence is presented to suggest that these functions appear to be dependent upon active mitochondria. In this study it has also been shown that key caspase substrates may be conserved between humans and the yeasts Saccharomyces cerevisiae and Candida albicans. Many substrates, particularly those which are essential, have retained their caspase cleavage motifs. 14 protease mutants displayed altered activity against caspase 1, 3, 6 or 8 substrates during acetic acid-induced PCD and caspase 1-like activity appeared to be particularly associated with PCD. Using a novel bioinformatic analysis of experimental LC-MS/MS data, changes in the degradation patterns of the proteome (destructome) following acetic acid-induced cell death have been investigated in wild-type yeast. In addition, potential native substrates of the yeast Mca1 have also been identified. The future challenge is to characterise the destructome of different proteases under a range of cell death conditions. In this way it may be possible to identify key components of the cell death machinery and their substrates and so reveal the most promising targets for future therapeutics.
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Dhillon, Harsharan. "Mechanisms of Piperlongumine-Induced Cancer Cell Death." Diss., North Dakota State University, 2015. http://hdl.handle.net/10365/25178.
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Piperlongumine (PPLGM), a bioactive agent obtained from long pepper plants, possesses
potent antitumor activity by inducing reactive oxygen species (ROS). However, the mechanisms
for PPLGM?s antitumor actions are not well defined. We investigated PPLGM?s antitumor
effects and molecular mechanisms against pancreatic and colon cancer, two of the leading causes
of cancer death for both men and women in the U.S. We found that PPLGM activated a ROSmediated
DNA damage pathway that lead to pancreatic cancer cell death in vitro. Further, mice
treated with PPLGM showed reduced pancreatic tumor volume, which was associated with a
decrease in tumor cell proliferation and enhanced oxidative stress levels. To elucidate the target
pathways responsible for PPLGM-mediated cell death, RNA sequencing was performed. 684
genes were differentially expressed in pancreatic cancer cells treated with PPLGM compared to
the control. Genes related to ER-stress and UPR pathways were activated in PPLGM-treated
pancreatic cancer cells. To determine the therapeutic efficacy of PPLGM in combination with
currently used chemotherapy in vivo, an orthotopic mouse model of pancreatic cancer was used.
The combination of PPLGM with gemcitabine resulted in greater reduction of tumor weight and
volume than either agent alone, and PPLGM-treated mouse tumors showed decreased expression
of Ki-67, a proliferation marker. In vitro studies supported the in vivo results where the
combination of PPLGM with gemcitabine and erlotinib significantly decreased pancreatic cancer
cell viability and survival, and induced apoptosis compared to control cells or cells treated with
the chemotherapeutic agents alone. PPLGM inhibited the growth of colorectal cancer cells to a
greater degree than normal colon cells and activated p-ERK protein expression. The use of a
MEK inhibitor attenuated the activation of p-ERK and partially blocked PPLGM-mediated cell
death, indicating the involvement of the MEK/ERK pathway in colon cancer cell death. These
results suggest PPLGM holds potential as a therapeutic agent to treat pancreatic and colon cancer
in the clinics.North Dakota State University. Department of Biological Sciences
NDSU Graduate School Doctoral Dissertation Fellowship
NDSU Center for Protease Research COBRE (NIH 2P20 RR015566, P30 GM103332-01)
NDSU Development Foundation Centennial
Engebretson Family Research Endowments