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1
Schymkowitz, Joost Wilhelm Hendrik. "Protein engineering studies on cell-cycle regulatory proteins." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621312.
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Gad, Annica. "Cell cycle control by components of cell anchorage /." Stockholm : Division of Pathology, Karolinska institutet, 2005. http://diss.kib.ki.se/2005/91-7140-359-0/.
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Dibble, Taylor Raymond. "Cell Cycle Regulation of the Centriolar Protein Ana2." Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/579244.
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The centrosome functions to nucleate microtubule growth and organize the mitotic spindle during cell division. The centrosome normally duplicates once per cell cycle, ensuring a bipolar spindle that divides sister chromatids equally between two daughter cells during mitosis. However, improper duplication or over-duplication of centrosomes can lead to chromosomal instability, a hallmark of cancer. Two barrel-shaped structures called centrioles function as the duplication factors for centrosomes. Mutations in important centriole structural proteins can cause either down-regulation or amplification of centriole duplication. One of these proteins, Ana2, is required for duplication and mutations in its human orthologue, STIL, can cause disorders in neurological development. Normally, Ana2 localizes to an existing ‘mother' centriole during S-phase and plays an essential role in the assembly of the procentriole that will become a mature ‘daughter' during G2. In this study, we identified changes in total cellular levels of Ana2 by arresting S2 Drosophila cells in different phases of the cell cycle and immunoblotting for Ana2. We found that levels of both endogenous Ana2 and transiently overexpressed Ana2 are low during G1 and increase during S-phase. Endogenous Ana2 levels were highest in G2, consistent with centriole maturation during this phase of the cell cycle.
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Ashford, Anne Louise. "The role of the protein kinase DYRK1B in cancer cell survival and cell cycle control." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648671.
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Gilker, Eva Adeline Gilker. "INTERACTIONS AND LOCALIZATION OF PROTEIN PHOSPHATASES, YWHA PROTEINS AND CELL CYCLE CONTROL PROTEINS IN MEIOSIS." Kent State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1532699317257539.
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Chan, Ho Man. "Molecular basis of cell cycle control : p300 and pRb." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326430.
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Vaillant, Remi. "The role of adenoviral capsid protein VI in cell cycle modulation." Thesis, Bordeaux, 2014. http://www.theses.fr/2014BORD0297/document.
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Les Adénovirus humains sont des virus non enveloppés se répliquant dans le noyau des cellules hôtes.Durant l’infection et après leur entrée par endocytose, les Adénovirus sont transportés au noyau pourinitier l’expression du génome viral. Dans l’endosome, les capsides virales subissent un désassemblagepartiel et libèrent le facteur viral lytique, la protéine VI (pVI). Au niveau de la membrane de l’endosome,cette protéine va alors induire sa rupture permettant ainsi le relargage des virions au sein du cytoplasmegrâce à son hélice amphipatique N-terminale. Par la suite, pVI est transportée vers des structuresnucléaires appelées PML nuclear bodies (PML-NB), associée une ubiquitine ligase cytoplasmique, laNedd4.2. Les PML-NB sont des complexes nucléaires multi-protéiques qui ont des propriétésantivirales. Celles-ci impliquent le recrutement de facteurs de transcription répressifs comme parexemple la protéine anti apoptotique Daxx ou encore le suppresseur de tumeur p53, impliqué dans larégulation du cycle cellulaire. Il a été montré que la protéine pVI en complexe avec Nedd4.2 induit larelocalisation de Daxx des PML-NB dans le cytoplasme, ce qui permet une expression efficace dugénome viral. Ainsi, l’inhibition fonctionnelle de Daxx par pVI suggère que cette protéine virale puisseaussi être impliquée dans la restriction de p53.Dans cette étude, nous avons montré que le nombre des modifications post-traductionnelles (PTM) dep53 augmentent en présence de pVI dans la cellule. De plus, les données obtenues montrent quel’expression de pVI affecte la transcription dépendante de p53 et que l’interaction avec Nedd4.2 n’estpas nécessaire pour inhiber les fonctions de p53. Pour étudier l’implication de pVI dans la modulationdu cycle cellulaire, nous avons créé une lignée cellulaire humaine exprimant cette protéine virale defaçon stable. La caractérisation de cette lignée a permis de mettre en évidence une prolifération cellulaireaccrue. Nos observations ont aussi montré une perte importante des PML-NB et une réduction desprotéines clés du cycle cellulaire p53 et pRb, un autre suppresseur de tumeur. Par des techniques demicro-injection et l’utilisation de l’inhibiteur MG132, nous avons observé que ces deux facteurscellulaires sont ciblés vers le protéasome et dégradés lors de la surexpression de pVI. L’étude desfonctions de cette protéine virale laisse penser que la protéine pVI présente un potentiel oncogéniquecar en effet, sa surexpression induit la dérégulation de l’homéostasie cellulaire et l’inhibition desuppresseurs de tumeur, comme p53 et pRbHuman Adenovirus are non-enveloped viruses which replicate inside the host cell nucleus. Uponinfection and after receptor-mediated entry, they are transported towards the nucleus to initiate the viralgene expression. Viral capsids deliver from the endosome into the cytoplasm by partial disassembly andrelease inside the endosome mediated by viral lytic factor protein VI (pVI). pVI is targeted to themembrane via an amphipathic helix structure in the N-terminus of the viral protein. After membranerupture and capsid release, pVI is transported to sub-nuclear structures, so-called PML nuclear bodies(PML-NBs), together with the cytoplasmic ubiquitin ligase Nedd4.2. PML-NBs represent multiproteinaggregates in the host-cell nucleus with an antiviral capacity, as to several PML-associated repressivetranscription factors, such as the anti-apoptotic Daxx protein and the tumor suppressor p53 were reportedto localize at these foci. In addition, pVI-mediated displacement of Daxx from PML-NBs was shown tooccur in dependency of Nedd4.2 to support efficient viral gene expression. Therefore, we postulate thatbesides Daxx functional inhibition, pVI might also be involved in p53 restriction.Here, we show that p53 posttranslational modification (PTM) is increased when pVI protein is presentin the host-cell. Moreover, we obtained data that pVI expression severely impacts p53 inducedtransactivation of cellular transcription. Biochemical approaches indicate that pVI binding of theubiquitin ligase Nedd4.2 is no prerequisite for the capacity to inhibit p53 functions. In a next step toelucidate the role of pVI on cell cycle regulation, we generated a human cell line stably expressing theviral pVI protein. Our characterization analyses show significantly that these cells benefit from thepresence of pVI as we proved increased cell proliferation rates. We also observed an intense loss ofPML-NBs and reduced protein concentrations of cycle key regulators p53 and pRb. Usingmicroinjection and the inhibitor MG132 we were able to show that both cellular restriction factors weresequestered into the proteasomal degradation pathway of the cell. Evaluation of pVI functions temptedus to speculate, whether pVI might execute oncogenic potential upon overexpression, due toderegulation of host-cell homeostasis and inhibition of tumor suppressive determinants
Humane Adenoviren (HAdV) sind unbehüllte Doppelstrang-DNA-Viren mit einem Proteinkapsid, diesich im Wirtzellkern replizieren. Der lytische Infektionsverlauf beginnt mit dem rezeptor-vermitteltenEintritt des Viruspartikels und dem gerichteten Transport des viralen Genoms zum Wirszellkern. Dasvirale Protein VI (pVI) ist nötig um den effizienten Austritt des bereits disassemblierten Viruspartikelsaus dem zellulären Endosom zu gewährleisten. Durch eine amphipathische Helix im N-terminalenProteinbereich interkaliert dieser lytische Faktor in die endosomale Membran und führt zum Aufbruchdes zellulären Organells. pVI wird anschließend an zelluläre Kernstrukturen, sogenannte PML nuclearbodies (PML-NBs) lokalisiert und komplexiert dort mit der zytoplasmatischen Ubiquitinligase Nedd4.2.PML-NBs stellen nukleäre Multiproteinkomplexe dar, die mittlerweile aufgrund ihrer antiviralenEigenschaften in den Mittelpunkt der virologischen Forschung gerückt sind. Diese zellulären Aggregatebestehen hauptsächlich aus repressiven Transkriptionsfaktoren, wie dem anti-apoptotischen DaxxProtein sowie dem Tumosupressor p53. In diesem Zusammenhang konnte bereits eine pVI-vermittelteRelokalisation des Daxx Proteins aus den PML-NBs gezeigt und als Vorraussetzung zur effizientenVirusgenexpression bestätigt werden. Es stellte sich im Rahmen der vorliegenden Arbeit die Frage, obneben der pVI-abhängigen Daxx Inhibition, auch p53 ein Zielprotein des viralen Capsidproteinsdarstellt.Unsere Arbeiten zeigen erstmals, dass nach der pVI Expression vermehrt posttranslationaleModifikationen am p53 Protein beobachtet werden. Weitere Befunde konnten außerdem einen Einflussvon pVI auf die p53-abhängige Transaktivierung zellulärer Promotoren beweisen. Mittelsbiochemischer Analysemethoden konnten wir zeigen, dass die Kooperation zwischen pVI und Nedd4.2keine Rolle bei der p53 Inhibition zu spielen scheint. Um im nächsten Schritt die Rolle von pVI imZellzyklus genau zu beleuchten, wurde zunächst ein zell-basiertes Modelsystem mit stabilerÜberexpression des viralen Faktors generiert, Anschließende phenotypische Analysen konnten zeigen,dass die Anwesenheit von pVI zur Steigerung der Zellproliferationsrate führt. Im Rahmen unsererUntersuchungen konnten wir auch einen signifikanten Verlust zellulärer PML-NBs beobachten sowieeine Reduktion der p53 und pRb Proteinkonzentration nachweisen. Mittels unter Verwendung vonMikroinjektion und dem Inhibitor MG132 war es uns möglich zu zeigen, dass pVI den proteasomalenProteinabbau der beiden Wirtszelldeterminaten p53 und pRb induziert. Deswegen kann man basierendauf den erhobenen Befunden zur pVI vermittelten Dysregulierung des zellulären Wachstums einonkogenens Potenzial des viralen Faktors annehmen
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Thomas, Elizabeth Baby. "Analysis of protein kinases regulating the Trypanosoma brucei cell cycle." Thesis, University of Glasgow, 2015. http://theses.gla.ac.uk/6229/.
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Trypanosoma brucei spp. are protozoan parasites that cause Human African Trypanosomiasis in humans, and Nagana in cattle. These diseases are mostly fatal if left untreated and there is an urgent need for safe, effective drugs that can be easily administered. T. brucei has a complex cell cycle, the regulation of which appears to be divergent compared to other model eukaryotes. This implies that the regulators of the T. brucei cell cycle could be exploited as a source of novel drug targets. One such cell cycle regulator of interest is T. brucei polo-like kinase (TbPLK), a serine/threonine protein kinase thought to diverge from its canonical functions in eukaryotic mitosis and be mainly involved in the duplication of the parasite’s cytoskeletal structures. This study sought to investigate how the activity and localisation of TbPLK is regulated in procyclic form (PCF) and bloodstream form (BSF) parasites. A second aim of this study was to identify novel protein kinases (PKs) which regulate the T. brucei cell cycle by screening part of a kinome-wide RNA interference (RNAi) library of BSF cell lines, that has recently been established (Jones et al. 2014). The cell lines had already been assessed for proliferation defects upon RNAi induction by using an Alamar blue viability assay. In this study, the cell lines which displayed proliferation defects were further screened for cell cycle defects using growth curves and DAPI staining, to identify as yet uncharacterised protein kinases required for T. brucei cell cycle regulation. 50 PKs had been shown to be required for viability in vitro and were screened for potential cell cycle roles. Of these, 25 were identified as potential cell cycle regulators, 15 of which were detected for the first time. The majority of the hits were deemed to be involved in either just cytokinesis, or cytokinesis in combination with kinetoplast duplication or mitosis, with surprisingly few in G1/S. Knockdown of a number of these putative cell cycle PKs induced cell death signifying their potential as drug targets. Indeed, one of the hits, CLK1, was genetically validated as a potential drug target in a mouse model. The identification of these putative cell cycle kinases has also provided valuable starting points by which the signalling pathways that regulate the cell division cycle of these parasitic organisms can be elucidated.
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Tait, Xavier Alastair Claude. "Investigation of human Pix protein regulation during cell cycle progression." Thesis, University of Leicester, 2012. http://hdl.handle.net/2381/10853.
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Proteomic analyses of centrosomes from diverse species are helping to identify conserved components of these organelles. Amongst these studies, a group of novel proteins has been identified and postulated as candidate core centriolar components, dubbed Poc proteins, for proteome of centriole. Meanwhile, studies on the Xenopus germ plasm protein, Xpat, led to the identification of an interacting protein, named Pix for protein that interacts with Xpat. Later sequence comparison revealed that Poc1 and Pix are the same protein and will here be referred to as Pix. Pix proteins localize to centrosomes and spindle poles in human cells and the basal bodies of Chlamydomonas and Tetrahymena. It has been suggested that Pix proteins are required for centriole duplication and length control, as well as potentially ciliogenesis. Pix proteins have also been localized to mitochondria in human cells where they might act as molecular adaptors to anchor microtubules to mitochondria. Human cells encode two Pix proteins and the aim of this thesis was to investigate the cell cycle-dependent regulation of Pix1 and Pix2 in human cells. For this purpose, we first generated polyclonal rabbit antibodies that were specific for either Pix1 or Pix2. We then showed for the first time that both Pix isoforms localize to centrosomes throughout the cell cycle and independently from one another. Using the antibodies, we also confirmed that Pix1, but not obviously Pix2, is not an intrinsic mitochondrial protein but localizes to the surface of mitochondria. Through a proteomic approach, we identified two molecular chaperons that potentially interact with Pix proteins, HSP90 and TCP1, and demonstrated that Pix proteins can form dimers. In addition, we produced the first experimental evidence that human Pix proteins are alternatively spliced, suggesting that additional, undiscovered Pix isoforms might be expressed in human cells. Finally, we found that Pix1 is phosphorylated in a mitosis-specific manner, and that this is potentially regulated by Cdk1. Thus, we propose that Pix proteins have a specific and previously unidentified role in human mitotic cell division.
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Helt, Anna-Marija. "Multiple biological activities of the human papillomavirus type 16 E7 oncoprotein contribute to the abrogation of human epithelial cell cycle control /." Thesis, Connect to this title online; UW restricted, 2002. http://hdl.handle.net/1773/11514.
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Potapova, Tamara. "Exploring mechanisms that control the activity of cyclin-dependent kinase 1 during mitotic transitions in somatic cells." Oklahoma City : [s.n.], 2009.
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Lowery, Drew M. "Modulation of mitotic progression and cell cycle checkpoints by phosphorylation-dependent protein-protein interactions." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/40953.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2007.Includes bibliographical references.
Alteration of mitotic gene function has recently been discovered to play a key role in tumor formation and cancer progression through the induction of chromosomal aberrations and genomic instability. Polo-like-kinase-1 is a critical mitotic regulator, overexpressed in human tumors, that functions in mitotic entry after cellular stress, centrosome maturation, mitotic spindle control, and cytokinesis, which are all disregulated in cancer cells. To study the role of Polo-like kinases we took advantage of the recent discovery that the polo-box domain of Polo-like kinases is a phosphorylation-dependent binding module that regulates targeting of Polo-like kinases to their substrates. To identify the interactors of Polo-box domains we developed and performed a mitotic-specific yeast two hybrid and a pulldown mass spectrometry screen. This yielded a large number of specific interactors known to be involved in a vast variety of mitotic processes including those previously described to be involved in tumor progression. We demonstrate that Polo-like kinase regulation of cytokinesis-specific guanine-nucleotide exchange factors for the small G-protein Rho is necessary for proper actomyosin ring contraction and cytokinesis. Additionally we demonstrate that Polo-like-kinase-1 directly regulates the activity of the Rho-effector-kinase ROCK2, and thus Polo-like kinases modulate Rho signaling both upstream and downstream of Rho during cytokinesis. In addition to Polo-box domains we also worked on two other phosphorylation-dependent binding domains involved in cell cycle checkpoints that become disregulated in cancer cells, tandem BRCT domains and WW domains.
(cont.) We examined the molecular basis for phosphorylation-dependent recognition by the tandem BRCT domains of BRCA1 through oriented-peptide-library screening and determination of an X-ray crystal structure of the domain bound to a phosphopeptide. This allowed us to rationalize why inherited mutations within the tandem BRCT domains of BRCA1 promote breast and ovarian cancer in humans. Secondly, we assayed WW domains that were generated from in silicon determined sequences for natural-like function to more fully understand the folding and binding requirements of this domain class. All three domains (tandem BRCT domains, Polo-box domains, and WW domains) are attractive targets for cancer therapeutics as they participate in control of processes necessary for genomic stability that become disregulated in cancer.
by Drew M. Lowery.
Ph.D.
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Wells, Glenn Paul. "Swi6 protein interactions and the regulation of the yeast cell cycle." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271950.
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Hindley, Christopher Jon. "Regulation of the proneural protein xNgn2 by cell cycle-mediated phosphorylation." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609878.
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Hong, Angela M. "Cell cycle protein expression in AIDS-related and classical Kaposi's sarcoma." Connect to full text, 2004. http://hdl.handle.net/2123/583.
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Thesis (Ph. D.)--University of Sydney, 2004.Title from title screen (viewed 5 May 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Faculty of Medicine. Includes list of published articles and presentations. Includes bibliographical references. Also available in print form.
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Hong, Angela Manyin. "Cell cycle protein expression in AIDS-related and classical Kaposi's sarcoma." Thesis, The University of Sydney, 2004. http://hdl.handle.net/2123/583.
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Kaposi�s sarcoma (KS) is a peculiar vascular neoplasm that occurs mainly in elderly Mediterranean men and patients with acquired immunodeficiency syndrome (AIDS). The current literature indicates that KS is initiated by the human herpes virus 8 (HHV8) as a reactive polyclonal process but with deregulation of oncogene and tumour suppressor genes, it can progress to a true malignancy with monoclonality. Clinically, classical KS often presents as an indolent disease affecting mainly the lower extremities whereas AIDS-related KS has no site predilection and can progress rapidly with systemic involvement. Histologically, KS can be classified into patch, plaque and nodular stages. Interestingly, classical and AIDS-related KS are indistinguishable histologically and this suggests that AIDS-related KS and classical KS might be initiated by a common aetiology but given their different clinical courses, they may progress through different mechanisms. In view of the importance of the cell cycle proteins in the development and progression of many human malignancies, this thesis aims to examine the role of these proteins in the progression of the two main clinical subtypes of KS. The cell cycle protein expressions in a cohort of 47 patients with KS with welldocumented clinical and histological features were studied. Using a monclonal antibody against the latent nuclear antigen-1 molecule of HHV8, HHV8 was detected in 78% of the cases. The more advanced nodular lesions were found to have a higher level of proliferative activity as measured by the proliferation x marker, Ki-67. This suggests it is valid to use the histological specimens as a tumour progression model of KS. The role of the Rb/cyclin D1/p16 pathway was examined. The more advanced nodular stage KS lesions were more likely to be positive for cyclin D1, suggesting that cyclin D1 is important in the progression from patch stage to nodular stage. p16 acts as a tumour suppressor and it has an inhibitory effect on cyclin D1. The p16 expression rate was low in early stage KS but high in the more advanced lesions. It seems that reduced p16 expression occurs early in KS and may be important in its development. The rate of Rb expression, on the other hand, did not differ significantly among the histological subtypes. The results revealed the significant role of the Rb/cyclin D1/p16 pathway in the progression of KS. Of the mitotic cyclins examined, cyclin A expression was correlated with the advanced tumor stage. The rate of p34cdc2 expression was high in the lesions and there was no correlation with histological stage. This suggests that p34cdc2 is important in the early development of the tumour but not necessarily in its progression. Along the p53-apoptotic pathway, mutant p53 expression was significantly more common in the nodular stage. The cyclin G1 (a protooncogene, one of the target genes of p53) expression also paralleled that of mutant p53 with the majority of the KS lesions showing cyclin G1 expression and significant xi correlation between advanced histological stage and increasing rate of cyclin G1 expression. These findings suggest that progression along the p53 pathway may be important in the advanced stage development of KS. On the other hand, expression of the CDK inhibitor, p27, a protein that normally negatively regulates cyclin G1, was reduced in nodular KS. These findings suggest that some KS lesions may progress through a deregulated or abnormal p53 pathway. There were correlations between cyclin D1, cyclin A, cyclin G1, mutant p53 and negative HIV status. The findings suggest that components of both the Rb/cyclin D1/p16 and p53-apoptotic pathways are important in the progression of classical KS. Rb protein was the only cell cycle protein whose rate of expression correlated significantly with HHV8 status in KS. The majority of HHV8 positive lesions were also positive for Rb protein, unlike HHV8 negative lesions. This suggests that some of the HHV8 negative lesions can progress through a defective Rb pathway whereas the role of Rb in the progression may not be as important in the HHV8 positive lesions. This was an unexpected finding given that one of the postulated mechanisms of tumour initiation by the HHV8 virus is via the viral cyclin it produces. The viral cyclin produced by HHV8 acts through the Rb pathway much the same as cyclin D1 and one would have expected that HHV8 positive cases are less likely to be positive for the Rb protein. In summary, the majority of the KS lesions examined in this thesis show HHV8 infection. The Rb/cyclin D1/p16 pathway appears to be important in the progression of the different stages of KS and expression of the proteins involved in the p53 pathway were found to be important in the advanced stages of the development of KS. There were differential expressions of cell cycle proteins between AIDS-related and classical KS, and between HHV8 positive and HHV8 negative lesions. The findings also provided some clues to the possible mechanisms of development in KS lesions that were not initiated by HHV8.
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Hong, Angela Manyin. "Cell cycle protein expression in AIDS-related and classical Kaposi's sarcoma." University of Sydney. Pathology, 2004. http://hdl.handle.net/2123/583.
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Kaposi�s sarcoma (KS) is a peculiar vascular neoplasm that occurs mainly in elderly Mediterranean men and patients with acquired immunodeficiency syndrome (AIDS). The current literature indicates that KS is initiated by the human herpes virus 8 (HHV8) as a reactive polyclonal process but with deregulation of oncogene and tumour suppressor genes, it can progress to a true malignancy with monoclonality. Clinically, classical KS often presents as an indolent disease affecting mainly the lower extremities whereas AIDS-related KS has no site predilection and can progress rapidly with systemic involvement. Histologically, KS can be classified into patch, plaque and nodular stages. Interestingly, classical and AIDS-related KS are indistinguishable histologically and this suggests that AIDS-related KS and classical KS might be initiated by a common aetiology but given their different clinical courses, they may progress through different mechanisms. In view of the importance of the cell cycle proteins in the development and progression of many human malignancies, this thesis aims to examine the role of these proteins in the progression of the two main clinical subtypes of KS. The cell cycle protein expressions in a cohort of 47 patients with KS with welldocumented clinical and histological features were studied. Using a monclonal antibody against the latent nuclear antigen-1 molecule of HHV8, HHV8 was detected in 78% of the cases. The more advanced nodular lesions were found to have a higher level of proliferative activity as measured by the proliferation x marker, Ki-67. This suggests it is valid to use the histological specimens as a tumour progression model of KS. The role of the Rb/cyclin D1/p16 pathway was examined. The more advanced nodular stage KS lesions were more likely to be positive for cyclin D1, suggesting that cyclin D1 is important in the progression from patch stage to nodular stage. p16 acts as a tumour suppressor and it has an inhibitory effect on cyclin D1. The p16 expression rate was low in early stage KS but high in the more advanced lesions. It seems that reduced p16 expression occurs early in KS and may be important in its development. The rate of Rb expression, on the other hand, did not differ significantly among the histological subtypes. The results revealed the significant role of the Rb/cyclin D1/p16 pathway in the progression of KS. Of the mitotic cyclins examined, cyclin A expression was correlated with the advanced tumor stage. The rate of p34cdc2 expression was high in the lesions and there was no correlation with histological stage. This suggests that p34cdc2 is important in the early development of the tumour but not necessarily in its progression. Along the p53-apoptotic pathway, mutant p53 expression was significantly more common in the nodular stage. The cyclin G1 (a protooncogene, one of the target genes of p53) expression also paralleled that of mutant p53 with the majority of the KS lesions showing cyclin G1 expression and significant xi correlation between advanced histological stage and increasing rate of cyclin G1 expression. These findings suggest that progression along the p53 pathway may be important in the advanced stage development of KS. On the other hand, expression of the CDK inhibitor, p27, a protein that normally negatively regulates cyclin G1, was reduced in nodular KS. These findings suggest that some KS lesions may progress through a deregulated or abnormal p53 pathway. There were correlations between cyclin D1, cyclin A, cyclin G1, mutant p53 and negative HIV status. The findings suggest that components of both the Rb/cyclin D1/p16 and p53-apoptotic pathways are important in the progression of classical KS. Rb protein was the only cell cycle protein whose rate of expression correlated significantly with HHV8 status in KS. The majority of HHV8 positive lesions were also positive for Rb protein, unlike HHV8 negative lesions. This suggests that some of the HHV8 negative lesions can progress through a defective Rb pathway whereas the role of Rb in the progression may not be as important in the HHV8 positive lesions. This was an unexpected finding given that one of the postulated mechanisms of tumour initiation by the HHV8 virus is via the viral cyclin it produces. The viral cyclin produced by HHV8 acts through the Rb pathway much the same as cyclin D1 and one would have expected that HHV8 positive cases are less likely to be positive for the Rb protein. In summary, the majority of the KS lesions examined in this thesis show HHV8 infection. The Rb/cyclin D1/p16 pathway appears to be important in the progression of the different stages of KS and expression of the proteins involved in the p53 pathway were found to be important in the advanced stages of the development of KS. There were differential expressions of cell cycle proteins between AIDS-related and classical KS, and between HHV8 positive and HHV8 negative lesions. The findings also provided some clues to the possible mechanisms of development in KS lesions that were not initiated by HHV8.
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Chen, Chunnuan. "Animal cell culture in a fibrous-bed bioreactor : protein production, cell immobilization, and cell cycle and apoptosis /." The Ohio State University, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=osu148819366523437.
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Helton, Eric Scott. "A role for p63 in the regulation of cell cycle progression and cell death." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. http://www.mhsl.uab.edu/dt/2007p/helton.pdf.
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Atway, Nader G. "The Association of Cell Cycle and Growth Related Protein Kinases with the Fibroblast Cytoskeleton." Connect to online version at Digital.Maag Connect to online version at OhioLINK ETD, 1999. http://hdl.handle.net/1989/4814.
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Sahota, Navdeep Kaur. "Cell cycle studies on the human Nek3, Nek5 and Nek11 protein kinases." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/9452.
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The NIMA-related kinases represent a family of serine/threonine protein kinases implicated in cell cycle control and ciliogenesis. The founding member of this family, the NIMA kinase of Aspergillus nidulans, contributes to multiple aspects of mitotic progression including the timing of mitotic entry, chromatin condensation, spindle organisation and mitotic exit. Mammals contain a family of eleven NIMA related kinases, named Nek1 to Nek11. Of these, to date there is substantial evidence that Nek2, Nek6, Nek7 and Nek9 regulate mitotic spindle formation, while Nek1 and Nek8 are implicated in microtubule organisation in non-dividing cells during ciliogenesis. The common underlying theme between spindle formation and ciliogenesis is the role of microtubules and microtubule organising centres. Hence, the emerging hypothesis is that all Neks may play a role in the organisation of microtubules. However, for several Neks, little if any information is available. In this thesis, I therefore began to examine the properties of three less well researched human Neks, Nek3, Nek5 and Nek11. First of all, antibodies against each of these kinases were generated or characterised. This allowed a broad study of the localisation, expression and activity of these kinases. Intriguingly, Nek3, Nek5 and Nek11 were all localised to centrosomes. Based on these results a more detailed study was performed with human Nek5 for which there is currently no published data. Human Nek5 is a nuclear protein that localises to the centrosomes during interphase, spindle poles during early mitosis, and to basal bodies in mono- ciliated cells. Specifically, Nek5 localised at the proximal ends of centrioles peaking in intensity in early mitosis. Importantly, siRNA-mediated depletion of Nek5 results in premature centrosome splitting and loss of centrosomal γ-tubulin. Hence, Nek5 is uncovered as a potential player in the negative regulation of centrosome separation.
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Crozier, Thomas William Monteiro. "Proteomic analysis of protein complexes and cell cycle regulation in Trypanosoma brucei." Thesis, University of Dundee, 2016. https://discovery.dundee.ac.uk/en/studentTheses/1f6425b2-ab6e-4827-84ca-d1268dea1dee.
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Trypanosoma brucei is a unicellular trypanosomatid protozoan parasite and the etiological agent of sleeping sickness in sub-Saharan Africa. The trypanosomatid order also includes the parasites Trypanosoma cruzi (Chagas disease) and Leishmania major (Leishmaniasis). Sleeping sickness is estimated to cause ~10,000 deaths per year and current treatments are expensive, difficult to administer and toxic. Although genomic sequencing of all three parasites has identified the coding sequences of these organisms, much is still unknown about protein function, with 64% of identified genes annotated as “hypothetical”, lacking obvious homology with proteins of known function. To further understand the unusual biology of this family of eukaryotes, this thesis aimed to provide evidence for protein function in Trypanosoma brucei in a high-throughput manner, utilising global proteomic analyses. This work has encompassed two main approaches: The global analysis of protein interactions and the analysis of proteome changes across the cell-cycle. To enable these approaches, I developed protocols for proteome wide analysis of protein complexes in Trypanosoma brucei, combining multiple forms of chromatography on ‘native’ lysates of cells to produce a proteome wide map of core, soluble protein complexes in this organism. I further performed preliminary studies to optimise in vivo formaldehyde crosslinking in T. brucei in order to characterise membrane bound protein complexes. I also developed methodologies to produce large populations of procyclic T. brucei cells highly enriched in different phases of the cell-cycle for proteomic analysis. In conjunction with the optimisation of methods for isobaric tag quantitation on Fusion mass spectrometers, I provide the first characterisation of protein regulation during cell division in T. brucei at an unparalleled proteomic depth. Together, these datasets provide a wealth of information about the interaction and cell cycle regulation of many thousands of proteins in T. brucei, and contributes greatly to the understanding of protein function in trypanosomatid organisms. I highlight the ability of these methods to predict novel protein complexes, predict interactions between “hypothetical” proteins with proteins of known function, and to identify “hypothetical” cell-cycle regulated proteins that are essential for growth of the parasite, that are a potentially interesting source for novel drug targets. Data visualisation tools to browse the data in a user-friendly format will further allow the trypanosmatid research community to mine these datasets to understand function of proteins of interest and continue to extract functional information from these datasets to extend our understanding of trypanosomatid biology.
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Milojkovic, Ana [Verfasser]. "The tumour suppressor protein p14ARF regulates cell cycle checkpoint control and induces cell death / Ana Milojkovic." Berlin : Freie Universität Berlin, 2010. http://d-nb.info/1024744140/34.
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Hung, Kwok Wang. "Identification of the EphA4-interacting proteins by yeast two-hybrid screening /." View abstract or full-text, 2006. http://library.ust.hk/cgi/db/thesis.pl?BICH%202006%20HUNG.
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Linseman, Tara. "Functional Analysis of a Coding Variant In ZC3HC1 at 7q32.2 Associated with Protection Against Coronary Artery Disease (CAD)." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34329.
Full textAbstract:
Coronary artery disease (CAD), characterized by the narrowing of coronary
arteries through the complex manifestation and development of atherosclerosis, is a
complex disease and one of the leading causes of death worldwide. Both genetic
and environmental factors are believed to contribute equally to the risk of CAD.
Recently, a study identified a non-synonymous coding variant, rs11556924, (MAF,
0.38) in ZC3HC1 associated with protection against CAD (p= 9.8x10-18; OR= 0.90).
NIPA, encoded by ZC3HC1, is a characterized F-Box protein and regulator of cell
cycle. Since the amino acid change (Arg363His) is in a conserved region of NIPA
and is predicted to have functional effects (Polyphen-2), this study aimed at
understanding the functional implications of this amino acid change on NIPA and cell
cycle regulation. Here we are able to effectively show a) allele specific differences in
mRNA expression in whole blood, b) a slight structural difference between
NIPA363Arg and NIPA363His variants, c) proliferation rates of NIPA363Arg
expressing cells were significantly increased, and d) phosphorylation of a critical
serine residue in close proximity to aa.363 is not statistically different between the
two variants. These results suggest that rs11556924 plays a direct role in
development of CAD through its disruption of cell cycle regulation and NIPA mRNA
availability. This study is the first to identify a molecular basis for the association of
rs11556924 to CAD development.
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Bartosch, Birke. "The stability and turnover of Xenopus cyclin E." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341884.
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Martinho, Rui Goncalo V. R. C. "Analysis of Rad3 and Chk1 checkpoint protein kinases." Thesis, University of Sussex, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297946.
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Hassumani, Daniel Omar. "Expression of Growth Arrest and DNA Damage Protein 45-alpha (gadd45-alpha) and the CCAAT/enhancer binding protein-delta (C/EBP-delta) in Fishes Exposed to Heat and Hypoxia." PDXScholar, 2013. https://pdxscholar.library.pdx.edu/open_access_etds/943.
Full textAbstract:
The cellular stress response (CSR) is one of the most highly conserved mechanisms among all organisms. Cellular stress can be defined as damage or the threat of damage to proteins, macromolecules and/or DNA. The response to damage can involve cell cycle regulation, protein chaperoning, DNA repair or, if macromolecular damage is too severe, apoptotic mechanisms can be initiated. This thesis details experiments that were designed to examine the cellular response to non-lethal environmental stressors at the protein level, using two fish species as study models. Two proteins that can cause cell cycle arrest and apoptosis mechanisms were examined. Expression of the CCAAT enhancer binding protein-delta (C/EBP-[delta]) was examined in the zebrafish, Danio rerio, exposed to acute, non-lethal hypoxic conditions. While C/EBP-[delta] was expressed constitutively in control individuals during all time points, exposure to hypoxic conditions did not have a consistent significant effect on C/EBP-[delta] expression (two-way ANOVA, P>0.05) in zebrafish white muscle tissue. In a second study, the expression of the growth arrest and DNA damage 45-alpha protein (gadd45-[alpha], a mediator of cell cycle arrest and perhaps apoptosis was examined in heat-stressed liver tissue of an extremely cold-adapted Antarctic fish, Trematomus bernacchii. Gadd45-[alpha] levels were higher in fish exposure to 2°C across all time points (one-way ANOVA; P
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Andrusiak, Matthew. "Differential Roles for the Retinoblastoma Protein in Cycling and Quiescent Neural Populations." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/24037.
Full textAbstract:
While the genetics of retinoblastoma and the implications of the retinoblastoma susceptibility gene, RB1, are well described, there is still scarce evidence to suggest why RB1 acts in such a cell-type specific manner. Using the murine cortex as a model, we examined the effects of RB1 deletion of cycling neural progenitors and post-mitotic neurons, in order to ascertain cell-type specific functions in the central nervous system. Using the previously identified cell-cycle independent role for Rb in tangential migration, we validated Rb/E2f regulation of neogenin and implicated it in this process. In quiescent cortical neurons, we identified a pivotal role for Rb in neuronal survival. Unlike in cycling progenitors, in post-mitotic neurons Rb specifically represses the expression of cell-cycle associated genes in an E2f-dependent manner. Finally, in cortical neurons in the absence of Rb, we observe an activation of chromatin at E2f associated promoters. To determine the role of direct interaction between Rb and chromatin modifying enzymes, we utilized an acute LXCXE-binding deficient mutant paradigm. We report that the LXCXE binding motif is dispensable in establishment and maintenance of cortical neuron quiescence and survival. The activation state of E2f-responsive promoters appears to be dependent on E2f-activity and not simply Rb-mediated repression. Taken as a whole, this thesis serves to support the hypothesis that Rb plays a diverse role in different cell-types by regulation of unique gene targets and regulatory mechanisms. Characterizing specific cancer-initiating populations and understanding the specific function of Rb will help in the treatment of many cancers resulting from RB1 mutation or mutation within the Rb/E2f pathway.
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Mokashi, Alison Ann. "Thymoquinone the evaluation of its cytotoxic potential effects on P53 status and the cell cycle in various cancer cell lines /." Lexington, Ky. : [University of Kentucky Libraries], 2004. http://lib.uky.edu/ETD/ukyphsc2004t00141/Mokashi.pdf.
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Thesis (M.S.)--University of Kentucky, 2004.Title from document title page (viewed June 21, 2004). Document formatted into pages; contains viii, 76 p. : ill. Includes abstract and vita. Includes bibliographical references (p. 69-74).
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Son, Sunghun. "Systematic analysis of phosphatase genes in aspergillus nidulans and a role of FCP1 in cell cycle regulation." The Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1196228508.
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Bernard, Emmanuelle Alexa. "Cloning and characterisation of the Xenopus laevis bloom's protein." Thesis, University of Sussex, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367351.
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Dieckhoff, Patrick. "Protein modification and degradation in the cell cycle of the yeast Saccharomyces cerevisiae." Doctoral thesis, [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972638644.
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Zalli, Detina. "Regulation of the human Nek8/NPHP9 protein during cell cycle progression and ciliogenesis." Thesis, University of Leicester, 2012. http://hdl.handle.net/2381/10326.
Full textAbstract:
The primary cilium, once considered an evolutionary vestige, has re-emerged as an essential organelle for the normal functioning of a wide variety of cellular processes. It is now clear that it has important roles in the control of cell proliferation and signalling during development, with defects in primary cilia being a major cause of many human diseases. These disorders, collectively referred to as ciliopathies, include the cystic kidney diseases that are characterized by aberrant cell proliferation and cyst formation. Mutations in the NIMA-related kinase, Nek8, are associated with cystic kidney disease in both humans and mice, with Nek8 being the candidate NPHP9 gene in the human juvenile cystic kidney disease, nephronophthisis. Previous localisation studies have shown that Nek8 localises to centrosomes and cilia in dividing and ciliated cells, respectively, strengthening the ciliary hypothesis of cystic kidney disease. However, the role of Nek8 in ciliogenesis remains to be defined and no substrates for this kinase have yet been identified. In this thesis, I present data from a series of biochemical and cell biology experiments aimed at investigating the regulation and function of Nek8 with respect to cell cycle progression and ciliogenesis. I first of all show that localization of Nek8 to centrosomes and cilia is dependent upon both its kinase activity and its C-terminal non-catalytic RCC1 domain. Interestingly, Nek8 was capable of phosphorylating the RCC1 domain, which in isolation also localized to centrosomes and cilia. This leads us to propose that centrosome recruitment is mediated by the RCC1 domain, but requires a conformational change in the full-length protein that is promoted by autophosphorylation. I then established conditions required for measurement of Nek8 catalytic activity. Besides confirming the predicted activity of catalytic site mutants, this revealed that the three NPHP9-associated point mutants did not exhibit loss of activity. However, as one of these mutants, H425Y, failed to localize correctly, we predict that this mutation, which lies in the RCC1 domain, alters the RCC1 conformation such that it disrupts its centrosome targeting motif. Importantly, I also show that serum starvation induces proteasomal degradation of Nek8, specifically in cell lines in which serum starvation induces quiescence and ciliogenesis. Strikingly, serum starvation also induces Nek8 kinase activity, whilst maintained expression of Nek8 appears to suppress ciliogenesis. Taken together, these findings not only reveal important mechanisms through which Nek8 activity and localization are regulated, but suggest that Nek8 itself may have both positive and negative activities in the process of ciliogenesis.
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Landsberg, Rebecca L. (Rebecca Lynn) 1975. "The role of E2F·pocket protein repressive complexes in cell cycle control and differentiation." Thesis, Massachusetts Institute of Technology, 2003. http://hdl.handle.net/1721.1/29363.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2003.Includes bibliographical references.
The pocket protein family is comprised of pRB (the protein product of the retinoblastoma susceptibility gene), p107, and p130. This family regulates the GI/S transition by interacting with their major downstream target, the E2F transcription factor. E2F is a heterodimeric protein composed of one DP subunit and one E2F subunit. The E2F family can be subdivided into three categories based upon structural and functional homology: E2F6; the 'activating E2Fs' (1-3); and 'the repressive E2Fs' (4-5). The focus of this study is E2F4 and E2F5, the members of the repressive E2F subgroup. The repressive E2Fs function by occupying E2F responsive promoters during Go and recruiting in the pocket proteins. As cells begin cycling, E2F4 and E2F5 are replaced at promoters by members of the activating E2Fs subgroup. Loss of either E2F4 or E2F5 does not result in cell cycle defects but instead lead to the abnormal development of specific tissues. The lack of a cell cycle phenotype in single mutants could be due to compensation by the other repressive E2F. In order to determine the role that E2F4·pocket protein repressive complexes play in regulating cell cycle control, differentiation, and development, mice lacking E2F4 and two members of the pocket protein family, p107 and p130, were generated. Analysis of mouse embryonic fibroblasts derived from mutant embryos revealed that while loss of E2F4 alone did not lead to defects in cell cycle control, it did significantly enhance the ability of cells to differentiate into adipocytes. This phenotype could be further enhanced by additional loss of p107 and p130. Analysis of mice lacking E2F4, p107, and p130 revealed a requirement for these proteins in regulating fetal hematpoiesis. Taken together, these data suggest that E2F·pocket protein repressive complexes are critical regulators of differentiation and development.
by Rebecca L. Landsberg.
Ph.D.
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BEAUMAN, SHIRELYN RAE. "THE FUNCTION OF CALCIUM/CALMODULIN DEPENDENT PROTEIN KINASE II IN CELL CYCLE REGULATION." University of Cincinnati / OhioLINK, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1054300335.
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Fülöp, Katalin. "Analysis of two plant protein complexes associated with transcription and cell cycle progression." Szegedi Tudományegyetem, 2005. http://www.theses.fr/2005PA112194.
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Escoté, Miró Xavier. "Control of cell cycle progression by the last MAPK Hog1." Doctoral thesis, Universitat Pompeu Fabra, 2005. http://hdl.handle.net/10803/7186.
Full textAbstract:
Exposure of yeast to increases in extracellular osmolarity activates the stress-activated Hog1 MAP kinase, which is essential for cell survival upon osmotic stress. Activation of the Hog1 MAPK results in cell growth arrest, suggesting a possible role of the MAP kinase in the control of the cell cycle. Our results have shown that Hog1 activation resulted in accumulation of cells in the G1/S and G2/M transitions. At G1, Hog1 regulates the cell cycle progression by a dual mechanism that involves downregulation of G1 cyclin expression and direct targeting of the CDK-inhibitor protein Sic1. The MAPK interacts with Sic1, and phosphorylates a single residue of Sic1, which, in combination with the downregulation of cyclin expression, results in Sic1 stabilization and inhibition of cell cycle progression. Consistently, sic1_ cells, or cells containing a SIC1 allele mutated in the Hog1 phosphorylation site, are unable to arrest at G1 phase after Hog1 activation, and become sensitive to osmostress. Together, our data indicate that Sic1 is the molecular target for Hog1 that is required to modulate cell cycle progression in response to stress at G1. On the other hand, activation of the Hog1 MAPK also results in an increase of cells in the G2 phase. Arrested cells displayed down regulation of the Clb2-Cdc28 kinase activity and consequently enlarged buds, defects in spindle formation and orientation. These effects were prevented by deletion of the SWE1 gene. Thus, swe1Ä cells failed to arrest at G2, which resulted in a premature entry into mitosis and mislocalization of nuclei. Consistently, swe1Ä cells were osmosensitive. Swe1 degradation was reduced in response to activation of Hog1. Swe1 accumulation is mediated by the activity of the complex Hsl1-Hsl7. Hog1 phosphorylates a single residue at the regulatory domain of Hsl1, which leads to the mislocalization of Hsl7 from the bud neck, and consequent Swe1 accumulation. In addition, Hog1 downregulates G2 cyclin expression, reinforcing the inhibition of cell cycle progression at G2/M. These results indicate that Hog1 imposes a delay in critical phases of cell cycle progression necessary for proper cellular adaptation to new extracellular conditions.
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Wang, Haizhen. "The C-Phycocyanin/Beta Protein Inhibits Cancer Cell Proliferation." unrestricted, 2008. http://etd.gsu.edu/theses/available/etd-04212008-155113/.
Full textAbstract:
Thesis (M.S.)--Georgia State University, 2008.Title from file title page. Zhi-Ren Liu, committee chair; Delon W. Barfuss, Jenny J. Yang, committee members. Electronic text (69 p. : ill. (some col.)) : digital, PDF file. Description based on contents viewed June 11, 2008. Includes bibliographical references (p. 61-67).
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Zarkowska, Tamara Anna. "Phosphorylation of the retinoblastoma protein, pRB, by CDK4-cyclin D1." Thesis, Institute of Cancer Research (University Of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321951.
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Bhaduri, Samyabrata. "Regulation of CDK1 Activity during the G1/S Transition in S. cerevisiae through Specific Cyclin-Substrate Docking: A Dissertation." eScholarship@UMMS, 2014. http://escholarship.umassmed.edu/gsbs_diss/871.
Full textAbstract:
Several cell cycle events require specific forms of the cyclin-CDK complexes. It has been known for some time that cyclins not only contribute by activating the CDK but also by choosing substrates and/or specifying the location of the CDK holoenzyme. There are several examples of B-type cyclins identifying certain peptide motifs in their specific substrates through a conserved region in their structure. Such interactions were not known for the G1 class of cyclins, which are instrumental in helping the cell decide whether or not to commit to a new cell cycle, a function that is non-redundant with B-type cylins in budding yeast. In this dissertation, I have presented evidence that some G1 cyclins in budding yeast, Cln1/2, specifically identify substrates by interacting with a leucine-proline rich sequence different from the ones used by B-type cyclins. These “LP” type docking motifs determine cyclin specificity, promote phosphorylation of suboptimal CDK sites and multi-site phosphorylation of substrates both in vivo and in vitro. Subsequently, we have discovered the substrate-binding region in Cln2 and further showed that this region is highly conserved amongst a variety of fungal G1 cyclins from budding yeasts to molds and mushrooms, thus suggesting a conserved function across fungal evolution. Interestingly, this region is close to but not same as the one implicated in B-type cyclins to binding substrates. We discovered that the main effect of obliterating this interaction is to delay cell cycle entry in budding yeast, such that cells begin DNA replication and budding only at a larger than normal cell size, possibly resulting from incomplete multi-site phosphorylation of several key substrates. The docking-deficient Cln2 was also defective in promoting polarized bud morphogenesis. Quite interestingly, we found that a CDK inhibitor, Far1, could regulate the Cln2-CDK1 activity partly by inhibiting the Cln2-substrate interaction, thus demonstrating that docking interactions can be targets of regulation. Finally, by studying many fungal cyclins exogenously expressed in budding yeast, we discovered that some have the ability to make the CDK hyper-potent, which suggests that these cyclins confer special properties to the CDK. My work provides mechanistic clues for cyclinspecific events during the cell cycle, demonstrates the usefulness of synthetic strategies in problem solving and also possibly resolves long-standing uncertainties regarding functions of some cell cycle proteins.
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Dessalles, Renaud. "Stochastic models for protein production : the impact of autoregulation, cell cycle and protein production interactions on gene expression." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLX005/document.
Full textAbstract:
Le mécanisme de production des protéines, qui monopolise la majorité des ressources d'une bactérie, est hautement stochastique: chaque réaction biochimique qui y participe est due à des collisions aléatoires entre molécules, potentiellement présentes en petites quantités. La bonne compréhension de l'expression génétique nécessite donc de recourir à des modèles stochastiques qui sont à même de caractériser les différentes origines de la variabilité dans la production ainsi que les dispositifs biologiques permettant éventuellement de la contrôler.Dans ce contexte, nous avons analysé la variabilité d'une protéine produite avec un mécanisme d'autorégulation négatif: c'est-à-dire dans le cas où la protéine est un répresseur pour son propre gène. Le but est de clarifier l'effet de l'autorégulation sur la variance du nombre de protéines exprimées. Pour une même production moyenne de protéine, nous avons cherché à comparer la variance à l'équilibre d'une protéine produite avec le mécanisme d'autorégulation et celle produite en « boucle ouverte ». En étudiant un modèle limite, avec une mise à l'échelle (scaling), nous avons pu faire une telle comparaison de manière analytique. Il apparaît que l'autorégulation réduit effectivement la variance, mais cela reste néanmoins limité : un résultat asymptotique montre que la variance ne pourra pas être réduite de plus de 50%. L'effet sur la variance à l'équilibre étant modéré, nous avons cherché un autre effet possible de l'autorégulation: nous avons observé que la vitesse de convergence à l'équilibre est plus rapide dans le cadre d'un modèle avec autorégulation.Les modèles classiques de production des protéines considèrent un volume constant, sans phénomènes de division ou de réplication du gène, avec des ARN-polymérases et les ribosomes en concentrations constantes. Pourtant, les variation au cours du cycle de chacune de ces quantités a été proposée dans la littérature comme participant à la variabilité des protéines. Nous proposons une série de modèles de complexité croissante qui vise à aboutir à une représentation réaliste de l'expression génétique. Dans un modèle avec un volume suivant le cycle cellulaire, nous intégrons successivement le mécanisme de production des protéines (transcription et traduction), la répartition aléatoire des composés à la division et la réplication du gène. Le dernier modèle intègre enfin l'ensemble des gènes de la cellule et considère leurs interactions dans la production des différentes protéines à travers un partage commun des ARN-polymérases et des ribosomes, présents en quantités limitées. Pour les modèles où cela était possible, la moyenne et la variance de la concentration de chacune des protéines ont été déterminées analytiquement en ayant eu recours au formalisme des Processus Ponctuels de Poisson Marqués. Pour les cas plus complexes, nous avons estimé la variance au moyen de simulations stochastiques. Il apparaît que, dans l'ensemble des mécanismes étudiés, la source principale de la variabilité provient du mécanisme de production des protéines lui-même (bruit dit « intrinsèque »). Ensuite, parmi les autres aspects « extrinsèques », seule la répartition aléatoire des composés semble avoir potentiellement un effet significatif sur la variance; les autres ne montrent qu'un effet limité sur la concentration des protéines. Ces résultats ont été confrontés à certaines mesures expérimentales, et montrent un décalage encore inexpliqué entre la prédiction théorique et les données biologiques, ce qui appelle à de nouvelles hypothèses quant aux possibles sources de variabilité.En conclusion, les processus étudiés ont permis une meilleure compréhension des phénomènes biologiques en explorant certaines hypothèses difficilement testables expérimentalement. Des modèles étudiés, nous avons pu dégager théoriquement certaines tendances, montrant que la modélisation stochastique est un outil important pour la bonne compréhension des mécanismes d'expression génétiqueThe mechanism of protein production, to which is dedicated the majority of resources of the bacteria, is highly stochastic: every biochemical reaction that is involved in this process is due to random collisions between molecules, potentially present in low quantities. The good understanding of gene expression requires therefore to resort to stochastic models that are able to characterise the different origins of protein production variability as well as the biological devices that potentially control it.In this context, we have analysed the variability of a protein produced with a negative autoregulation mechanism: i.e. in the case where the protein is a repressor of its own gene. The goal is to clarify the effect of this feedback on the variance of the number of produced proteins. With the same average protein production, we sought to compare the equilibrium variance of a protein produced with the autoregulation mechanism and the one produced in “open loop”. By studying the model under a scaling regime, we have been able to perform such comparison analytically. It appears that the autoregulation indeed reduces the variance; but it is nonetheless limited: an asymptotic result shows that the variance won't be reduced by more than 50%. The effect on the variance being moderate, we have searched for another possible effect for autoregulation: it havs been observed that the convergence to equilibrium is quicker in the case of a model with autoregulation.Classical models of protein production usually consider a constant volume, without any division or gene replication and with constant concentrations of RNA-polymerases and ribosomes. Yet, it has been suggested in the literature that the variations of these quantities during the cell cycle may participate to protein variability. We propose a series of models of increasing complexity that aims to reach a realistic representation of gene expression. In a model with a changing volume that follows the cell cycle, we integrate successively the protein production mechanism (transcription and translation), the random segregation of compounds at division, and the gene replication. The last model integrates then all the genes of the cell and takes into account their interactions in the productions of different proteins through a common sharing of RNA-polymerases and ribosomes, available in limited quantities. For the models for which it was possible, the mean and the variance of the concentration of each proteins have been analytically determined using the Marked Poisson Point Processes. In the more complex cases, we have estimated the variance using computational simulations. It appears that, among all the studied mechanisms, the main source of variability comes from the protein production mechanism itself (referred as “intrinsic noise”). Then, among the other “extrinsic” aspects, only the random segregation of compounds at division seems to have potentially a significant impact on the variance; the other aspects show only a limited effect on protein concentration. These results have been confronted to some experimental measures, and show a still unexplained decay between the theoretical predictions and the biological data; it instigates the formulations of new hypotheses for other possible sources of variability.To conclude, the processes studied have allowed a better understanding of biological phenomena by exploring some hypotheses that are difficult to test experimentally. In the studied models, we have been able to indicate theoretically some trends; hence showing that the stochastic modelling is an important tool for a good understanding of gene expression mechanisms
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Ho, Chui Chui. "Characterization of the regulation of p53 and checkpoint kinases in DNA integrity checkpoints /." View abstract or full-text, 2006. http://library.ust.hk/cgi/db/thesis.pl?BICH%202006%20HO.
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Hu, Yun. "Study of the yeast Noc3p homolog in human cells /." View abstract or full-text, 2006. http://library.ust.hk/cgi/db/thesis.pl?BICH%202006%20HU.
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Schramm, Carolin. "Functional characterisation of the spindle pole body component Bbp1p." Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366182.
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Rodríguez, José M. "Bcl-2 related ovarian killer, Bok, is cell cycle regulated and sensitizes to stress-induced apoptosis." [Tampa, Fla.] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0002146.
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Siam, Rania. "Mechanisms of C. crescentus regulation of chromosome replication by a cell cycle regulator protein." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37838.
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Caulobacter crescentus divides asymmetrically to produce two different progeny, a swarmer progeny that is replication incompetent, and a stalked cell progeny that is replication competent. Upon cell division, a cell cycle regulator protein (CtrA) was identified only in the swarmer cells, and additional circumstantial evidence links this protein to being a repressor of chromosome replication. For example, this response regulator protein binds to five specific sites in the replication origin (Cori) designated [a-e]. We carefully studied the binding characteristics of both phosphorylated (CtrA~P) and unphosphorylated forms of the protein to the five binding sites [a-e] in the replication origin (Chapter 2) and upstream of the ctrA gene (Chapter 3). We showed that phosphorylation significantly enhances binding affinity in the replication origin (Chapter 2) but not upstream of ctrA (Chapter 3). In addition a "pseudo-active" protein form (CtrA D51E) that resembles the phosphorylated form in vivo did not improve the binding characteristics (Chapter 3). These results suggest that enhanced binding on phosphorylation is not the only signal achieved on phosphorylation. In fact, CtrA half-site mutation binding studies shows that phosphorylation stimulates protein/protein interaction and cooperative binding between sites [a] and [b] in the replication origin (Chapter 2). We show that CtrA binding site [b] is the major contributor in the cooperative CtrA binding between [a] and [b] (Chapter 4). We demonstrate that cooperative binding of CtrA~P to sites [a] and [b] repress transcription from a strong promoter (Ps), which in turn blocks plasmid replication. In addition, mutating site [b] to block CtrA binding to [a] and [b] has a deleterious effect on chromosome replication (Chapter 4).This cooperative CtrA binding at [a] and [b] is independent from the upstream binding sites [c-e] (Chapter 2). CtrA∼P binding in the origin is altered in the presence of the histone-like protein (IHF) that also binds and overlaps CtrA binding site [c] (Chapter 5). In-fact, IHF binds and overlaps binding site [c] (Chapter 5). We propose a replication model in the stalked cell were IHF binding hinders active CtrA binding in the replication origin and regulates cooperative transcription that coincides with replication initiation.
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Fenger, Douglas David 1969. "The pan gu protein kinase : regulator of the early embryonic cell cycle in drosophila." Thesis, Massachusetts Institute of Technology, 1999. http://hdl.handle.net/1721.1/85289.
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Chin, Wing Hong. "Identification of TrkB as a p35 interacting protein and a Cdk5 substrate /." View abstract or full-text, 2005. http://library.ust.hk/cgi/db/thesis.pl?BICH%202005%20CHIN.
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Clark, Alysen. "The Role of the Retinoblastoma Protein in Dentate Gyrus Development." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/23742.
Full textAbstract:
New neurons continue to be added to the dentate gyrus (DG) throughout adulthood and enhancing neurogenesis in this region holds therapeutic potential. However, the molecular mechanisms underlying DG neurogenesis remain elusive. Since developmental and adult neurogenesis often share the same signaling pathways, understanding how the DG develops is crucial to understanding adult neurogenesis. This study aims to determine the role of the retinoblastoma (Rb) protein in DG development and to determine if modulation of this pathway holds potential for enhancing neurogenesis in an adult system. A FoxG1 driven Cre is used to delete Rb in the developing forebrain and the resulting effects are analyzed in in vitro and in vivo mouse models. We show that Rb deletion enhances DG neurogenesis by specifically increasing proliferation of immature neurons. Overall this study suggests that Rb pathway modulation could hold potential for enhancing neurogenesis in the adult.