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1
Cuddihy, Jane. "The non-Wnt functions of APC : unravelling the link between APC and apoptosis." Thesis, University of Dundee, 2016. https://discovery.dundee.ac.uk/en/studentTheses/bfb0d6ce-149b-4152-a591-943d61e2c714.
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Colorectal cancer (CRC) is the second most common cause of cancer-related death in the UK and Western world. More than 90% of sporadic CRCs harbour mutations in the multi-functional tumour suppressor gene Adenomatous polyposis coli (Apc). The most commonly studied function of APC is its role as a scaffold for the β-catenin destruction complex involved in Wnt signalling. However, APC binds many other proteins. For example, it directly binds to and stabilises microtubules and actin. These non-Wnt related functions of APC are poorly understood. My PhD examines non-Wnt functions of APC. To this end, I created degron-tagged APC in DT40 cells that allowed for the rapid, conditional degradation of endogenous APC. The aim was to identify the immediate effects on cellular processes. Then, to identify the contribution of different APC domains by measuring the ability to rescue any defects when reintroducing fragments of APC. However, creation of these degron-tagged Apc knock-in cell lines resulted in hypomorphic phenotypes and auxin-associated off-target effects. Nonetheless, I compared the response of APChigh, APClow, and APCminimal cells to DNA damaging agents and Taxol® but found no significant differences. Subsequently, I focused on the relationship between APC and apoptosis. Previous observations suggested that deficiency in Apc rendered cells less sensitive to low doses of Taxol®. However, Apc deficient cells were more readily killed when Taxol® was combined with the Bcl-2 inhibitor, ABT-737. One possible explanation is the increase in Bcl-2 protein upon Apc depletion. However, I found that ABT-737, Taxol® and Apc depletion each cause activation of the unfolded protein response. This suggests that these treatments elicit a stress response that can stimulate apoptosis. Moreover, the same treatments also cause changes in mitochondria. Importantly, all of these effects do not require an increase in the β-catenin protein. Together, my data reveal novel links between APC and apoptosis that could be exploited clinically.
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Rauh, Nadine. "Regulation des APC/C Inhibitors ERP1." Diss., lmu, 2006. http://nbn-resolving.de/urn:nbn:de:bvb:19-52598.
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McCaffery, Dennis. "The role of Apc in medulloblastoma." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/2693.
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Medulloblastomas represent the most frequent malignant brain tumour in children, and are thought to develop in the posterior fossa of the cerebellum. Some patients with medulloblastomas have a deficiency in the tumour suppressor gene Apc (Turcot’s syndrome). Although the majority of medulloblastomas arise sporadically, people with Apc mutations are 92 times more likely to develop medulloblastomas. Apc encodes a very large protein known to function as a regulator of the Wnt signalling pathway. Activation of the canonical Wnt pathway leads to the stabilisation of beta-catenin. In response to Wnt signals, beta-catenin translocates to the nucleus where it interacts with the LEF/TCF family of transcription factors to activate transcription of target genes such as c-myc and cyclinD1. Mutations of Apc that cause an increase in beta-catenin are found to be tumourgenic, whereas other mutations are not. Therefore it is thought that the main tumour suppression function of Apc is in its ability to destabilise and hence reduce cytoplasmic beta-catenin. The central hypothesis of this thesis is that the loss of Apc can lead to the development of medulloblastoma. Work from other groups has reported activation of Wnt signalling in a proportion of primary medulloblastomas. We undertook a study to assess this by using the cre-loxP recombination system to mutate Apc in a temporal and spatial manner. This approach is necessary as Apc has many functions in development and Apc mutant mice (Apcmin) do not develop past embryonic day 6.5 (E6.5). To date, there are no known cre-strains available to mutate Apc specifically in the cerebellum at early postnatal stages, so we combined the creloxP method with an avian retrovirus mediated method for tissue specific gene delivery (RCAS/tv-a system), in an attempt to create a strain of mice which carried the genotype Ntv-a +;ApcLoxP/LoxP. This would allow us to infect an RCAS-cre virus directly into the hindbrain at postnatal day 4 (P4). However subsequent genotyping of these animals showed that none carried the desired genotype of Ntv-a +;ApcLoxP/LoxP, making it impossible for both copies of Apc to be mutated in a mouse most likely because both the Ntv-a and Apc transgenes were located on the same chromosome. Consistent with this, out of a total of 265 mice none were found to have the Ntv-a +;ApcLoxP/LoxP genotype. We then adopted an alternative method for mutating Apc by infecting ApcLoxP/LoxP mice directly with an AdCre virus. PCR analysis showed that Apc was mutated, however the AdCre virus did not infect cells of the cerebellum, and instead only infected the choroid plexus. In these animals, 7 of 94 (7%) developed hydrocephalus indicating that losing Apc in the choroid plexus may promote hydrocephalus. Finally, to address the role of Apc in normal hindbrain development, we crossed our ApcLoxP/LoxP mice to an En1cre strain which caused mutation in Apc from E8.5 in the midhindbrain region. The resulting En1cre+;ApcLoxP/LoxP mutants displayed hydrocephalus in all ventricles and an in-growth of mesenchyme tissue at the mid-hindbrain border, closely associated with a tumour-like area of cells showing activated Wnt signalling. No mice were found to live past E18.5. In conclusion, the role of Apc in medulloblastoma remains unclear. Future studies could use a different technique to mutate Apc such as crossing ApcLoxP/LoxP mice to the new nestin-creER strain and inducting cre with administration of tamoxifen.
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Menéndez, Vilà Mireia. "Variants del gen APC i càncer colorectal." Doctoral thesis, Universitat de Barcelona, 2007. http://hdl.handle.net/10803/1885.
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Les mutacions germinals d'elevada penetrància del gen APC que originen una proteïna truncada són les responsables de la majoria de casos de poliposi, mentre que les variants missense, que canvien un aminoàcid de la proteïna, es detecten en una minoria dels casos. S'han identificat diverses variants missense en el gen APC, però el seu potencial patogènic és encara motiu de controvèrsia, el què limita la utilitat de la seva detecció en el consell genètic. L'estudi de la presència de les variants en la població control i en les diferents poblacions de càncer colorectal (CCR) esporàdic i hereditari, juntament amb la realització d'anàlisis funcionals, podrien ajudar a conèixer l'impacte de les variants del gen APC en el desenvolupament del CCR. El nostre objectiu és determinar el significat funcional de les variants identificades en el gen APC en pacients afectes de poliposi adenomatosa familiar en relació al risc de desenvolupar CCR tant esporàdic com hereditari.L'anàlisi molecular de la regió codificant del gen APC realitzat en 138 famílies amb poliposi adenomatosa familiar clàssica (n= 98) i poliposi adenomatosa familiar atenuada (n= 40) ha permès la identificació de deu variants missense del gen APC: G101E, K957N, N1026S, L1129S, I1307K, E1317Q, D1822V, A2274V, G2502S i P2681L. En el nostre estudi s'han caracteritzat amb diferent profunditat set d'aquestes deu variants: G101E, N1026S, L1129S, D1822V, A2274V, G2502S i P2681L. La variant APC G101E, identificada en una família de poliposi clàssica, no s'associa a la malaltia ni sembla tenir cap funció modificadora del fenotip de poliposi. L'efecte biològic de les variants APC A2274V i APC P2681L, identificades en dues famílies de poliposi, és encara desconegut. La variant APC G2502S és un polimorfisme que no sembla tenir rellevància clínica. La variant APC L1129S, identificada en dues famílies de poliposi, no altera la interacció de la proteïna APC 4x15 amb la beta-catenina. La variant APC D1822V és un polimorfisme que incrementa el risc de desenvolupar CCR en pacients amb història prèvia d'adenomes i no s'associa amb la història familiar de CCR. La variant APC N1026S, que està present de forma exclusiva en una família de poliposi adenomatosa familiar atenuada, disminueix la unió d'APC amb beta-catenina i activa moderadament la transcripció mitjançada pel complex beta-catenina/Tcf-4. Aquests resultats indiquen que la variant APC N1026S és patogènica i és la mutació responsable del desenvolupament de la poliposi atenuada a la família on es va identificar.
La caracterització funcional de les variants del gen APC és de gran importància per conèixer la seva contribució en el desenvolupament de la poliposi i facilitar l'assessorament genètic.
Truncating germline mutations in the APC gene are responsible for the majority of Familial Adenomatous Polyposis (FAP) cases, while in a minority of cases missense mutations, leading to single amino acid changes, are detected. Germline missense variants in the APC gene have been reported although their contribution to FAP is controversial, limiting their use in genetic counseling. The aim of this thesis is to determine the functional relevance of the variants identified in the APC gene in FAP patients in order to establish its pathogenicity.
The molecular analysis of the APC gene was performed in 138 classical (n= 98) and attenuated (n= 40) FAP families and allowed the identification of ten missense variants. In this thesis, seven out of these ten APC variants have been characterised: G101E, N1026S, L1129S, D1822V, A2274V, G2502S and P2681L. The APC G101E variant, identified in a classical FAP family, is not associated with the disease. The biological effect of APC A2274V and APC P2681L variants, identified in two FAP families, remains unknown. The APC G2502S variant is a polymorphism without clinical relevance. The APC L1129S variant, identified in two FAP families, does not modify the interaction of the APC 4x15 protein with beta-catenin. The APC D1822V variant is a polymorphism associated with an increased risk of adenoma transformation and does not associate with family history of colorectal cancer. The APC N1026S variant, identified for the first time in an attenuated FAP family, diminishes beta-catenin binding to APC and moderately activates beta-catenin/Tcf-4-mediated transcription. These findings strongly support a pathogenic role of the APC N1026S variant in the AFAP phenotype.
In summary, functional characterization of APC variants is crucial to elucidate their contribution to FAP and improve genetic counseling.
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Ivaniutsin, Uladzislau. "The role of Apc in cortical development." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/29174.
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This thesis is devoted to examining the role of Apc protein in the development of the mouse telencephalon. As Apc-/- embryos die at gastrulation, a conditional knock-out approach was used to examine Apc’s role in cortical development. Mutant mice with conditional (flowed) alleles of Apc were crossed to a strain in which Cre expression is driven by the Emx1 promoter (Emx1Cre), allowing specific deletion of Apc in the dorsal telencephalon. The current work presents a detailed description and possible explanations of Apc’s functions in the developing cerebral cortex. Conditional knock-out of Apc in the cortex led to severe developmental defects in this region, showing that Apc is required for normal development of the cerebral cortex. The deletion of Apc leads to over-activation of the canonical Wnt pathway and disregulation of PCP Wnt pathway. I examined the expression of regional markers in the residual dorsal telencephalon in conditional Apc mutant embryos. Expression of Foxg1 is lost, showing that the mutant dorsal telencephalon loses telencephalic identify from E12.5. My data show that Apc is important for proper patterning of the cortex probably mostly by antagonizing the canonical Wnt pathway. Measurement of cell-cycle times revealed that in the absence of Apc, S-phase and cell cycle length remains similar to controls. Deletion of Apc in the dorsal telencephalon leads to defects in maintenance of the size of the progenitor pool and regulation of apoptosis. The conditional Apc deletion has a pleiotropic effect on cortical development. Developmental defects found include disregulation of Wnt signalling, loss of cell polarity, adhesion defects, cell identify defects, and disregulation of apoptosis. Assignment of these defects to particular functions of Apc is not completely clear yet.
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Naughton, Catherine. "Analysing Apc function in the mammary gland." Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/23133.
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Tickenbrock, Lara. "Das Tumorsuppressor-Protein APC strukturelle und biochemische Aspekte /." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=966017064.
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Cullingworth, J. "Tumour suppression mediated through DPC4, P53 and APC." Thesis, University of Edinburgh, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.649002.
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Mutations in the tumour suppressor genes SMAD4 (or DPC4, deleted in pancreatic cancer locus 4), APC (adenomatous polyposis coli) and p53 have been implicated in pancreatic cancer in humans. This thesis firstly documents the in vivo effects of mutations in these genes singly and in combination through spontaneous and carcinogen-induced murine models of pancreatic tumourigenesis. Second, it examines the in vitro effects of TGF-β signalling, of which Smad4 is the central mediator, on murine primary cultured pancreatic acinar cells. Previously p53-/- ApcMin/+ mice have been shown to develop pancreatic tumours. To examine the effect of Smad4 heterozygous mutation on the development of these tumours, Smad4+/- mutation was introduced into p53-/- and p53-/- ApcMin/+ mice. No pancreatic phenotype was found in p53-/-Smad4+/- animals. p53-/- ApcMin/+ Smad4+/- animals did not exhibit promotion of tumourigenesis in any tissue compared to the p53-/-ApcMin/+ mice. Immunohistochemical studies revealed loss of Smad4 protein within the majority of the lesions arising in p53-/-ApcMin/+Smad4+/- animals. Furthermore microdissection and mutational analysis revealed LOH for Apc and Smad4. Treatment of wild-type (WT) Smad4+/-, ApcMin/+ or ApcMin/+ Smad4+/- mice with N-Nitroso-N-Methyl Urea (NMU) resulted in abnormal foci in pancreatic acinar cells characterised by β-catenin stabilisation. Previously these foci have been shown to be the precursors of pancreatic neoplasia. Interestingly, only NMU-treated ApcMin/+Smad4+/- mice exhibit a significant increase in abnormal pancreas, which was found to be due to increased number of abnormal foci rather than increased focus size. A range of foci sizes were analysed, but only smaller abnormal foci were characterised by morphological nuclear atypia. These studies suggest functional co-operation between TGF-β and Wnt signalling pathways in the suppression of pancreatic tumourigenesis in the mouse.
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Segditsas, Stefania. "Mechanisms of intestinal tumorigenesis resulting from APC mutations." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/15923/.
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Colorectal cancer typically arises through the sequential accumulation of mutations in different genes. Mutations in the adenomatous polyposis coli (APC) gene are thought to be the initiating step in this sequence of events and are found in the majority of early colorectal tumours. Investigation of these lesions has revealed that selection of 'optimal' combinations of mutations at the APC locus is in place, but the roles of such selected combinations have never been clarified. In the work presented in this thesis, I have demonstrated that similar constraints on APC mutations are active in tumours from attenuated FAP (AFAP) patients and that given the sub-optimal location of the germline APC mutation in these patients, additional somatic mutations are often required, especially in patients with germline mutations in the alternatively spliced region of exon 9. I have also shown that APC promoter hypermethylation does not appear to play a fundamental role in the selection of optimal APC genotypes. I have shown that the optimum combinations of mutations at APC are those that allow retention of some APC activity with respect to β-catenin degradation and that this has effects on the resulting activation of the Wnt signalling pathway. Optimal combinations of APC mutations result in intermediate nuclear β-catenin levels, which surprisingly highly activate a selection of Wnt targets. In an attempt to identify novel Wnt targets that are important for tumorigenesis and could serve as therapeutic targets, I have validated results from a cross-species comparison that identified a set of genes showing consistent differential expression between early tumour samples carrying APC mutations and normal tissue. In addition, I have investigated the biological function of one such-identified molecule, the serum/glucocorticoid-regulated kinase (SGK1), and I have revealed its potential role as a key regulator of intestinal cell differentiation and apoptosis.
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Sporri, Roman Andreas. "Reciprocal control of T cell and APC activation." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411991.
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Kelly, Shane. "Proteomic analysis of APC deficient mouse intestinal epithelium." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609442.
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Rossanese, Lillian Barbosa de Queiroz 1980. "Estudo de mutações no gene APC em famílias com polipose adenomatosa familiar = APC germile mutations in families with familal adenomatous polyposis." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/313231.
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Orientador: Carmen Silvia BertuzzoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Mutações germinativas no gene APC (Polipose adenomatosa coli) são responsáveis pela ocorrência de polipose adenomatosa familiar (PAF). Mutações somáticas levam à transformação maligna de adenomas. O objetivo desse trabalho foi identificar mutações germinativas no gene APC. No presente estudo, 20 pacientes com PAF foram estudados. A determinação das mutações germinativas no APC foi realizada por meio de sequenciamento, e as mutações foram comparadas com marcadores clínicos (sexo, idade no momento do diagnóstico, tabagismo, estádio TNM, classificação Coller-Astler e o grau de diferenciação do adenocarcinoma). Os dados foram comparados por meio do programa SPSS , com o teste de Fisher e teste de ?2 , considerando ? = 0,05. De acordo com os principais resultados da nossa amostra, 16 alelos com mutações deletérias (80 % dos pacientes) foram identificados, enquanto 7 (35%) pacientes não tinham mutações deletérias. Houve um predomínio de mutações nonsense (45% dos pacientes) e de mutações frameshift (20% dos pacientes). Não houve significância estatística entre as mutações germinativas identificadas e as variáveis clínicas consideradas em nosso estudo. Apenas a fase TNM foi associada com a presença de mutações deletérias. Os portadores com mutações deletérias tinha uma OR , 0,086 ( IC = 0,001-0,984 ); TNM I + II em comparação com III + IV , quando comparado com os pacientes sem mutações deletérias identificados. Neste estudo, demonstramos a heterogeneidade molecular de mutações germinativas no APC em portadores de PAF e a dificuldade para realizar diagnóstico molecular em uma população brasileira
Abstract: Adenomatous polyposis coli (APC) germline mutations are responsible for the occurrence of familial adenomatous polyposis (FAP). Somatic mutations lead to malignant transformation of adenomas. In this context, considering the significance of APC germline mutations in FAP, we aimed to identify APC germline mutations. In the present study, 20 FAP patients were enrolled. The determination of APC germline mutations was performed using sequencing, and the mutations were compared with clinical markers (gender, age at diagnosis, smoking habits, TNM stage, Astler-Coller stage, degree of differentiation of adenocarcinoma). The data were compared using the SPSS program, with the Fisher's exact test and ?2 test, considering ?=0.05. According to the main results in our sample, 16 alleles with deleterious mutations (80% of the patients) were identified while 7 (35%) patients had no deleterious mutations. There was a predominance of nonsense (45% of the patients) and frameshift (20% of the patients) mutations. There was no statistical significance between the APC germline mutations identified and the clinical variables considered in our study. Only TNM stage was associated with the presence of deleterious mutations. Patients with deleterious mutations had an OR, 0.086 (IC=0.001-0.984); TNM stage I + II in comparison with III + IV, when compared with the patients with no deleterious mutations identified. In this context, as a conclusion, we demonstrated the molecular heterogeneity of APC germline mutations in FAP and the difficulty to perform molecular diagnostics in a Brazilian population, considering the admixed population analyzed
Doutorado
Clinica Medica
Doutora em Ciências
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Dimova, Nevena Varbinova. "Defining the Ubiquitin and E2-Enzyme Requirements for APC/C-Mediated Degradation of Cyclin B1." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10401.
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Post-translational modification of proteins with ubiquitin regulates many aspects of cell physiology, including protein degradation. A uniform polyubiquitin chain that is linked through Lys48 has been widely accepted as central for recognition and destruction by the 26S proteasome. Work in more recent years has demonstrated that the repertoire of proteolytic signals may encompass chains of other linkage types, including Lys11-linked ubiquitin chains and short assemblies of mixed linkage. In this dissertation I examine whether catalysis mediated by the Anaphase-Promoting Complex/Cyclosome (APC/C) is dependent on polyubiquitination and whether the proteolytic machinery exerts a requirement for specific ubiquitin linkages to efficiently degrade cyclin B1. In chapter II, I describe a novel method in which Xenopus cell-cycle extracts are made largely dependent on exogenous ubiquitin by inhibiting ubiquitin recycling, allowing us to evaluate the relative contribution of distinct ubiquitin linkages in APC/C-mediated ubiquitination and degradation. Utilizing this approach, in chapter III, I found that the conjugation of single ubiquitin moieties to multiple lysine residues in cyclin promotes efficient degradation of cyclin B1 in mitotic Xenopus extracts. Lysine11-ubiquitin chain-formation becomes essential to proteasomal targeting only when the number of available lysine residues in cyclin B1 is restricted. Analysis in a reconstituted system revealed that APC/C catalyzes multiple monoubiquitination with rapid kinetics and species bearing four or more monoubiquitins on distinct lysines are recognized by ubiquitin receptors. These multiply monoubiquitinated species are rapidly degraded by purified proteasomes. In chapter IV, I examine the role of distinct E2 enzymes in APC/C-dependent proteolysis. I demonstrate that the chain-extending E2 UBE2S and long Lys11-linked ubiquitin assemblies are dispensable for cyclin B1 degradation, but become increasingly important with restriction of the number of ubiquitination sites. Our findings support a model where through attachment of monoubiquitin to multiple lysine residues, and possibly elaboration of some short chains, UBCH10, or possibly members of the UBC4/5 family, cooperate with the APC/C to generate a robust proteolytic signal on cyclin B1.
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Ors, Aslihan. "Identification of novel APC/C regulators in fission yeast." Thesis, Institute of Cancer Research (University Of London), 2009. http://publications.icr.ac.uk/10297/.
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Sequential degradation of cell cycle proteins is a major regulatory mechanism for proper cell proliferation. Turnover of these proteins is performed by the ubiquitin/proteasome pathway, which poly-ubiquitylates and subsequently degrades the target proteins. The anaphase-promoting complex/cyclosome (APC/C) is a multi subunit E3 ubiquitin ligase that provides substrate specificity and regulation of the ubiquitin pathway. Two of the most important substrates are Cut2/securin and Cdc13/cyclin B, enabling chromosome segregation and exit from mitosis, respectively. Since APC/C function is very important for the cell cycle progression, its activity is strictly regulated. The aim of this study is to understand the regulation of APC/C and how its subunits contribute to this regulation. For this purpose, we have focused on the two least understood subunits: Apc1/Cut4 and Apc5. Conditionally lethal temperature sensitive mutants of these two subunits were created in fission yeast and the used for suppressor screening. We identified atf1+ as a multicopy suppressor of apc5-1, a mutation causing mitotic arrest. Fission yeast Atf1, which is homologous to human ATF2/CRE-BP1, is a bZIP domain mutant of Atf1, which has lost its transcription activation function, was still able to suppress the ts phenotype of apc5-1. The atf1+-dependent rescue was specific to the apc5-1 allele, rather than rescuing other APC/C subunit mutants and deletion of atf1+ increased the mitotic defects of the mutant. Interestingly, Atf1 physically binds to the APC/C in vivo. Furthermore, in vitro studies proved that Atf1 stimulates ubiquitylation activity of the APC/C. Finally; this interaction was shown to contribute to conjugation/mating efficiency of S. pombe cells upon nitrogen starvation and G1 arrest. Altogether, these results reveal a novel role for Atf1 in regulating the APC/C ubiquitin ligase, besides its transcription factor activity.
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Shailes, Hannah. "Targeting APC loss using synthetic lethality in colorectal cancer." Thesis, Queen Mary, University of London, 2018. http://qmro.qmul.ac.uk/xmlui/handle/123456789/43996.
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Mutations in the tumour suppressor gene Adenomatous polyposis coli (APC) are found in 80 % of sporadic colorectal cancer (CRC) tumours and are also responsible for the inherited form of CRC, Familial adenomatous polyposis (FAP). In order to identify novel therapeutic targets for the treatment of APC mutated CRC, we have generated an in vitro model of APC mutant CRC using CRISPR-cas9 gene editing. Using the APC wildtype colorectal carcinoma cell line RKO, we targeted the cells with guide RNA (gRNA) targeting exon 2 or exon 15 (encodes 80 % of APC) of the APC gene. We generated isogenic cell lines which differed in the expression of APC, the controls were APC wildtype and the APC mutant (APC Lys736fs) cell lines expressed a truncated ~80 kDa APC protein. We used these cell lines to perform an siRNA screen against 720 kinases and kinase-related genes. We selected seven genes to investigate further, unfortunately none of the potential hits validated. Additionally, we performed an FDA-approved compound screen targeting over 1000 compounds. From this, we identified a group of HMG-CoA reductase (HMGCR) inhibitors known as statins, which selectively cause a greater loss in cell viability in the APC mutated cell lines, compared to the APC wildtype cells. Mechanistically, our data suggests this synthetic lethal relationship is due to a greater decrease in the anti-apoptotic protein survivin. We propose this is due to statins altering the localisation of Rac1, reducing Pak1 activation and reducing the level of Wnt signalling. This results in the reduction of the Wnt target gene survivin. We have successfully identified an FDA-approved family of compounds, which show synthetic lethality with the APC mutation in our in vitro model.
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Hankey, William C. IV. "Chromatin-associated functions of the APC tumor suppressor protein." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1480198247672881.
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Woodbury, Erika L. "Regulation of spindle stability by Cdk1 and the APC." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3261256.
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Rodolpho, Joice Margareth de Almeida. "Avaliação da expressão das moléculas CD80, CD86 e MHCII em eosinófilos durante a síndrome da larva migrans visceral." Universidade Federal de São Carlos, 2012. https://repositorio.ufscar.br/handle/ufscar/7012.
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Previous issue date: 2012-02-28Eosinophils are a hematopoietic cell originated from precursor cells found in bone marrow, whose differentiation and proliferation is regulated by cytokines such as GM-CSF, IL-3 and IL-5. When activated, eosinophils are capable of phagocytosis of small particles and bacteria, but their main form of activity in the inflammatory process is the release of toxic proteins, cytokines, enzymes, lipid mediators and reactive oxygen products. The increase in eosinophil is an important feature in many diseases such as allergy and parasitic infections. Provided APC (Antigen-Presenting Cells), eosinophils are considered similar to the CD (Dendritic Cells) in its potential to activate naïve T cells and may have potential as efficient as the CD in stimulating lung T cells in the upper airways in the model inflammation. The APC are defined by being able to take, processing and presenting antigen such as CD, macrophages, B lymphocytes and possibly eosinophils. The surface expression of APC is characterized by coestimatórias molecules CD80 (B7-1) and CD86 (B7-2) and also by MHCII. The proposed model for this evaluation was to Visceral Larva Migrans syndrome (VLMS) caused by Toxocara canis, one of the most frequent helminth in young dogs. One of the main consequences of this infection is the marked increase in circulating and tissue eosinophils. Eosinophilia has been associated with parasitic diseases particularly when the parasite invades or promotes tissue damage at mucosal surfaces In the present study we evaluated the expression of MHC II and CD80 and CD86 molecules coestimulatórias in eosinophils in VLMS. Our results showed that the molecules studied were expressed in eosinophils in the blood of mice infected with Toxocara canis compared with the control group. Correlating an intense eosinophil still during the course of the disease with increased IL-5 in the infected group. Suggests that during the course of Toxocara canis, eosinophils can exhibit behavior of an APC, increasing the expression of MHCII molecules coestimulatorias and possibily amplifyng the immune response in this model.
O eosinófilo é uma célula hematopoiética, originada a partir de células precursoras presentes na medula óssea, cuja diferenciação e proliferação são reguladas por citocinas como GMCSF, IL-3 e IL-5. Quando ativados, os eosinófilos são capazes de realizar fagocitose de pequenas partículas e bactérias, mas sua principal forma de atuação no processo inflamatório consiste na liberação de proteínas tóxicas, citocinas, enzimas, mediadores lipídicos e produtos reativos de oxigênio. O aumento no número de eosinófilos é uma característica importante em diversas doenças como a alergia e as infecções parasitárias. Na condição de APC (Células Apresentadoras de Antígenos), os eosinófilos são considerados similares as CD (Células Dendríticas) em seu potencial para ativar células T naïve, podendo ter potencial tão eficiente quanto as CD pulmonares em estimular células T nas vias aéreas superiores no modelo da inflamação. As APC são definidas por serem capazes de ingerir, processar e apresentar o antígeno como: CD, macrófagos, linfócitos B e possivelmente os eosinófilos. A expressão na superfície da APC é caracterizada por moléculas coestimatórias CD80 (B7-1) e CD86 (B7-2) e ainda pelo MHCII. O modelo proposto para esta avaliação foi a Síndrome da Larva Migrans Visceral (SLMV) causada pelo Toxocara canis, um dos helmintos mais freqüentes em cães jovens. Uma das principais consequências desta infecção é o aumento marcante de eosinófilos circulantes e teciduais. A eosinofilia tem sido associada com doenças parasitárias particularmente quando o parasita invade os tecidos ou promove danos na superfície das mucosas. No presente estudo avaliamos a expressão de MHC II e moléculas coestimulatórias CD80 e CD86 em eosinófilos na SLMV. Nossos resultados mostraram que as moléculas analisadas foram expressas em eosinófilos no sangue de camundongos infectados com Toxocara canis quando comparado com o grupo controle. Correlacionando ainda uma intensa eosinofilia durante o curso da doença com o aumento de IL-5 no grupo infectado. Sugere que, durante o curso da infecção pelo Toxocara canis, eosinófilos podem apresentar comportamento de uma APC, aumentando a expressão de moléculas coestimulatórias e MHCII e possivelmente amplificando a resposta imune nesse modelo.
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Ohlhoff, Janneke. "Abwesenheit von Mutationen an der APC-Bindungsstelle und an den APC-Schnittstellen Arginin336 und Arginin562 des Gerinnungsfaktor VIII bei 65 Patienten mit venöser Thrombose." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=971440646.
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Silk, Jonathan David. "T-cell function : effects of MHC level, APC and apoptosis." Thesis, Imperial College London, 2002. http://hdl.handle.net/10044/1/11905.
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Qian, Jiang. "Charaterization of transcription-independent APC tumor suppressor function in apoptosis." Cincinnati, Ohio : University of Cincinnati, 2006. http://www.ohiolink.edu/etd/view.cgi?ucin1141329403.
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Thesis (Ph. D.)--University of Cincinnati, 2006.Advisor: Joanna Groden. Title from electronic thesis title page (viewed May 20, 2008). Keywords: APC; Apoptosis; caspase; hTid-1; Transcription-independent. Includes abstract. Includes bibliographical references.
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Daly, Carl S. "The roles of the Apc proteins in homeostasis and tumourigenesis." Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/51008/.
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The adenomatous polyposis coli (APC) gene encodes a multifunctional tumour suppressor protein that is essential for normal development. The most characterised role of APC is its ability to mediate the Wnt signaling pathway, a pathway disrupted in the majority of human cancers. The identification of a second adenomatous polyposis coli gene (APC2) which possesses many shared structural characteristics with APC and potentially comparable functions raises the possibility that APC2 also functions both in development and in tumour suppression, and that some redundancy may exist between the two proteins. Analysis of these proteins in the mouse has been hampered due to the lethality of the Apc mutation and the lack of a suitable Apc2 mutation. However, to circumvent the first of these difficulties, Cre-lox technology was employed to conditionally delete Apc in adult mouse tissues and so study its function in vivo. To circumvent the second difficulty, a novel Apc2 null allele had become available from the laboratory of Professor Hans Clevers. Remarkably, constitutive deletion of Apc2 does not lead to embryonic lethality, permitting study of the effects of Apc2 deficiency within adult tissues. In this thesis I aimed to characterise the consequences of Apc2 loss alone, and in the context of tissue specific Apc loss, in a range of tissues. Apc2 deficiency led to subtle changes in Wnt signaling in the intestines and liver however, no detectable differences of this pathway were apparent within the mammary gland. Phenotypically, altered homeostasis was only observed within the intestines. Apc2 deficiency led to an increase in epithelial cell division, an increase in markers of intestinal stemness and increases in intestinal cell migration. However, loss of Apc2 failed to induce tumourigenesis in the intestines or indeed any other tissue. In the context of Apc loss, the effect was dependent upon the tissue. Within the intestines, additional loss of Apc2 altered the immediate phenotype of Apc loss but failed to modify Apc induced tumourigenesis. Within the mammary gland, whilst either Apc protein alone was dispensable, combined loss synergised to disrupt homeostasis and drive tumourigenesis. Contrary to this, in the liver the additional loss of Apc2 attenuated tumourigenesis induced by reduced levels of Apc. Together, these studies highlight the importance of these proteins and their interactions and redundancies in homeostasis and tumourigenesis.
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Passmore, Lori Anne. "Structural and functional studies of the anaphase promoting complex (APC)." Thesis, Institute of Cancer Research (University Of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406167.
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Sedgwick, Garry Gray. "Identification and functional characterisation of novel APC/C interacting proteins." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/1090/.
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The anaphase promoting complex /cyclosome (APC/C) is a multi-protein E3 ubiquitin ligase complex that regulates cellular proliferation through its ability to target essential cell cycle regulators such as cyclin A, cyclin B, securin and S-phase kinase-associated protein 2 (SKP2) for proteasomal-dependent degradation. APC/C substrates and coactivators are aberrantly expressed in many cancers. It is thought that the APC/C can also regulate cellular proliferation by controlling p21 and cell division cycle 6 homologue (CDC6) transcription. It is therefore of great interest to study other cellular proteins that interact with the APC/C as these proteins may also be important in cell cycle regulation and hence may enhance our understanding of the molecular basis of cancer. Therefore, the aim of my study was to identify novel APC/C interacting proteins through mass spectrometric analysis of APC/C subunit 7 (APC7) immunoprecipitates and go on to examine the functional significance of these interactions. I identified six novel APC7 interacting proteins, and decided to focus on two of these interactions. Initially I examined the interaction between APC7 and transcriptional intermediary factor 1\(\gamma\) (TIF1\(\gamma\)), a transcriptional repressor previously reported to be aberrantly expressed in cancer. Data presented in this study demonstrate that the APC/C and TIF1\(\gamma\) cooperate to regulate mitotic progression. Notably TIF1\(\gamma\) displays in vivo interactions with APC/C subunits 1-8, the APC/C‟s mitotic coactivator CDC20 and mitotic substrate cyclin A. Moreover, TIF1\(\gamma\) depletion by RNAi arrests cells in a metaphase-like state characterised by elevated levels of APC/C substrates, cyclin A, cyclin B and CDC20. In support of a role for TIF1\(\gamma\) in regulating mitotic progression by directly targeting the APC/C, cells treated with TIF1\(\gamma\)-specific siRNA exhibit reduced APC/C E3 ubiquitin ligase activity. This work defines TIF1\(\gamma\) as a novel mitotic regulatory protein essential for APC/C function and suggests that loss of TIF1\(\gamma\) may compromise genomic integrity by allowing the mis-segregation of chromosomes. I also investigated the functional relationship between APC7 and the nuclear factor 90/45 heterodimer (NF90/NF45), given that all of these proteins function as transcription factors. Results obtained demonstrate that APC5 and APC7 bind directly to NF90 in vitro and also form complexes with NF90 in vivo. It appears that APC/C interaction with NF90 is important in the regulation of interleukin-2 (IL-2) and tumour neucrosis factor (TNF) transcription, as exogenous APC5 and APC7 cooperate with NF90/NF45 to transactivate IL-2 and TNF promoter constructs. Lastly endogenous APC5 and APC7 bind to the IL-2 promoter in vivo while endogenous APC5 represses TNF transcription in vivo. Given that TNF and IL-2 stimulate cellular proliferation data presented here suggests that the APC/C might control cellular proliferation by regulating TNF and IL-2 transcription.
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Cliffe, Adam Nicholas. "The functions of the Drosophila E-APC and Axin proteins." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619925.
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Qian, Jiang. "Characterization of transcription-independent APC tumor suppressor function in apoptosis." University of Cincinnati / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1141329403.
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Lui, Christina Ka-Wing. "Characterisation of APC localisation, dynamics and functions at the centrosome." Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/12507.
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Adenomatous polyposis coli (APC) is a tumour suppressor protein and regulator of the wnt signalling pathway. APC is mutated in >90% of colorectal tumours and these mutations often translate a shorter truncated protein. Truncated APC has now been linked to mitotic spindle dysfunction. Mitotic spindles are nucleated from centrosomes and in cells expressing cancer mutant forms of APC cause aberrant spindle attachments leading to an increased rate of chromosome instability. Both full-length and mutant APC persistently localise to the centrosome throughout the cell cycle, however its role at interphase centrosomes are ill-defined. In this thesis, using a combination of immunofluorescence microscopy, retention assays and fluorescence recovery after photobleaching (FRAP) techniques, both wild-type and mutant forms of APC were found to be highly dynamic at the interphase centrosome, but highly retained at the mitotic centrosome, and targeted by the Armadillo domain of APC. Using various centrosome functional assays, APC was found to contribute to microtubule nucleation, but was not involved in centrosome amplification or separation. Using protein interaction methods, several novel APC binding partners ranging from protein regulators of the centrosome to microtubule-associated proteins were also discovered.
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Zhang, Suyang. "Mechanism of APC/C activation and substrate specificity in mitosis." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/275479.
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In eukaryotes, cell proliferation and cell cycle transitions are strictly controlled by the anaphase-promoting complex/cyclosome (APC/C). The APC/C is an E3 ubiquitin ligase that regulates chromatid segregation at the metaphase to anaphase transition, exit from mitosis and the establishment and maintenance of G1. The APC/C’s catalytic activity and substrate specificity are controlled by its interactions with two coactivators, Cdc20 and Cdh1. In contrast to Cdh1, APC/C activation by Cdc20 during mitosis requires hyper-phosphorylation of APC/C subunits by cyclin-dependent kinase (Cdk) and polo kinase. The aim of the first part of this thesis was to understand how mitotic phosphorylation regulates APC/C activity. Using cryo-electron microscopy and biochemical analysis, we found that an auto-inhibitory segment of the Apc1 subunit acts as a molecular switch that in apo unphosphorylated APC/C interacts with a coactivator-binding site (C-box binding site), thereby obstructing engagement of Cdc20. Phosphorylation of the auto-inhibitory segment displaces it from the C-box binding site to relieve APC/C auto-inhibition. Efficient phosphorylation of the auto-inhibitory segment requires the recruitment of the kinase Cdk-cyclin-Cks to a hyper-phosphorylated loop of Apc3. In addition to regulation of APC/C activity by phosphorylation, ordered cell progression is ensured by the ability of the APC/C to target substrate degradation in a defined order. At mitosis onset, degradation of securin and cyclin B1 is inhibited by the spindle assembly checkpoint, exerted by the mitotic checkpoint complex (MCC), whereas both cyclin A2 and Nek2A are not subject to MCC inhibition. The aim of the second part of the thesis was to elucidate the mechanism of how the APC/C achieves its substrate specificity. Our biochemical analysis showed that the resistance of cyclin A2 to MCC inhibition is due to its ABBA motif and the Cdk-associated Cks2 subunit. Furthermore, we found that it is the Cdc20 molecule of the MCC that binds to the ABBA motif to allow for cyclin A2 ubiquitination. Strikingly, mutating all three known degrons (KEN box, D box and ABBA motif) of cyclin A did not affect its ubiquitination by APC/CCdc20. Deletion of a potential novel degron found within residues 60-80 of cyclin A2 impaired cyclin A2 ubiquitination.
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Mathieu-Rivet, Elodie. "Etude du rôle de l'activateur de l'APC/C CCS52 dans la transition du cycle mitotique vers l'endocycle au cours du développement du fruit de tomate (Solanum lycopersicum Mill.)." Thesis, Bordeaux 2, 2009. http://www.theses.fr/2009BOR21654/document.
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Au cours de cette étude, nous avons isolé 4 ADNc codant pour des protéines activatrices putatives de l'APC/C de tomate : SlCCS52A, SlCCS52B, SlCDC20-1, et SlCDC20-2. Des données obtenues par RT-qPCR et par hybridation in situ révèlent des profils d'expression différents au niveau tissulaire mais également au cours du développement du fruit de tomate, suggérant que différentes protéines activatrices pourraient assurer la modulation spatio-temporelle de l'activité de l'APC/C chez la tomate. De plus, les transcrits du gène SlCCS52A s'accumulent plus particulièrement dans le fruit durant la phase d'expansion cellulaire, tandis que les transcrits du gène SlCCS52B sont plutôt présents durant les premiers stades de développement, caractérisés par une forte activité de division cellulaire. Afin de préciser le rôle de SlCCS52A et SlCCS52B dans le contrôle du cycle cellulaire et de l'endocycle chez la tomate, ces gènes ont fait l'objet d'une étude fonctionnelle. La réduction de l'expression de SlCCS52A entraîne une réduction de la taille des fruits et de la taille cellulaire, qui s'accompagne d'une diminution du niveau de ploïdie. La surexpression de ce gène modifie la cinétique de développement des fruits. La mise en place de l'endocycle est retardée, mais l'augmentation de la ploïdie est plus rapide et la croissance relative du fruit est alors plus importante. Enfin, la réduction de l'expression de SlCCS52B entraîne une augmentation de l'expression de SlCCS52A au niveau des fruits, suggérant l'existence de mécanismes compensatoires. L'ensemble de ces résultats montrent que SlCCS52A est impliqué dans la mise en place de l'endoréduplication chez la tomate, et participe au contrôle de l'expansion cellulaireIn this study, we have isolated 4 cDNAs encoding putative proteins activating the APC/C in tomato: SlCCS52A, SlCCS52B, SlCDC20-1, and SlCDC20-2. Data obtained by RT-qPCR and in situ hybridization revealed different expression profiles in tissues but also during the development of tomato fruit, suggesting that different activator proteins could provide the spatio-temporal modulation of the APC/C activity in tomato. In addition, the SlCCS52A transcripts accumulate especially in the fruit during the cell expansion phase, while transcripts of the SlCCS52B gene are rather present during the early stages of development, characterized by a high activity of cell divisions. To clarify the role of SlCCS52A and SlCCS52B in cell cycle control and endocycle in tomato, we performed a functional analysis of these genes. Reducing the expression of SlCCS52A leads to reduced fruit size and cell size, accompanied by a decrease in the level of ploidy. The overexpression of this gene alters the kinetics of fruit development. The establishment of endocycle is delayed, but the increase in ploidy is faster and the relative growth of the fruit is much more important then. Finally, the reduced expression of SlCCS52B leads to an increased expression of SlCCS52A in fruit, suggesting the existence of compensatory mechanisms. All these results show that SlCCS52A is involved in the establishment of endoreduplication in tomato, and participates in the control of cell expansion
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Dücker, Christina [Verfasser]. "Proteolytische Aktivität von APC bei der Inaktivierung verschiedener Faktor VIII-Präparate und bei der Faktor VIIIa-Inaktivierung in Gegenwart eines APC-DNA-Aptamers / Christina Dücker." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/1027815820/34.
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Castro, José Luís Draper Mineiro Romano de. "Listeria monocytogenes em alimentos prontos para consumo." Bachelor's thesis, Universidade Técnica de Lisboa. Faculdade de Medicina Veterinária, 2011. http://hdl.handle.net/10400.5/3506.
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Dissertação de Mestrado Integrado em Medicina VeterináriaNota introdutória - Bactéria matou 13 em 22 meses Um surto de Listeriose que se regista na região de Setúbal e Almada há 22 meses, desde Janeiro de 2009, já afectou, pelo menos, 24 pessoas, 13 das quais morreram. O CM apurou que uma grávida perdeu o filho na 32ª semana de gestação após comer alimentos infectados com a bactéria Listeria. As vítimas mortais foram idosos e pessoas imunodeprimidas (com o sistema imunitário debilitado) ou com doenças crónicas. Fonte das autoridades de saúde admitiu “ser muito difícil” apurar a origem da infecção provocada pela bactéria. “Não se descobriu muito, mas o que se sabe é que estaremos perante uma estirpe portuguesa da bactéria”, disse a fonte. A contaminação poderá ter ocorrido em produtos de “charcutaria e queijos cremosos, daqueles que não são normalmente produzidos em Portugal”. A mistura de alimentos contaminados com outros em frigoríficos ou microondas terá desencadeado o surto. A Direcção Geral da Saúde e a Administração Regional de Lisboa e vale do Tejo desenvolvem um estudo epidemiológico que envolve os familiares das pessoas infectadas e das vítimas mortais. O consumo de alimentos contaminados provoca febres, diarreias e, nos casos mais graves, meningites, que podem ser fatais. In Correio da Manhã, 9 de Outubro de 2010. - Esta notícia publicada em Outubro de 2010 suscitou algumas questões para as quais se procurou encontrar algumas respostas com este trabalho. O objectivo deste trabalho é fornecer elementos para a melhor compreensão do fenómeno e com isso contribuir para que estas situações sejam menos frequentes. Neste trabalho estudaremos como se comporta Listeria monocytogenes Scott A inoculada em produtos prontos a comer, ao longo do seu tempo de vida útil. Estabeleceremos curvas de crescimento e procuraremos compará-las com os modelos preditivos já existentes no mercado. Tomar-se-ão em consideração, como ponto de partida, as opiniões da EFSA sobre esta matéria. Bactéria matou 13 em 22 meses Um surto de Listeriose que se regista na região de Setúbal e Almada há 22 meses, desde Janeiro de 2009, já afectou, pelo menos, 24 pessoas, 13 das quais morreram. O CM apurou que uma grávida perdeu o filho na 32ª semana de gestação após comer alimentos infectados com a bactéria Listeria. As vítimas mortais foram idosos e pessoas imunodeprimidas (com o sistema imunitário debilitado) ou com doenças crónicas. Fonte das autoridades de saúde admitiu “ser muito difícil” apurar a origem da infecção provocada pela bactéria. “Não se descobriu muito, mas o que se sabe é que estaremos perante uma estirpe portuguesa da bactéria”, disse a fonte. A contaminação poderá ter ocorrido em produtos de “charcutaria e queijos cremosos, daqueles que não são normalmente produzidos em Portugal”. A mistura de alimentos contaminados com outros em frigoríficos ou microondas terá desencadeado o surto. A Direcção Geral da Saúde e a Administração Regional de Lisboa e vale do Tejo desenvolvem um estudo epidemiológico que envolve os familiares das pessoas infectadas e das vítimas mortais. O consumo de alimentos contaminados provoca febres, diarreias e, nos casos mais graves, meningites, que podem ser fatais. In Correio da Manhã, 9 de Outubro de 2010 2 A European Food Safety Authority (EFSA), sedeada em Parma, Itália, foi fundada e estabelecida pela Comunidade Europeia como uma entidade independente em 2002, após uma série de surtos de origem alimentar que alertaram para a possível incapacidade das autoridades reguladoras de proteger os consumidores. Também serão levados em consideração os dados disponibilizados pelo ECDC. O European Centre for Disease Prevention and Control (ECDC), é uma agência Europeia sedeada em Estocolmo (Suécia), que se estabeleceu em 2005. O objectivo da ECDC é fortificar as defesas Europeias no combate às doenças infecciosas.
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Green, Rebecca Anne. "Elucidating the role of adenomatous polyposis coli (APC) in chromosome segregation /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2005. http://uclibs.org/PID/11984.
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Moalem, Adnan. "Stellenwert der Argon-Plasma-Koagulation (APC) in der therapeutischen gastroenterologischen Endoskopie." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972305238.
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Cooper, Cindy Anne. "Clinical and experimental studies on the role of APC in neoplasia." Thesis, University of Edinburgh, 2001. http://hdl.handle.net/1842/27826.
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This thesis describes firstly, the generation and initial characterisation of a murine APC transgenic founder line designed as a model to investigate the effects of aberrant expression of APC. Several Apc mutant murine models of FAP already exist. These all carry a heterozygous mutation in the Apc gene. The Min mouse (multiple intestinal neoplasia) is an example and carries a mutation at codon 850. All current models however are of limited use as mice homozygous for Apc mutations die at approximately 6.6 days post coitum, limiting analysis to Apc heterozygotes. Homozygous loss of Apc therefore depends upon additional somatic events that are not under direct experimental control and this may be associated with additional, undisclosed genetic events. Here a transgenic approach has been taken to generate animals where the expression of the APC transgene is conditionally inactivated using the Cre-lox P recombination system of the bacteriophage P1. APC cDNA was flanked by lox P sequences and the phosphoglycerate kinase (Pgk) ubiquitous promoter DNA sequence cloned upstream of the APC cDNA to drive the expression of the gene. Pro-nuclear injection was used to deliver the APC transgene into oocytes of wild type mice (F1 (C57B1/6 x CBA)). In one founder line transgene copy number was determined by southern blotting and transcription of the APC cDNA confirmed in a wide variety of tissues using reverse transcription polymerase chain reaction (PCR). Transgenic positive mice on an Apc wildtype background showed no gross phenotype. Embryonic fibroblasts were derived and Cre-recombinase delivered by infection with a replication deficient adenovirus. APC cDNA excision was confirmed by PCR. The founder line was crossed with the C57BL/6 Apc Min/Wt line. Transgenic positive Apc Min/Wt mice were intercrossed and offspring screened to identify whether the APC transgene can rescue the Apc Min/Min lethal phenotype. To date embryonic rescue has not been identified.
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Brugge, Jeroen Martijn. "The molecular basis of APC-resistance: role of coagulation factor abnormalities." Maastricht : Maastricht : UPM, Universitaire Pers Maastricht ; University Library, Maastricht University [Host], 2006. http://arno.unimaas.nl/show.cgi?fid=7669.
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Shen, Ying. "Regulation of EphA4 expression through the APC-mediated ubiquitin-proteasome pathway /." View abstract or full-text, 2007. http://library.ust.hk/cgi/db/thesis.pl?BICH%202007%20SHEN.
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Griffin, Colin. "Investigating the role of EB1 and APC in epithelial cell migration." Thesis, University of Leeds, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.445849.
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Ward, David Barry. "The detoxification of dioxin contaminated APC residue by energy efficient sintering." Thesis, University of Sheffield, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.370082.
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Zarkadis, D. J. "16Kb/s APC and 9.6Kb/s RELP for satellite mobile systems." Thesis, University of Surrey, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.378213.
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Cham, Laura Cecilia. "Understanding bus service reliability : a practical framework using AVL/APC data." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/34381.
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Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Civil and Environmental Engineering, 2006.Includes bibliographical references (leaves 141-142).
Service reliability on a transit system can have significant impacts on its provider and both existing and potential users. To passengers, unreliable service affects their perception of service quality and transit utility compared to other mode choices, while to transit agencies, this translates to loss of ridership and revenues and higher costs to provide additional service to compensate for poor service operations. The introduction of technologies such as Automatic Vehicle Location (AVL) and Automatic Passenger Counters (APC) provides the opportunity to gather large sets of data at relatively low cost and evaluate service to improve performance, schedule planning and operations control. This thesis presents a comprehensive review of key elements of service reliability, focused on the measures of reliability, the causes of unreliability and the application of strategies to improve service. The most significant causes of service reliability are presented: deviations at terminals, passenger loads, running times, environmental factors (or externalities) and operator behavior. Each is reviewed in terms of how they impact service and the complexities and interrelationship between different causes are explored. Also reviewed are the potential preventive and corrective strategies, and the links between the causes of service unreliability and best strategy according to the source of problems. A practical framework is developed to assess service reliability, exploring the uses of Automated Data Collection (ADC) systems to characterize service reliability and evaluate the causes of unreliability that may exist. Its goal is to serve as a guide for transit agencies to begin to analyze the large sets of data available from these systems
to evaluate performance and implement efficient strategies to improve service planning and operations. The proposed framework consists of three blocks: 1) characterization of service reliability through service measures and performance reports; 2) identification of causes of reliability problems; and 3) selection of strategies which target critical causes of unreliability to improve service. Characterization of service reliability involves examining five key elements an agency should analyze: a) data inputs, b) output calculations, c) service measures, d) threshold values, and e) performance reports. Identifying the causes of unreliability includes two sequential processes to infer the causes of service reliability problems. The first focuses on deviations at terminals, because good on-time performance and headway adherence is expected at the terminals and deviations at this point tend to propagate down the route and create further reliability problems. The second process examines deviations at other points on the route, and follows a set of steps to infer the causes of unreliability: initial deviations at terminal, passenger loads, poor schedule planning, operator behavior and externalities. Application of strategies includes an assessment of the best strategies to prevent reliability problems and reduce the impacts on service performance, based on the results of the previous analysis. The application of the proposed framework on the Silver Line Washington Street in Boston (MA) revealed that variability of running times and headway distributions are high. This indicates that bus arrivals and passenger wait times on this route are unpredictable and travel times are irregular. As a Bus Rapid Transit route,
which is suppose to provide bus service with rail transit quality, headway adherence is poor on this route, with a tendency for buses to bunch together or leave gaps in service. Further analysis revealed that service reliability has recently deteriorated as a result of the implementation of a new Automatic Fare Collection (AFC) system. The new fare collection system presented delays in the boarding process, which resulted in increased travel times and passenger wait times. The main cause of service unreliability on this route was identified to be deviations at the terminals. Trips are departing the terminal with poor headway adherence (and therefore, poor on-time performance), which propagates and creates further reliability problems down the route. The causes of these terminal deviations were inferred to be a combination of poor terminal supervision and operator behavior. Recovery times, externalities and passenger loads at this terminal are inferred to cause only minor problems. At other points in the route, operator behavior and passenger loads are observed to affect reliability in the inbound direction. As for strategies to improve service reliability, emphasis is given to better supervision at the terminal. Supervisors at terminals are needed to enforce good operator behavior, balance headways, apply control strategies, and coordinate passenger loads to avoid poor departure headways and overcrowding of buses. Along the route, operator training, corrective strategies and traffic signal priority are highlighted as potential strategies to reduce the variability in running times and balance headways to reduce the occurrence of bunches and gaps in service.
by Laura Cecilia Cham.
S.M.
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Harnisch, Lars-Olav [Verfasser]. "Evaluation der lumbalen Spondylodese mittels APC-behandelter Titanimplantate / Lars-Olav Harnisch." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2010. http://d-nb.info/1024784274/34.
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Gay, David Michael. "Investigating the cooperation of APC and KRAS mutations in colorectal cancer." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/9089/.
Full textAbstract:
Colorectal Cancer (CRC) progresses in a stepwise manner accumulating mutations in particular signalling pathways. Despite our knowledge of the genetic progression of the disease, the resulting phenotypes of the different mutation combinations remains poorly understood. I used genetically engineered mouse models to investigate the cooperation of two frequent early mutations - loss of the tumour suppressor gene APC and activating KRAS mutations, to try and identify potential therapeutic targets. Hyperactivated Wnt signalling is a hallmark of CRC, although efficacious therapies are limited. In chapter 3 I focussed on targeting this pathway at the level of β-catenin mediated transcription. I showed that deletion of BLC9 and BCL9l, two proteins involved in β-catenin mediated transcription, suppresses proliferation and the expression of a subset of Wnt target genes following loss of APC and KRAS activation. I showed that these two proteins are dispensable intestinal homeostasis. I also showed that deletion of BCL9 and BCL9l significantly accelerated tumour initiation. In chapter 4 I performed unbiased quantitative proteomics on crypt cultures from VillinCreER Apcfl/fl (APC) and VillinCreER Apcfl/fl KrasG12D/+ (APC KRAS) mice to identify deregulated signalling pathways between these two genotypes. I identified a ‘nutrient stress’ phenotype in APC KRAS crypts. I show that this might be driven by a significant increase in protein synthesis, since APC KRAS cells are trying to regulate their rates of protein synthesis via eIF2α signalling. In chapter 5 I investigated changes in the metabolomes between APC and APC KRAS cells. I show that APC KRAS crypt cultures are highly dependent on glutamine for growth and upregulate many genes involved in glycolysis and glutaminolysis. I show that APC KRAS cells are metabolically flexible and also highlight the role the environment plays in metabolic phenotypes. Overall, I have shown that intestinal epithelial cells with high-Wnt and high-MAPK signalling are sensitive to Wnt inhibition. I have also shown that these two signalling pathways cooperate to drive increased protein synthesis and deregulated metabolism to fuel proliferation.
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Vijaya, Chandra Shree Harsha [Verfasser], and Jürgen [Akademischer Betreuer] Behrens. "Functional analysis of truncated APC protein in human colorectal cancers = Funktionelle Analyse von verkürztem APC Protein in humanem kolorektalen Krebs / Shree Harsha Vijaya Chandra. Betreuer: Jürgen Behrens." Erlangen : Universitätsbibliothek der Universität Erlangen-Nürnberg, 2011. http://d-nb.info/1015474802/34.
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Grünberg, John. "Studies on potential APC/β-catenin target genes in the Notch pathway." Thesis, Linköping University, Department of Physics, Chemistry and Biology, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-18443.
Full textAbstract:
Both Notch and the Wnt pathways are key regulators in maintaining the homeostasis in the intestine. Defects on the key tumor suppressor adenomatous polyposis coli, APC a gene in the Wnt pathway is most frequently mutated in colorectal cancer. Previous studies have indicated that there is a crosstalk between these two pathways. We investigate if there is correlation by first using bioinformatics to find Lef1/Tcf sites in several of the Notch pathway gene promoters. Bioinformatically we found that a lot of the genes contained theses sites controlled by the APC's destruction target β-catenin. By using semi quantitative PCR and western blot we found that Hes 1, Hes 7, JAG 2, MAML 1, Notch 2, NUMB, NUMBL, RFNG and LFNG was downregulated in HT29 colon cancer cells carrying a vector containing wild type APC. All but JAG 2 contains at least one Lef1/Tcf site in their promoter region. The results were verified in HT29 cells transfected with siRNA against β-catenin. We also investigated what would happen to the Lef1/Tcf target gene program of the Wnt pathway, if the Notch pathway was inhibited with the gamma-secretase inhibitor DAPT. Results showed no downregulution of β-catenin or its target gene Cyclin D1.Taken together, these results demonstrate that the Wnt pathway can be placed upstream of the Notch pathway and regulates the latter through β-catenin and the Lef1/Tcf target gene program. However, preliminary results indicate that there is no regulation of APC/β-catenin by the Notch pathway.
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Wallace, W. D. "The role of Dietry folate in intestinal tumourigenesis in the Apc+/- mouse." Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.517648.
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Thomas, Christopher. "APC/C processivity and cell cycle regulation in meiosis I mouse oocytes." Thesis, University of Newcastle upon Tyne, 2018. http://hdl.handle.net/10443/4070.
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Accurate cell division is a strictly ordered, highly regulated event. In mitosis, a robust spindle checkpoint ensures that chromosome division errors occur at a relatively low frequency, maintaining high levels of cyclin B1 and securin until chromosomes are accurately aligned. In contrast, in mouse oocytes, cyclin B1 and securin are targeted for destruction in late prometaphase I, at a time when the spindle is yet to fully migrate to the cortex and checkpoint proteins are still at kinetochores. This has been suggested to be symptomatic of an inefficient spindle checkpoint in meiosis I oocytes and a potential contributor to the high rates of aneuploidy observed in human oocytes. Curiously however, these observations have been made in mouse oocytes which ordinarily experience much lower rates of error. The seemingly early loss of cyclin B1 and securin rarely has a negative impact. This study demonstrates that cyclin B1 and securin destruction in late prometaphase I is not simply due to an inefficient spindle checkpoint, but instead due to controlled novel mechanisms of destruction within the oocyte. Meiotic cyclin B1 and securin destruction can in fact be split into two distinct periods; a later period that resembles mitotic destruction where the D-box is sufficient for APC/C targeting, and a much earlier period of destruction requiring previously unidentified motifs able to bypass the spindle checkpoint. Due to the location of these motifs, it is likely that they are hidden when in complex; cyclin B1 with Cdk1 and securin with separase. A model is proposed by which free pools of cyclin B1 and securin act as buffer zones, protecting Cdk1 activity and separase inhibition when the spindle checkpoint may become insufficient over the extended prometaphase period in the huge cell volume of an oocyte. Furthermore, meiotic cyclin A2 regulation is investigated. When put alongside cyclin B1 and securin data this begins to shed light on overall APC/C processivity in meiosis I.
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Williams, Gareth Haydn. "The role of RET, RAS and APC genes in human thyroid neoplasia." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627283.
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Medina, Bethan Ann. "Characterisation of the KA1 & KA2 domains and interaction with APC/C." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5653.
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Ubiquitin is a highly conserved 76 amino acid protein which is a unique and versatile signalling molecule. Ubiquitin can be attached by an isopeptide bond between its C-terminal diglycine to a lysine residue of a target substrate. However, it can also bind to itself though one of its own seven lysine residues allowing the formation of different chain types. These chains act as signals for different pathways, such as DNA damage repair, and in particular lysine-48 chains signal for proteins to be degraded via the proteasome by the ubiquitin proteasome system (UPS). This allows cells to control the concentration of proteins which is important in triggering cellular events, such as cyclin levels in cell division. Whilst old and incorrect proteins need to be removed so they do not interfere with normal processes. In order to recognise and ubiquitinate substrates an enzyme cascade has evolved. Ubiquitin is transferred from an ubiquitin activation enzyme (E1) to an ubiquitin conjugating enzyme (E2). The E2 which along with a ubiquitin ligase (E3) ubiquitinates a specific substrate. Research has focused on the E3 ligases since they are responsible for identifying substrates. One important ligase is the anaphase promoting complex/cyclosome (APC/C) which is responsible for faithful segregation of chromosome during mitosis. Failure to regulate this process can lead to aneuploidy, one of the main causes of cancer. It is therefore important to understand the function and regulation of APC/C and the UPS. This work firstly shows that four S. pombe kinases, Ssp2, Ppk9, Kin1 and Chk1 all contain a kinase associated 1 (KA1) or KA2 domain which they use to interact specifically with APC/C when it contained an unphosphorylated form of a subunit called Cut9. Yeast two hybrid and native far Westerns demonstrated that the KA domains interact with the APC/C co activator Slp1. Phosphorylation assays showed that three of these kinases phosphorylated a ~30kDa band of the APC/C complex which was shown to be Mad2, an important subunit of the APC/C inhibitor complex the mitotic checkpoint complex (MCC). These finding suggest a new role for KA contain kinases as regulators of APC/C activity. Future studies to identify the residues of Mad2 which are phosphorylated by these kinases, as well as the binding site of Slp1 that the KA domains recognise, would provide a more detailed understanding of the molecular mechanisms involved in regulating APC/C activity. Secondly, this study investigated the role of the ubiquitin associated (UBA) domains in the S. pombe shuttle factor Rhp23. This protein can recognise the proteasome via an ubiquitin like (UBL) domain and ubiquitin chains via one of two UBA domains: an internal UBA1 and a C-terminal UBA2. To dissect the different functions of these two UBA domains point mutations were made that abolished the domains ability to recognise ubiquitin without altering the protein structure. The minimal domains and full length domains were tested in vitro and in vivo. These surprising results showed that the domains act differently in isolation when compared to the full length protein. They also demonstrate that the UBA1 domain is responsible for ubiquitin recognition in Rhp23, whilst the UBA2 domain appears to have little to no binding ability.
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Belahmer, Hanane [Verfasser]. "APC/C Cdh1 modulates the ER stress response via Gadd34 / Hanane Belahmer." Hannover : Technische Informationsbibliothek und Universitätsbibliothek Hannover (TIB), 2011. http://d-nb.info/1021438804/34.
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Rial, Nathaniel S. "The Adenomatous Polyposis Coli Tumor Suppressor Gene Suppresses Deoxycholic Acid Induction of the Chemotactic Cytokine CXCL8 in Human Colorectal Cancer." Diss., The University of Arizona, 2007. http://hdl.handle.net/10150/194449.
Full textAbstract:
Elevated deoxycholic acid (DCA) and mutations in the Adenomatous Polyposis Coli (APC) tumor suppressor gene have been associated with increased risk of colorectal cancer (CRC). Chronic inflammation has also been associated with increased risk of CRC. It is unclear if DCA mediates inflammation in the normal or transformed colonic mucosa. The status of APC was manipulated in human CRC cell lines to study the role of DCA mediated inflammation. The chemotactic cytokine, CXCL8, was used as a marker of inflammation. Addition of DCA to the HT29-parental cell line with mutant-APC increased the steady state mRNA and protein levels of CXCL8. Conversely, addition of DCA to the HT29-APC cell line with wild type-APC was protective for increased steady state RNA and protein levels of CXCL8. DCA activated transcription factors which had binding regions in the CXCL8 5’-promoter. To elucidate the mechanism of induction, the 5’-promoter of CXCL8 was investigated. DCA increased promoter-reporter activity of the CXCL8 gene in HT29-parental cell line but wild type-APC blocked this effect. Chromatin immunoprecipitation (ChIP) revealed that DCA activated transcription factors, AP-1 and NF-κB were bound to the 5’-promoter of CXCL8. The transcription factor, β-catenin, was also bound to the 5’-promoter of CXCL8. Phenotypic effects were measured. Increased CXCL8 lead to matrix metalloproteinase-2 (MMP-2) production and increased invasion by HT29-parental cells on laminin coated filters. The DCA-mediated invasion was blocked by antibody directed against CXCL8 and wild type- APC. Therefore DCA-mediated inflammation occurs in transformed colonic epithelium and increases the invasive phenotype of CRC cells by CXCL8.