Dissertations / Theses: 'Apg-1'

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Nonoguchi, Kosuke. "Cloning of human cDNAs for Apg-1 and Apg-2, menbers of the Hsp 110 family, and chromosomal assignment of their genes." Kyoto University, 2000. http://hdl.handle.net/2433/180836.

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Berglund, Carl Johan. "Det uppskjutna gränsöverskridandet : Apg 10:1–11:18, Luk 7:1–10 och frågan om narrativ enhet mellan Lukasevangeliet och Apostlagärningarna." Thesis, Uppsala universitet, Nya testamentets exegetik, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-288474.

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För att utvärdera H. J. Cadburys axiom att Luk och Apg utgör ett kontinuerligt verk i två delar, görs en översikt över frågorna om gemensamt författarskap, receptionshistoria, genre och narrativ enhet, samt en narrativ analys av Apg 10:1–11:18 och Luk 7:1–10 med syfte att bedöma om de två delberättelserna visar tecken på att tillhöra en samlad eller två skilda huvudberättelser. De två delberättelsernas narrativa värld och karaktärsgalleri är likartade, deras implice rade författares attityder och tendenser är desamma, och deras intriger passar väl in i en övergripande intrig, oavsett om Luk och Apg ses som en berättelse i två delar, eller som två berättelser med litterära relationer till varandra. Delberättelsernas radikalt olika narra tiva struktur, och att ingen i Apg 10:1–11:18 visar någon kunskap om att händelserna i Luk 7:1–10 ägt rum, talar för att de två delberättelserna tillhör två olika huvudberättelser.

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Carlbark, Linnea. "”Vad Gud har gjort rent skall inte du göra orent.” : Inkluderingen av hedningarna i den tidiga Jesusrörelsen En studie av Apg 10:1–48." Thesis, Uppsala universitet, Nya testamentets exegetik, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-352363.

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Litterär och historisk studie av Apostlagärningarna 10:1-48 som försöker svara på frågeställningarna: Hur presenterar Apg 10:1–48 inkluderingen av hedningar i den tidiga judiska Jesusrörelsen? Vilka problem övervinns och vilka aktörer driver igenom förändringen? Uppstatsen studerar både perikopen i sitt historiska sammanhang och genom att studera narrativet. För att närma sig texten och se vilka bibliska motiv det finns för att möjliggöra den etiskt pluralistiska religion kristendomen är idag. Uppsatsen studerar litteratur historiska länkar, judiska renhetsföreskrifter, geografiska platser för perikopen, de olika karaktärerna och narrativets struktur.

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Stegh, Alexander H. "Effektormechanismen CD95-(APO-1-FAS)-vermittelter Apoptose." [S.l.] : [s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=961531592.

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Arias, Chávez Dennis, and Sevillano Luis Miguel Cangalaya. "Investigar y escribir con APA 7 [Capítulo 1]." Universidad Peruana de Ciencias Aplicadas (UPC), 2021. http://hdl.handle.net/10757/654533.

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El propósito de este libro es ayudar a los estudiantes, docentes y profesionales de las ciencias sociales y humanas a comunicar los resultados de investigación, ya sea en formato tesis o artículo científico. Para ello, el texto proporciona un conjunto de pautas formales para la organización, estructuración y redacción de estos dos géneros. Investigar y escribir con APA 7 toma como base los lineamientos establecidos en la séptima edición del Manual APA (2020) y desarrolla ejemplos reales y modélicos que ayudarán al lector a tener un mejor entendimiento de la forma de presentar estos textos. De esa manera, el libro es una herramienta que ayuda a dinamizar el proceso formativo de los estudiantes de pregrado y posgrado, mejorar los procesos de enseñanza y encaminar las actividades investigativas con miras a publicar los resultados.

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Rama, Nicolas. "La Nétrine-1, un facteur de guidage et de survie neuronale pendant le développement du système nerveux central." Thesis, Lyon 1, 2011. http://www.theses.fr/2011LYO10059/document.

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Le développement du système nerveux central fait intervenir de nombreux processus cellulaires comme la prolifération, la différenciation, l'apoptose, la migration neuronale et le guidage axonal. Ces processus sont finement régulés et aboutissent à la formation d'un système nerveux central fonctionnel. Au cours de cette thèse, je me suis principalement intéressé à une molécule chimiotropique, la Nétrine-1 et à ses récepteurs APP (Amyloïd-b Precursor Protein) et DCC (Deleted in Colorectal Cancer). La Nétrine-1 est impliquée à la fois dans le contrôle de la navigation neuronale (ie migration neuronale et guidage axonal) et dans celui de la survie neuronale. Un premier aspect de mon travail a consisté à étudier le rôle d'un nouveau récepteur à la Nétrine-1 : APP. Nous avons donc démontré que APP est un récepteur à la Nétrine-1 impliqué dans le guidage des axones commissuraux. En effet, APP collabore avec DCC afin de stimuler la croissance axonale en réponse à la Nétrine-1. Le second aspect de mon travail a été l'étude du rôle de la Nétrine-1 en tant que facteur de survie neuronale. En effet, son récepteur DCC appartient à la famille des récepteurs à dépendance. En absence de Nétrine-1, DCC ne reste pas inactif, mais déclenche une signalisation pro-apoptotique qui va éliminer la cellule. Nous avons démontré que pendant le développement du système nerveux, la Nétrine-1 inhibe cette signalisation et contrôle la survie des neurones commissuraux. Le contrôle de la signalisation pro-apoptotique de DCC par la Nétrine-1 pourrait ainsi réaliser un contrôle qualité des projections axonales et faciliter l'orientation du cône de croissance lors du guidage du cône de croissance
The development of the central nervous system requires several cellular processes such as proliferation, differentiation, apoptosis, neuronal migration and axon guidance. This whole process is finely regulated and leads to the formation of a functional central nervous system. During my thesis, I have mainly worked on a chemotropic molecule, Netrin-1 and its receptors APP (Amyloid-ß Precursor Protein) and DCC (Deleted in Colorectal Cancer). Netrin-1 is involved in both neuronal navigation (neuronal migration and axonal guidance) and neuronal survival. I have firstly investigated the role of a new Netrin-1 receptor, APP during axonal guidance. We have shown that APP is involved in the guidance of commissural axons. Indeed, APP collaborates with DCC in order to promote axonal outgrowth in response to Netrin-1. Thereafter, I have investigated the role of Netrin-1 as a neuronal survival factor. In fact, the Netrin-1 receptor DCC belongs to the dependence receptor family. In absence of Netrin-1, DCC does not remain inactive, since it triggers a pro-apoptotic signalling pathway. During the development of the central nervous system, we have shown that Netrin-1 blocks the pro-apoptotic signalling pathway and promotes neuronal survival. The Netrin-1 control of DCC pro-apoptotic signalling might carry out a “quality control” of the axonal projection or/and it could promote the steering of the growth cone during axonal guidance

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Jackson, David Brian. "Functional characterisation of Drosophila AP-1." Thesis, University of London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407390.

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Mühlenbeck, Frank. "Aktivierung nicht-apoptotischer Signalwege durch TRAIL und anti-APO-1." [S.l.] : Universität Stuttgart , Fakultät Geo- und Biowissenschaften , Institut für Zellbiologie und Immunologie, 2000. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB8619084.

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9

Camus, Grégory. "Rôle du complexe AP1 dans la morphogenèse du VIH-1." Paris 7, 2008. http://www.theses.fr/2008PA077189.

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La formation de virions infectieux lors des étapes tardives de la réplication du VIH requiert trois composants structuraux du virus, (1) le précurseur Gag qui forme le corps des virions ; (2) la glycoprotéine d'enveloppe (Env) qui, incorporée dans les virions, leur confère leur infectiosité ; (3) les ARN génomiques viraux. Récemment, plusieurs liens ont été établis entre la biogenèse des rétrovirus et la voie endosomale : il a été montré que des interactions entre Gag et des facteurs cellulaires du transport vésiculaire étaient cruciales pour la production des virions. Durant ma thèse, nous avons rapporté une nouvelle interaction entre Gag du VIH-1, et le complexe d'adaptine AP1. Le domaine Matrice de Gag interagit directement avec la sous-unité mu d'AP1. De plus, l'absence d'AP1 réduit la libération de virions, alors qu'au contraire sa surexpression augmente la production virale. Enfin, nous avons montré qu'AP1 interagit avec Tsg101 : composant de la machinerie ESCRT indispensable au bourgeonnement du VIH. En conclusion, nos résultats suggèrent qu'AP1 est essentiel à la production virale du VIH-1. Au cours de ma thèse, je me suis également intéressé aux processus d'incorporation des glycoprotéines d'enveloppe virales. Nous avons, au laboratoire, montré que le cofacteur cellulaire TIP47 agit comme un connecteur entre Gag et Env du VIH-1 et est crucial pour l'incorporation d'Env dans les virions. Enfin, j'ai étudié les processus d'incorporation d'autres envefoppes virales. Nos résultats préliminaires suggèrent que l'incorporation des enveloppes de MLV et VSVg serait indépendante de TIP47 alors que celle du lentivirus VISmac nécessiterait la présence de ce cofacteur
Infectious virions morphogenesis during the late steps of HIV-1 replication cycle, requires three viral components: (1) Gag precursor, which forms the viral core; (2) the envelope glycoprotein (Env) which confers their infectivity to virions when incorporated ; (3) viral genomic RNA. Recently, several links have been made between retroviruses biogenesis and cellular proteins involved in the vesicular trafficking. During my PhD, we have found a new interaction between HIV-1 Gag and the adaptor complexe AP1. The matrix domain of Gag interacts directly with the mu subunit of AP1. Moreover, depletion of AP1 reduces virions production while overexpression increases it. Finally, we have shown that AP1 interacts with Tsg101, a component of the ESCRT machinery crucial to HIV-budding. In conclusion, our results suggest that AP1 is essential to HIV-1 virions production. I have also been interested in the incorporation process of the viral envelope glycoprotein. I have participated to a study, lead in the team, that shows that cellular factor TIP47 act as connector between HIV-1 Gag and Env proteins and is crucial for the incorporation of Env in virions. Finally, I have been interested in the incorporation process of other viral envelopes. Our first results indicate that incorporation of MLV Env ans VSVg would not be dependent on TIP47 while incorporation of SlVmac Env would require the presence of this cellular protein

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Gazon, Helène. "Étude de la régulation d’HBZ et son rôle sur la biogénèse des miARN chez les patients infectés par HTLV-1." Thesis, Antilles-Guyane, 2014. http://www.theses.fr/2014AGUY0806/document.

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HTLV-1, un rétrovirus endémique des Antilles-Guyane qui infecte plus de 10 millions de personnes dans le monde, est l’agent étiologique de l’ATL, une leucémie agressive des lymphocytes T CD4+ résistante aux traitements conventionnels actuels. Le rôle émergent des miARN dans la leucémogénèse et la résistance aux chimiothérapies a soulevé des interrogations quant à leurs rôles dans le développement de l’ATL. Les miARN sont de petits ARN non codant qui régulent l’expression génique. Récemment leur altération durant le cycle de vie du HTLV-1 a été mise en lumière. Une des caractéristiques de l’émergence de l’ATL est la perte d’expression des protéines virales codées par le promoteur en amont du génome proviral (LTR5’), à l’exception d’hbz dont l’expression est initiée dans le promoteur en aval du génome proviral (LTR3’). Dans une première étude, nous démontrons, dans un modèle mimant la cellule ATL, qu’HBZ module sa propre transcription à travers une boucle de rétrocontrôle qui implique une coopération avec le facteur de transcription de la famille AP-1 JunD. Nous montrons que l’expression d’HBZ induit des caractéristiques phénotypiques de fibroblastes transformés. Nous avons, ensuite, analysé l’effet d’HBZ sur les miARN dans les cellules ATL et montré qu’il induit une diminution des miARN cellulaires via l’inhibition d’un acteur clé de la maturation, Dicer. En accord avec notre première étude, nous montrons que l’induction d’HBZ dans les CD4+ de patients ATL corrèle avec une augmentation de la charge provirale (CPV) et donc l’évolution de l’ATL. Le traitement de ces cellules au VPA inhibe l’expression d’hbz, restaure celle de dicer et inverse la CPV et donc la prolifération des cellules malignes ex vivo
HTLV-1, a retrovirus endemic of Antilles-Guyana that infects more than 10 million people worldwide, is the etiological agent of ATL, an aggressive leukemia of CD4+ T lymphocytes resistant in currents treatments. The emerging role of miRNA in leukemogenesis and chemoresistance has risen questioning about their role in ATL development. MiRNAs are a class of non-coding RNAs that regulate gene expression. Involvement of their alteration in the HTLV-1 life cycle has recently come to light. One of the hallmarks of progression toward ATL is the emergence of LTR5’-deficient provirus and thereby eliminating the expression of all viral proteins on the sense strands in these cells, with the exception of the hbz gene regulated by an independent promoter in the 3’LTR. In a first study, using a provirus with the 5’LTR deleted, we found that HBZ modulates its own expression through a positive-feedback loop that involves cooperation with AP-1 transcription factor JunD. We also found that hbz-expressing fibroblasts displayed of a transformed phenotype. Then, we analyzed the effect of HBZ on miRNA expression in ATL patients and report that hbz reduce significantly expression of cellular miRNAs via inhibition of an enzyme essential for maturation, Dicer1. In agreement with our previous study, we show that hbz expression in ATL samples correlates with HTLV-1–provirus load (CPV) and consequently progression of the pathology. VPA treatment of these cells inhibits hbz expression, restores Dicer expression, and inverts the proviral charge thereby reducing cellular proliferation of malignant cells

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Concei??o, Thalita Santana. "Imunoexpress?o das prote?nas APE-1 e XRCC-1 em carcinoma epidermoide de l?ngua oral." Universidade Federal do Rio Grande do Norte, 2016. http://repositorio.ufrn.br/handle/123456789/20962.

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Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico - CNPq
Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES)
Os sistemas de reparo do DNA desempenham um papel cr?tico na prote??o do genoma humano contra danos causados por agentes cancer?genos presentes no ambiente. Muta??es em genes de reparo de DNA podem ser respons?veis pelo desenvolvimento de tumores e de resist?ncia das c?lulas malignas a agentes quimioterap?uticos. A principal via de reparo de danos oxidativos do DNA ? a via de reparo por excis?o de bases. O objetivo deste estudo foi investigar a imunoexpress?o da APE-1 e XRCC-1, que s?o prote?nas envolvidas no reparo do DNA por excis?o de bases, e sua associa??o com par?metros cl?nicos e histopatol?gicos em carcinoma epidermoide de l?ngua oral (CELO), a fim de investigar um poss?vel valor progn?stico para essas prote?nas. A express?o de APE-1 e XRCC-1 foi avaliada por meio de imuno-histoqu?mica em 50 casos de CELO. Os dados cl?nicos foram coletados no prontu?rio m?dico de cada paciente e a grada??o histopatol?gica foi efetuada para cada caso. A an?lise estat?stica com os testes de Qui-quadrado e Exato de Fisher foi realizada para determinar a associa??o entre as express?es das prote?nas e caracter?sticas cl?nico-patol?gicas; adotou-se um valor de signific?ncia de p<0,05. APE-1 foi altamente expressa no n?cleo e no citoplasma em 56% dos casos. XRCC-1 mostrou alta express?o apenas no n?cleo em 60% dos casos. A alta express?o de XRCC-1 foi significativamente associada aos est?dios cl?nicos I e II (p = 0,02). Ambas as prote?nas n?o foram associadas a outros par?metros cl?nicos ou grada??o histopatol?gica. Por fim, nossos resultados demonstraram que as prote?nas de reparo do DNA por excis?o de bases APE-1 e XRCC-1 est?o positivamente expressas em CELO, no entanto, n?o est?o relacionadas com par?metros cl?nicos e histol?gicos, exceto a associa??o de XRCC-1 com melhor estadiamento cl?nico. Os resultados deste experimento indicam que a express?o imuno-histoqu?mica dessas prote?nas n?o possui valor progn?stico para esta neoplasia.
DNA repair systems play a critical role in protecting the human genome from damage caused by carcinogens present in the environment. Mutations in DNA repair genes may be responsible for tumor development and resistance of malignant cells to chemotherapeutic agents. The major pathway for oxidative DNA damage repair is the base excision repair pathway. The objective of this study was to investigate the immunoexpression of APE-1 and XRCC-1, which are proteins involved in DNA base excision repair and its association with clinical and histopathological parameters in oral tongue squamous cell carcinoma (OTSCC), in order to investigate a possible prognostic value for those proteins. The expression of APE-1 and XRCC-1 was evaluated semi-quantitatively by immunohistochemistry in 50 OTSCC cases. Clinical data was collected from patients? medical charts and histopathological grading was performed for each case. Statistical analysis (Chi-square and Fisher?s exact tests; significance of 5%) was performed to determine the association between protein expressions and clinico-pathological characteristics. APE-1 was highly expressed in nucleus and cytoplasm in 56% of cases. XRCC-1 showed overexpression only in nucleus in 60% of cases. High expression of XRCC-1 was significantly associated to clinical stages I and II (P=0.02). Both proteins were not associated to other clinical parameters or histopathological grading. Our findings demonstrate that DNA base excision repair proteins APE-1 and XRCC-1 are upregulated in OTSCC, however, they are not related to clinical and histologic parameters, except for XRCC-1 association to better clinical staging. Our results indicate that the immunohistochemical expression of these proteins has no association with prognostic parameters in this tumor.

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Escudero-Lourdes, C., E. E. Uresti-Rivera, C. Oliva-González, M. A. Torres-Ramos, P. Aguirre-Bañuelos, and A. J. Gandolfi. "Cortical Astrocytes Acutely Exposed to the Monomethylarsonous Acid (MMA(III)) Show Increased Pro-inflammatory Cytokines Gene Expression that is Consistent with APP and BACE-1: Over-expression." SPRINGER/PLENUM PUBLISHERS, 2016. http://hdl.handle.net/10150/621476.

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Long-term exposure to inorganic arsenic (iAs) through drinking water has been associated with cognitive impairment in children and adults; however, the related pathogenic mechanisms have not been completely described. Increased or chronic inflammation in the brain is linked to impaired cognition and neurodegeneration; iAs induces strong inflammatory responses in several cells, but this effect has been poorly evaluated in central nervous system (CNS) cells. Because astrocytes are the most abundant cells in the CNS and play a critical role in brain homeostasis, including regulation of the inflammatory response, any functional impairment in them can be deleterious for the brain. We propose that iAs could induce cognitive impairment through inflammatory response activation in astrocytes. In the present work, rat cortical astrocytes were acutely exposed in vitro to the monomethylated metabolite of iAs (MMA(III)), which accumulates in glial cells without compromising cell viability. MMA(III) LD50 in astrocytes was 10.52 μM, however, exposure to sub-toxic MMA(III) concentrations (50-1000 nM) significantly increased IL-1β, IL-6, TNF-α, COX-2, and MIF-1 gene expression. These effects were consistent with amyloid precursor protein (APP) and β-secretase (BACE-1) increased gene expression, mainly for those MMA(III) concentrations that also induced TNF-α over-expression. Other effects of MMA(III) on cortical astrocytes included increased proliferative and metabolic activity. All tested MMA(III) concentrations led to an inhibition of intracellular lactate dehydrogenase (LDH) activity. Results suggest that MMA(III) induces important metabolic and functional changes in astrocytes that may affect brain homeostasis and that inflammation may play a major role in cognitive impairment-related pathogenicity in As-exposed populations.

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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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Silva, Flavio Sousa. "Clonagem, expressão, purificação e caracterização estrutural da região AP-1 da oncoproteína Jun." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/85/85131/tde-18092014-091537/.

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A proteína jun é um dos principais integrantes do complexo AP-1 e está envolvido nos processos inflamatórios, diferenciação, apoptose e migração celular. Esta proteína pode formar homodímeros e heterodímeros por meio da dimerização que ocorre pelo sítio de sequências de leucinas. Existem evidências de que a proteína jun pode ser inibida pela proteína RPL10 mediante a ligação destas proteínas, no mesmo sítio de sequências de leucinas no núcleo celular, parando a progressão de tumores. O objetivo deste trabalho foi expressar, isolar e caracterizar a região de ligação das sequências de leucinas (região AP-1), para estudos posteriores de ligação com a proteína RPL10. O cDNA para proteína jun foi amplificado por PCR e clonado nos vetores de expressão pET 26b(+), pET 28a-c(+) e p1813 e expressa em E.coli BL21 (DE3). A proteína expressa em vetor pET28_AP1 foi eficientemente purificada pela técnica de cromatografia de afinidade a íons metálicos, por possuir uma sequência (poli)histidina que facilitou a purificação, apresentando um excelente grau de pureza. A identidade da proteína foi confirmada através de análise feita por western blotting e dot blotting e também por analise por espectrometria de massas.
The jun protein is one of the main AP-1 complex members and is involved in the inflammatory process, differentiation, apoptosis and cell migration. The Jun protein may form homodimers and heterodimers by dimerization in the leucines sequences site. There are evidences that jun protein can be inhibited by RPL10 protein through these protein binding in the same leucine sequences site, in the cell nucleus, stopping the tumor progress. The objective of this study was to express, isolate and characterize the binding region of the leucine sequences (AP-1 region) for subsequent binding studies with RPL10 protein. The jun protein cDNA was amplified by PCR and cloned into pET 26b(+), pET 28a-c(+) and p1813 expression vectors, and was expressed in E.coli BL21 (DE3). The protein expressed in pET28_AP1 vector was efficiently purified by the affinity chromatography technique to metal ions because have a (poly)histidine sequence which facilitate the protein purification, showing an excellent high purity. The protein identity was confirmed by western blotting and dot blotting and also by mass spectrometry analysis.

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Tolza, Claire. "Fra-1 et Fra-2 dans les cancers du sein triple négatifs : mécanismes transcriptionnels et identification de cibles thérapeutiques potentielles." Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTT094/document.

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Les cancers du sein triple négatifs (TNBC) ne bénéficient d’aucune thérapie ciblée et restent incurables. L’identification de nouvelles cibles moléculaires diagnostiques et surtout, thérapeutiques constitue donc un enjeu majeur pour le traitement de ces cancers. Fra-1 et Fra-2, deux constituants du complexe transcriptionnel AP-1, sont surexprimés dans les TNBC où ils participent à l’agressivité tumorale et/ou la métastatisation. Les gènes cibles de Fra-1 et Fra-2, ainsi que les mécanismes moléculaires via lesquels ils gouvernent la transcription de leurs gènes cibles sont très peu caractérisés. Dans ce contexte, l’objectif général de ma thèse à été d’identifier les gènes codants sous contrôle de Fra-1 et/ou Fra-2 et de caractériser les sites de fixation de Fra-1 et Fra-2 sur la chromatine pour identifier des cibles directes, en combinant des approches transcriptomiques et génomiques combinées à l’interférence à l’ARN dans la lignée modèle MDA-MB231. Les résultats obtenus, associés à l’analyse de banques de données humaines, ont permis la sélection de gènes cibles pour les études mécanistiques et fonctionnelles. Le gène HMGA1, choisi en raison de son rôle maintenant bien établi dans l’agressivité des tumeurs épithéliales, a fait l’objet d’une étude portant sur les mécanismes transcriptionnels gouvernés par Fra-1 et/ou Fra-2 pour sa régulation. L’étude fonctionnelle a été focalisée sur CD68 dont l’expression est fortement induite par Fra-1 et Fra-2. CD68 code pour une protéine transmembranaire dont la fonction n’est pas clairement établie et dont l’implication dans le phénotype tumoral n’a jamais été étudiée
Triple negative breast cancers (TNBC) are characterized by a poor prognosis and no targeted therapy is currently available. The identification of new diagnostic and therapeutic targets is crucial for the treatment of these cancers. Fra-1 and Fra-2, two members of the AP-1 transcriptional complex, are frequently overexpressed in TNBC, where they contribute to the tumorigenic phenotype. The panel of genes under the control of Fra-1 and/or Fra-2 in TNBC, as well as the molecular mechanisms by which they control their target gene expression are mostly unknown. The aim of my thesis was to identify the panel of genes controlled by Fra-1 and/or Fra-2 in TNBC and to characterize the binding sites of Fra-1 and Fra-2 on chromatin to select direct targets for further studies, by using transcriptomic and ChIP-seq approaches combined to RNAi in the model cell line MDA-MB231. The results allowed us to select target genes for transcriptional and functional studies. The study of the transcriptional mechanisms governed by Fra-1 and/or Fra-2 was carried out on the HMGA1 gene, already known for its crucial role in the aggressiveness of epithelial tumours. The fonctional study was focused on CD68, as its expression in highly induced by Fra-1 and Fra-2. CD68 encodes a transmembrane protein which cellular fonction is still not known and its potential role in tumorigenesis has not been studied yet

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Wang, Wei-Ming. "AP-1-MEDIATED REGULATION OF HPV CHROMATIN TRANSCRIPTION." Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1199480473.

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Milord, Sandrine. "Contribution à l’étude du rôle et de la régulation de Fra-1 dans le cancer." Thesis, Montpellier 1, 2011. http://www.theses.fr/2011MON13505/document.

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Fra-1 appartient à la famille des facteurs de transcription AP-1. Son expression est particulièrement élevée dans les cellules de cancer du sein qui n'expriment pas le récepteur aux œstrogènes (RE-), c'est-à-dire les cellules les plus agressives. L'inhibition de Fra-1 dans ces cellules entraîne une diminution de la motilité, de l'invasion et de la prolifération, mais elle entraîne aussi de profonds changements de morphologie. Les cellules RE-, qui présentent un phénotype mésenchymateux s'arrondissent et établissent un plus grand nombre de contacts cellule-cellule après l'inhibition de Fra-1. Dans les cellules RE-, la β-caténine est localisée au noyau ou dans le cytoplasme, ce qui est un marqueur de mauvais pronostic. Au cours de cette thèse, j'ai montré que Fra-1 régule la localisation nucléaire de la β-caténine et ainsi régule son activité transcriptionelle en agissant très tardivement sur la voie Wnt. J'ai également mis en évidence une interaction physique directe entre Fra-1 et la β-caténine qui pourrait être responsable de cet effet. De plus, l'analyse de microarrays par RT-QPCR a révélé la régulation d'autres gènes comme la mœsine, la fibronectine et l'extracellular matrix protein 1, qui pourraient également jouer un rôle dans la régulation de l'agressivité tumorale par Fra-1. Par ailleurs, Fra-1 est une protéine instable et nous avons montré qu'elle est phosphorylée et stabilisée par PKCθ. Fra-1 est d'ailleurs nécessaire à l'effet de la kinase sur la motilité cellulaire
Fra-1 is a member of the AP-1 transcription factor family. It is aberrantly expressed in breast cancer cells lacking Estrogen Receptor (ER-) expression, which are the most aggressive ones. Fra-1 inhibition in these cells leads to a decreased in motility, invasion and proliferation, but also to deep morphologic changes. ER- cells, which present a mesenchymal phenotype, become rounder and establish a greater number of cell-cell contacts after Fra-1 inhibition. In ER- cells, β-catenin is nuclear or cytoplasmic, which is considering as a poor prognosis marker. During this PhD, I demonstrate that Fra-1, which acts very downstream in the Wnt/β-catenin signaling pathway, regulates the nuclear localization of β-catenin leading to up-regulation transcriptional activity of β-catenin. I also found that Fra-1 directly interacts with β-catenin. In addition, RT-QPCR microarrays analysis has revealed the regulation of other genes such as mœsin, fibronectin and extracellular matrix protein 1, which might also take part in the tumoral aggressiveness regulated by Fra-1. Moreover, we show that Fra-1, which is an unstable protein, is phosphorylated and stabilized by PKCθ. Furthermore, Fra-1 is necessary to mediate the kinase effect on cell motility

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Lafargue, Mathieu. "Plasminogen Activator Inhibitor-1 (PAI-1) and Activated Protein C (aPC) Modulation Mechanisms of Pseudomonas aeruginosa Induced Pulmonary Edema." Thesis, Bordeaux 2, 2012. http://www.theses.fr/2012BOR22020/document.

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Une coagulopathie aigue endogène (EAC) est présente chez 25% des patients de traumatologie dès leur arrivée. Des résultats d’études récentes montrent que cette EAC est liée à l’activation de la voie de la protéine C (aPC). Quelques heures après, se développe un état pro-coagulant associant un niveau abaissé d’aPC et un taux plasmatique élevé de l’inhibiteur de l’activateur du plasminogene (PAI-1). Nous trouvons que l’incidence des pneumopathies associées à la ventilation est significativement augmentée chez ces patients sans toutefois connaître le rôle exact de ces anomalies de coagulation. Basé sur cette hypothèse central de susceptibilité augmentée a l’infection et plus particulièrement aux pneumopathie a P.aeruginosa (PA) le but de ce travail est d’identifier les mécanismes par lesquels PAI-1 et aPC peuvent moduler la perméabilité de la barrière alveolo capillaire et ceci a travers 3 objectifs spécifiques1 – Objectif 1 : déterminer les mécanismes par lequel PA augmente la perméabilité endothéliale. 2 – Objectif 2 : déterminer le rôle d’aPC dans la modulation des effets de PA sur l’œdème pulmonaire lésionnel.3 – Objectif 3 : déterminer le rôle de PAI-1 dans la modulation des effets de PA sur l’œdème pulmonaire lésionnel.En utilisant un inhibiteur spécifique des petites GTPases nous démontrons le rôle centrale joué par RhoA dans le développement de l’œdème pulmonaire induit par PA. PAI-1 et aPC sont impliquées dans le mécanisme lésionnel pulmonaire. aPC et l’inhibition de la voie du RhoA attenue le développement de l’œdème pulmonaire et diminue la dissémination systémique bactérienne. Cependant le blocage invivo de la voie de PAI-1 est associé à une surmortalité et à une augmentation de la charge bactérienne suggérant un rôle de PAI-1 dans l’activation de la réponse inflammatoire nécessaire a l’éradication de PA
A clinically significant acute endogenous coagulopathy (EAC) is present in 25% of major trauma patients upon arrival in the emergency department, before any fluid resuscitation. Results from recent clinical studies indicate that EAC is primarily caused by the activation of the anticoagulant protein C pathway. Several hours later, there is the development of a systemic procoagulant activity associated with low plasma levels of activated protein C (aPC) and an inhibition of the fibrinolysis caused by elevated plasma levels of plasminogen activator inhibitor 1 (PAI-1). We have found that the incidence of ventilator-associated pneumonia (VAP) is significantly increased in trauma patients with these coagulation abnormalities [6, 9]. However, whether these coagulation abnormalities play a mechanistic role in the increased susceptibility to nosocomial lung infection observed after severe posttraumatic hemorrhage is unknown. Thus, the central hypothesis is that the increased susceptibility to P. aeruginosa (PA) pneumonia following severe trauma with tissue hypoperfusion is mediated in part by these posttraumatic coagulation abnormalities within the airspaces of the lung. Specifically, in this work, we will identify through 3 specific aims the mechanisms by which PAI-1 and aPC modulate PA–mediated increase in alveolar-capillary barrier permeability.1 - Specific Aim 1: To determine the mechanisms by which PA increases lung endothelial permeability.2 - Specific Aim 2 : To determine the Role of aPC in modulating the effect of PA on the lung endothelial barrier function3 - Specific Aim 3 : To determine the Role of PAI-1 in modulating the effect of PA on the lung endothelial barrier functionIn the present work, we demonstrated the central role small GTPases RhoA plays in the increase of permeability induced by pseudomonas infection. PAI-1 and aPC are deeply involved in the control of early lung inflammation. aPC and inhibition of the RhoA pathway attenuates the development of pulmonary edema and decrease in the systemic dissemination of P. aeruginosa. However, in vivo disruption of PAI-1 signalling is associated with higher mortality at 24 h and significant increase in the bacterial burden suggesting that PAI-1 is required for the activation of the innate immune response necessary for the eradication of PA from the distal airspaces of the lung

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19

Vrotsos, Emmanuel. "MCP-1 and APP Involvement of Glial Differentiation and Migration of Neuroprogenitor Cells." Doctoral diss., University of Central Florida, 2009. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/3421.

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Neuroprogenitor cells are an important resource because of their potential to replace damaged cells in the brain caused by trauma and disease. It is of great importance to better understand which factors influence the differentiation and migration of these cells. Previously it has been reported that neuroprogenitor cells undergoing apoptotic stress have increased levels of Amyloid precursor protein (APP) and increased APP expression results in glial differentiation. APP activity was also shown to be required for staurosporine induced glial differentiation of neuroprogenitor cells. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that is expressed during inflammatory. The binding of MCP-1 to its chemokine receptor induces expression of novel transcription factor MCP-1 induced protein (MCPIP). MCPIP expression subsequently leads to cell death. Previous studies have shown that pro apoptotic factors have the ability to induce neural differentiation. Therefore, we investigated if MCPIP expression leads to differentiation of NT2 neuroprogenitor cells. Results showed that MCPIP expression increased glial fibrillary acid protein expression and also caused distinct morphological changes, both indicative of glial differentiation. Similar results were observed with MCP-1 treatment. Interestingly, APP expression decreased in response to MCPIP. Instead, we found APP activity regulates expression of both MCP-1 and MCPIP. Furthermore, inhibition of either p38 MAPK or JAK signaling pathways significantly reduced APP's effect on MCP-1 and MCPIP. These data demonstrate the role APP has in glial differentiation of NT2 cells through MCP-1/MCPIP signaling. It is possible that increased APP expression after CNS injury could play a ii role in MCP-1 production, possibly promoting astrocyte activation at injured site. We next investigated the effect that MCP-1 has on NT2 cell migration. Studies have shown that when neuroprogenitor cells are transplanted into the brain they migrate towards damaged areas, suggesting that these areas express factors that recruit migrating cells. Generally, after neuronal injury there is a neuroinflammatory response that results in increased chemokine production. We demonstrate that MCP-1 significantly induces the migration of NT2 neuroprogenitor cells. Activation of intracellular cyclic adenosine monophosphate (cAMP) or protein kinase C with forskolin and phorbol 12-myristate 13-acetate (PMA), respectively, was able to completely abolish the MCP-1 induced migration. Contrarily, neither extracellular signal-regulated kinase or p38 mitogen activated protein kinase was required for NT2 cells to respond to MCP-1. Interestingly, APP's ability to activate MCP-1 expression was shown to play a role in NT2 cell migration. We showed that NT2 cells expressing APP were capable of inducing migration of other neuroprogenitor cells. Utilizing a MCP-1 neutralizing antibody we discovered that APP induced migration was not caused solely by increased MCP-1 production. Interestingly, APP increased expression of several C-C chemokines: MCP-1, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES), and macrophage inflammatory protein alpha (MIP-1 alpha). This demonstrates the unique role APP has in regulating chemokine production, which directly affects cell migration. Taken together, this study provides us with a greater understanding of the mechanisms involved in both glial differentiation and migration of NT2 neuroprogenitor cells.
Ph.D.
Department of Biomolecular Science
Burnett College of Biomedical Sciences
Biomedical Sciences PhD

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20

Bejjani, Fabienne. "Mécanismes transcriptionnels gouvernés par Fra-1 dans le cancer du sein triple négatif." Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT028.

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Le complexe transcriptionnel AP-1 est une famille ubiquitaire de facteurs de transcription dimériques. Ses composants les mieux étudiés sont les membres des familles multigéniques Fos et Jun. Les mécanismes transcriptionnels gouvernés par ce complexe sont encore mal caractérisés, en raison du grand nombre de dimères AP-1 possibles, de l’abondance et de l’activité finement régulées de ses constituants qui dépendent des contextes cellulaires et physiopathologiques. De plus, les limitations techniques ont longtemps donné l'impression que AP-1 régule l’expression de ses gènes cibles en se fixant principalement à proximité de leurs promoteurs. Fra-1 est la protéine de la famille Fos la plus souvent impliquée dans les cancers épithéliaux. En particulier, elle est surexprimée dans les cancers du sein triple négatifs (TNBCs) où elle contribue à la tumorigenèse et à l'agressivité tumorale par des effets pléiotropes. Dans ce contexte, l’objectif de mes travaux de thèse était d’aboutir à une meilleure compréhension des actions transcriptionnelles de Fra-1 au niveau du génome dans une lignée cellulaire TNBC de référence, la lignée MDA-MB-231. Pour ce faire, j'ai combiné des données transcriptomiques avec des données de ChIP-seq et de NG-Capture C (technique à haute résolution et à haut débit dérivée du 3C). J'ai également inclus dans ces études le membre Fra-2, de la famille Fos, qui présente la même spécificité de fixation à l’ADN et est également exprimé dans les TNBCs, bien qu'à un niveau beaucoup plus bas, où il contribue aussi au phénotype tumoral. En accord avec leurs effets pléiotropes, Fra-1 et Fra-2 activent ou répriment, soit individuellement soit de façon redondante ou complémentaire, l’expression de nombreux gènes associés à une large gamme de processus biologiques. Il est intéressant de noter que la régulation des gènes cibles est rarement due à la liaison de Fra-1 et/ou Fra-2 au niveau des régions promotrices de ces gènes mais fait intervenir leur liaison sur des enhancers distaux. Mes résultats de NG-Capture C suggèrent la présence d’interactions chromatiniennes à longue distance enhancer/promoteur, ainsi que des réseaux d’enhancers. Ces réseaux contiennent des enhancers liés par Fra-1 et d’autres indépendants de celui-ci. Aucune preuve d’un rôle de Fra-1 dans le contrôle des interactions chromatiniennes au niveau de ces réseaux n'a été trouvée en utilisant un panel de 35 gènes régulés par ce facteur. En parallèle, j'ai abordé les mécanismes de la répression transcriptionnelle médiée par Fra-1, mécanismes très rarement étudiés dans la littérature, en utilisant deux gènes modèles, TGFB2 et SMAD6. Ces études ont mis en évidence des mécanismes différents mis en jeu par Fra-1 pour la répression de ces deux gènes, ce qui montre la complexité des mécanismes de la régulation transcriptionnelle médiée par Fra-1
The AP-1 transcription complex is a ubiquitous family of dimeric transcription factors. Its best-studied components are the members of the Fos and Jun multigene families. The mechanisms whereby AP-1 exerts its transcriptional actions are still ill-understood due to the wide number of possible AP-1 dimers and the exquisitely regulated abundance and activity of its constituents, that all depend on the cell types and physiopathological contexts. Moreover, technical limitations have long given the impression that AP-1 mostly operates in the vicinity of gene promoters. Fra-1 is the Fos family protein that is most often implicated in epithelial cancers. In particular, it is overexpressed in triple negative breast cancers (TNBCs) where it contributes to tumorigenesis and tumor aggressiveness through pleiotropic effects. Based on this, the aim of my thesis was to gain a more comprehensive view of Fra-1 transcriptional actions at the genome-wide level in the MDA-MB-231 reference TNBC cell line, . To this aim, I have combined transcriptomic data with ChIP-seq and NG-Capture C (high resolution, high throughput 3C-derived technique) data. I have also included in my studies its Fos family kin Fra-2, as it displays the same DNA binding specificity and is also expressed in TNBCs, albeit at a much lower level, where it also contributes to the tumor phenotype. Consistently with their pleiotropic effects, Fra-1 and Fra-2 were found to up- or down-regulate either individually, together or redundantly many genes associated with a wide range of biological processes. Interestingly, the regulation of target genes is rarely due to Fra-1 and Fra-2 binding at gene promoters, but involves their binding to distal enhancers. My NG-Capture C results imply the presence of long-range chromatin interactions in Fra-1 modes of action, as well as enhancer hubs containing Fra-1- and non-Fra-1-binding enhancers. No evidence for a role for Fra-1 in the control of chromatin looping was however found using a panel of 35 Fra-1-regulated genes. Moreover, I have addressed the mechanisms of transcriptional repression mediated by Fra-1, as these have practically never been studied, using two model genes, TGFB2 and SMAD6. These studies underlined different mechanisms employed by Fra-1 for the repression of these genes, embodying the complexity of Fra-1 transcriptional regulation mechanisms

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Vrotsos, Emmanuel George. "MCP-1 and APP involvement in glial differentiation and migration of neuroprogenitor cells." Orlando, Fla. : University of Central Florida, 2009. http://purl.fcla.edu/fcla/etd/CFE0002517.

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22

Sudmann, Stefan. "Untersuchung zur Modulation der Fas-Rezeptor-(Apo-1, CD95) und Fas-Ligand- (Apo-1L) -Expression beim Ösophaguskarzinom Inzidenz und prognostische Relevanz /." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=969289820.

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Tuckermann, Jan Peter Gottfried. "In vivo Modulation des Transkriptionsfaktors AP-1 durch Glucocorticoide /." Karlsruhe : Forschungszentrum, 1999. http://www.gbv.de/dms/bs/toc/305077724.pdf.

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Zhang, Yafei. "Role of the Sh3 and Cysteine-Rich Domain 3 (STAC3) Gene in Proliferation and Differentiation of Bovine Satellite Cells." Thesis, Virginia Tech, 2013. http://hdl.handle.net/10919/76864.

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The STAC3 gene is a functionally undefined gene predicted to encode a protein containing two SH3 domains and one cysteine-rich domain. In this study, we determined the potential role of the STAC3 gene in proliferation and differentiation of bovine satellite cells. We isolated satellite cells from skeletal muscle of adult cattle and transfected them with STAC3 small interfering RNA (siRNA) or scrambled siRNA. Cell proliferation assays revealed that STAC3 knockdown had no effect on the proliferation rate of bovine satellite cells. We assessed the differentiation status of bovine satellite cells by quantifying the expression levels of myogenin and myosin heavy chain genes, and by quantifying fusion index. STAC3 knockdown stimulated mRNA and protein expression of myogenin, and myosin heavy chain 3 and 7, and increased fusion index of bovine satellite cells. These data together suggest that STAC3 inhibits differentiation of bovine satellite cells into myotubes. To determine the underlying mechanism, we identified and validated AP1?1 as a STAC3-interacting protein by yeast two-hybrid screening and co-immunoprecipitation. In C2C12 cells, STAC3 knockdown decreased the expression level of AP1?1 protein. In bovine satellite cells, STAC3 knockdown increased the membrane localization of glucose transporter 4 (GLUT4) and glucose uptake. These data together suggest the following mechanism by which STAC3 inhibits differentiation of bovine satellite cells: STAC3 increases AP1?1 stability in cells; a high level of AP1?1 keeps GLUT4 from translocating to the plasma membrane; reduced membrane localization of GLUT4 impedes glucose uptake; and restricted glucose uptake inhibits differentiation of satellite cells into myotubes.
Master of Science

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25

Tavares, Lucas Alves. "O envolvimento da proteína adaptadora 1 (AP-1) no mecanismo de regulação negativa do receptor CD4 por Nef de HIV-1." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17136/tde-06012017-113215/.

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O Vírus da Imunodeficiência Humana (HIV) é o agente etiológico da Síndrome da Imunodeficiência Adquirida (AIDS). A AIDS é uma doença de distribuição mundial, e estima-se que existam atualmente pelo menos 36,9 milhões de pessoas infectadas com o vírus. Durante o seu ciclo replicativo, o HIV promove diversas alterações na fisiologia da célula hospedeira a fim de promover sua sobrevivência e potencializar a replicação. A rápida progressão da infecção pelo HIV-1 em humanos e em modelos animais está intimamente ligada à função da proteína acessória Nef. Dentre as diversas ações de Nef está a regulação negativa de proteínas importantes na resposta imunológica, como o receptor CD4. Sabe-se que esta ação resulta da indução da degradação de CD4 em lisossomos, mas os mecanismos moleculares envolvidos ainda são totalmente elucidados. Nef forma um complexo tripartite com a cauda citosólica de CD4 e a proteína adaptadora 2 (AP-2), em vesículas revestidas por clatrina nascentes, induzindo a internalização e degradação lisossomal de CD4. Pesquisas anteriores demonstraram que o direcionamento de CD4 aos lisossomos por Nef envolve a entrada do receptor na via dos corpos multivesiculares (MVBs), por um mecanismo atípico, pois, embora não necessite da ubiquitinação de carga, depende da ação de proteínas que compõem os ESCRTs (Endosomal Sorting Complexes Required for Transport) e da ação de Alix, uma proteína acessória da maquinaria ESCRT. Já foi reportado que Nef interage com subunidades dos complexos AP-1, AP-2, AP-3 e Nef não parece interagir com subunidades de AP-4 e AP-5. Entretanto, o papel da interação de Nef com AP-1 e AP-3 na regulação negativa de CD4 ainda não está totalmente elucidado. Ademais, AP-1, AP-2 e AP-3 são potencialmente heterogêneos devido à existência de isoformas múltiplas das subunidades codificadas por diferentes genes. Todavia, existem poucos estudos para demonstrar se as diferentes combinações de isoformas dos APs são formadas e se possuem propriedades funcionais distintas. O presente trabalho procurou identificar e caracterizar fatores celulares envolvidos na regulação do tráfego intracelular de proteínas no processo de regulação negativa de CD4 induzido por Nef. Mais especificamente, este estudo buscou caracterizar a participação do complexo AP-1 na modulação negativa de CD4 por Nef de HIV-1, através do estudo funcional das duas isoformas de ?-adaptina, subunidades de AP-1. Utilizando a técnica de Pull-down demonstramos que Nef é capaz de interagir com ?2. Além disso, nossos dados de Imunoblot indicaram que a proteína ?2-adaptina, e não ?1-adaptina, é necessária no processo de degradação lisossomal de CD4 por Nef e que esta participação é conservada para degradação de CD4 por Nef de diferentes cepas virais. Ademais, por citometria de fluxo, o silenciamento de ?2, e não de ?1, compromete a diminuição dos níveis de CD4 por Nef da membrana plasmática. A análise por imunofluorêsncia indireta também revelou que a diminuição dos níveis de ?2 impede a redistribuição de CD4 por Nef para regiões perinucleares, acarretando no acúmulo de CD4, retirados por Nef da membrana plasmática, em endossomos primários. A depleção de ?1A, outra subunidade de AP-1, acarretou na diminuição dos níveis celulares de ?2 e ?1, bem como, no comprometimento da eficiente degradação de CD4 por Nef. Além disso, foi possível observar que, ao perturbar a maquinaria ESCRT via super-expressão de HRS (uma subunidade do complexo ESCRT-0), ocorreu um acumulo de ?2 em endossomos dilatados contendo HRS-GFP, nos quais também detectou-se CD4 que foi internalizado por Nef. Em conjunto, os resultados indicam que ?2-adaptina é uma importante molécula para o direcionamento de CD4 por Nef para a via ESCRT/MVB, mostrando ser uma proteína relevante no sistema endo-lisossomal. Ademais, os resultados indicaram que as isoformas ?-adaptinas não só possuem funções distintas, mas também parecem compor complexos AP-1 com diferentes funções celulares, já que apenas a variante AP-1 contendo ?2, mas não ?1, participa da regulação negativa de CD4 por Nef. Estes estudos contribuem para o melhor entendimento dos mecanismos moleculares envolvidos na atividade de Nef, que poderão também ajudar na melhor compreensão da patogênese do HIV e da síndrome relacionada. Em adição, este trabalho contribui para o entendimento de processos fundamentais da regulação do tráfego de proteínas transmembrana no sistema endo-lisossomal.
The Human Immunodeficiency Virus (HIV) is the etiologic agent of Acquired Immunodeficiency Syndrome (AIDS). AIDS is a disease which has a global distribution, and it is estimated that there are currently at least 36.9 million people infected with the virus. During the replication cycle, HIV promotes several changes in the physiology of the host cell to promote their survival and enhance replication. The fast progression of HIV-1 in humans and animal models is closely linked to the function of an accessory protein Nef. Among several actions of Nef, one is the most important is the down-regulation of proteins from the immune response, such as the CD4 receptor. It is known that this action causes CD4 degradation in lysosome, but the molecular mechanisms are still incompletely understood. Nef forms a tripartite complex with the cytosolic tail of the CD4 and adapter protein 2 (AP-2) in clathrin-coated vesicles, inducing CD4 internalization and lysosome degradation. Previous research has demonstrated that CD4 target to lysosomes by Nef involves targeting of this receptor to multivesicular bodies (MVBs) pathway by an atypical mechanism because, although not need charging ubiquitination, depends on the proteins from ESCRTs (Endosomal Sorting Complexes Required for Transport) machinery and the action of Alix, an accessory protein ESCRT machinery. It has been reported that Nef interacts with subunits of AP- 1, AP-2, AP-3 complexes and Nef does not appear to interact with AP-4 and AP-5 subunits. However, the role of Nef interaction with AP-1 or AP-3 in CD4 down-regulation is poorly understood. Furthermore, AP-1, AP-2 and AP-3 are potentially heterogeneous due to the existence of multiple subunits isoforms encoded by different genes. However, there are few studies to demonstrate if the different combinations of APs isoforms are form and if they have distinct functional properties. This study aim to identify and characterize cellular factors involved on CD4 down-modulation induced by Nef from HIV-1. More specifically, this study aimed to characterize the involvement of AP-1 complex in the down-regulation of CD4 by Nef HIV-1 through the functional study of the two isoforms of ?-adaptins, AP-1 subunits. By pull-down technique, we showed that Nef is able to interact with ?2. In addition, our data from immunoblots indicated that ?2- adaptin, not ?1-adaptin, is required in Nef-mediated targeting of CD4 to lysosomes and the ?2 participation in this process is conserved by Nef from different viral strains. Furthermore, by flow cytometry assay, ?2 depletion, but not ?1 depletion, compromises the reduction of surface CD4 levels induced by Nef. Immunofluorescence microscopy analysis also revealed that ?2 depletion impairs the redistribution of CD4 by Nef to juxtanuclear region, resulting in CD4 accumulation in primary endosomes. Knockdown of ?1A, another subunit of AP-1, resulted in decreased cellular levels of ?1 and ?2 and, compromising the efficient CD4 degradation by Nef. Moreover, upon artificially stabilizing ESCRT-I in early endosomes, via overexpression of HRS, internalized CD4 accumulates in enlarged HRS-GFP positive endosomes, where co-localize with ?2. Together, the results indicate that ?2-adaptin is a molecule that is essential for CD4 targeting by Nef to ESCRT/MVB pathway, being an important protein in the endo-lysosomal system. Furthermore, the results indicate that ?-adaptins isoforms not only have different functions, but also seem to compose AP-1 complex with distinct cell functions, and only the AP-1 variant comprising ?2, but not ?1, acts in the CD4 down-regulation induced by Nef. These studies contribute to a better understanding on the molecular mechanisms involved in Nef activities, which may also help to improve the understanding of the HIV pathogenesis and the related syndrome. In addition, this work contributes with the understanding of primordial process regulation on intracellular trafficking of transmembrane proteins.

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Eriksson, Anna-Lena. "Handledarens stödjande arbete i APL-uppgifterna för åk 1 : Med fokus på elevens lärande." Thesis, Karlstads universitet, Fakulteten för humaniora och samhällsvetenskap (from 2013), 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:kau:diva-28465.

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The aim of this essay is to examine the supervisor’s view on the structure and content of the tasks given to students during their vocational training. The investigation could be of help for teachers when devising new vocational training tasks. The study is based upon qualitative interviews with five supervisors, all of whom work at preschools. The supervisors were asked to grade all the vocational training tasks on a scale from one (easy) to five (difficult). The results were then used as a starting point for a discussion with the supervisors about their grading of the tasks. When devising vocational training tasks, one of the foundations is the knowledge requirements as expressed in the syllabus, and how they are reflected in the vocational training. An important aspect of the student’s learning is the supervisor’s ability to clarify the goals and criteria of vocational training. The supervisor plays an important role and is responsible for the student’s vocational training period. This study has given me a better understanding of the supervisor’s view on the structure of the vocational training tasks and I have been given many useful suggestions as to how it can be improved to strengthen the quality of the education. The Swedish Schools Inspectorate carried out an investigation in 2011 and noticed shortcomings in the grading of the vocational training, which is interesting and relevant for my study. The supervisor assesses the student’s performance during the vocational training according to a certain scale of grades. The findings suggest that we need to revise the structure and assessment of the vocational training tasks. At the upper secondary school used in this study, the tasks are devised in a way that makes it difficult for the supervisor to support the student in his/her learning process, because the tasks are too numerous and the instructions contain many ill-defined terms. The supervisors also want closer contact with, and visits from, the upper secondary school teachers, so that both the former and the students can receive more feedback and better support.
Syftet med denna uppsats är att undersöka handledares syn på praktikuppgifternas utformning och innehåll. Undersökningen kan vara till hjälp för lärare när nya praktikuppgifter ska utarbetas. Arbetet bygger på fem kvalitativa intervjuer som har genomförts med handledare som är verksamma inom förskoleverksamheten. Handledarna fick göra en bedömning av praktikuppgifterna utifrån en svårhetsskala från ett till fem, där fem är mycket svår och ett är mycket lätt. Utifrån skalans bedömning samtalade vi kring varför de gjord den bedömningen. Vid utformning av praktikuppgifter är en av byggstenarna kunskapsmålen som kopplas till praktiken utifrån ämnesplanerna. En viktig del i elevens lärande är att handledaren kan tydliggöra mål och kriterier i det arbetsplatsförlagda lärandet. Handledaren har en viktig roll och ansvar för eleven under praktikperioden. Under undersökningens gång har jag fått inblick i hur handledarna ser på praktikuppgifternas utformning och fått bra förslag på hur de kan förbättras för att stärka kvalitén på utbildningen. Då skolinspektionen genomfört en kvalitets undersökning 2011 och sett brister i betygsättningen kopplat till praktiken är detta intressant och relevant att koppla till mitt arbete. Handledarna sätter omdöme på eleven under praktikperioden utifrån en betygsskala. Resultatet tyder på att vi behöver se över praktikuppgifternas utformning och bedömning innan eleverna går ut på praktik i höst. Som praktikuppgifterna ser ut idag i åk 1 på den för studien aktuella gymnasieskolan har handledarna svårt att stödja elevens lärande, uppgifterna består av många svåra begrepp samt att de är för många till antalet. Det finns också önskemål om tätare kontakt med skolan samt praktikbesök för att stötta och ge återkoppling till både handledare och elev.

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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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28

Joseloff, Elizabeth 1969. "AP-1 regulation during malignant progression of mouse keratinocyte cells." Diss., The University of Arizona, 1997. http://hdl.handle.net/10150/282562.

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The mouse skin model that has been used to study skin carcinogenesis can be divided into three stages: initiation, promotion, and progression. One genetic change observed during tumor promotion and malignant progression is increased transactivation of the transcription factor AP-1. AP-1 consists of Jun (c-Jun, Jun B, Jun D) and Fos (c-Fos, Fos B, Fra-1, Fra-2) proteins that form Jun:Jun homodimers or Jun:Fos heterodimers. AP-1 binds to a consensus cis-promoter element, the TRE, and transcriptionally regulate a number of genes with various biological functions. By studying the benign mouse keratinocyte cells, 308, and its malignant variant, 10Gy5, it has been shown that 10Gy5 cells have elevated AP-1 activity compared to 308 cells. Reduced AP-1 transactivation in 10Gy5 cells has been correlated with suppression of its malignant phenotype. This research examined the differential AP-1 transactivation in benign 308 and malignant 10Gy5 cells. By examing mechanisms of AP-1 regulation in the two cell lines, differences were observed with post-translational modifications of AP-1. There were differences in phosphorylation of one of the AP-1 family members, Jun B. In addition, AP-1 proteins in 10Gy5 cells appear to be in a fully reduced state, unlike AP-1 proteins in 308 cells. A third difference that was observed was in Jun B steady state protein levels, with decreased Jun B protein in malignant 10Gy5 compared to benign 308 cells. Reduced Jun B protein in 10Gy5 cells was the result of decreased Jun B protein synthesis. Jun B protein may inhibit AP-1 transactivation and cell proliferation. Experiments were performed to determine whether Jun B protein could modulate AP-1 transactivation, cell growth, and tumor formation in 308 and 10Gy5 cells. Altering Jun B protein levels in these keratinocytes affected AP-1 transactivation. Overexpression of Jun B protein in malignant 10Gy5 cells corresponded to an inhibition of cell growth and tumor development. However, overexpression of Jun B protein in 10Gy5 cells was not sufficient to reverse the malignancy, indicating that additional genetic changes are involved in malignant conversion of these keratinocytes. The results of this research suggest that Jun B protein levels may be important during malignant progression of mouse skin.

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29

March, Helen Nicola. "Regulation of AP-1 family proteins by MAP kinase pathways." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612889.

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30

Maritz, Michelle Frances. "Inhibition of the transcription factor AP-1 in cervical cancer." Master's thesis, University of Cape Town, 2007. http://hdl.handle.net/11427/3138.

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Includes bibliographical references (leaves 100-110).
AP-I is a dimeric transcription factor comprised primarily of Jun and Fos family proteins, that regulates numerous genes involved in cell proliferation, differentiation and oncogenesis. The expression of AP-I is shown to play an important role in many human cancers and plays a key role in the regulation of the E6 and E7 oncoproteins of high-risk Human Papillomaviruses (HPV) that are etiologically associated with cervical cancer. The c-Jun and Jun B components of AP-I were shown to be expressed at higher levels in cervical cancer patients compared to nonnal patient tissue while Jun D levels were largely unchanged. To define the role of AP-I in cervical cancer, the effect of inhibiting AP-I actvity was determined using a dominantnegative deletion mutant T AM67. CaSki cervical cancer cells with a doxycycline inducible T AM67 demonstrated that inhibition of AP-I activity and expression resulted in an altered cell morphology, a significant decrease in cell proliferation and inhibition of colony formation. This was accompanied by a slower progression of T AM67 expressing cells through the cell cycle, with an accompanying increase in G21M phase. An increase in the expression of the cell cycle regulatory protein, p21 CIPI, was observed that appeared independent of p53 expression. siRNA directed at inhibiting individual AP-I components showed that Jun B was an important regulator of CaSki cell proliferation. These results suggest that AP-I is involved in the cell proliferation and tumourigenic phenotype of cervical cancer cells, such as CaSki cells, possibly via a direct repression of cell cycle regulator p21 CIP1

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31

Baust, Thorsten Gerhard. "Proteomic analysis of the sorting machineries involved in vesicular traffic between the biosynthetic and endosomal compartments." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2006. http://nbn-resolving.de/urn:nbn:de:swb:14-1157559481597-44919.

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Vesicular traffic along the biosynthetic and endocytic pathways is essential for homeostasis of eukaryotic cells. However, it raised the question of how the proteins characteristic for each compartment are transported to their destination (Bonifacino and Glick, 2004). This study is especially focusing on the connection between the Golgi apparatus and the endosomal compartment, mediated by two parallel trafficking pathways regulated by the clathrin adaptors AP-1A and AP-3 (Owen et al., 2004). Typical cargo molecules sorted along the AP-1A regulated pathway are mannose 6-phosphate receptors (MPRs) (Ghosh et al., 2003) or the gpI envelop glycoprotein of the Vesicular Zoster virus (Alconada et al., 1996), while sorting of lysosomal membrane proteins like Lamp-1 and LimpII is AP-3 regulated (Eskelinen et al., 2003). To study how AP-1A and AP-3 coats are stabilized on membranes and to identify the protein networks involved, a liposome based in vitro assay that recapitulates the fidelity of protein sorting in vivo was developed and combined with proteomic screens. Therefore, liposomes carrying cytoplasmic domains of gpI or Lamp-1/LimpII were used as affinity matrix to recruit selectively AP-1A or AP-3 and associated protein machineries. The coated liposomes were then analyzed by mass spectrometry. Using the in vitro recruitment assay, it was possible to demonstrate that efficient and selective recruitment of AP-1A and AP-3 coats depends on the presence of several low affinity binding sites on membranes. Thus, AP-1A and AP-3 recognize their target membranes by activated Arf1 GTPases, organelle specific phosphoinositides, PI-4P and PI-3P respectively, and distinct cargo molecules carrying intact signals in their cytoplasmic domains. The implication of PI-3P in AP-3 recruitment was further supported by in vivo experiments. During the biochemical characterization of the assay, several lines of evidence indicated that cargo tails containing intact sorting signals stabilize not only AP-1A and AP-3 coats on membranes but also influence the membrane recruitment of Arf1. It is possible that cargo molecules indirectly drive an Arf1 amplification loop, thereby ensuring efficient AP coat assembly. The proteomic screens identified protein networks of ≈40 proteins selectively recruited on AP-1A coated structures. The most appealing result of the analysis was the presence of two additional protein machineries, one involved in actin nucleation the other involved membrane fusion. More precisely, the AP-1A analysis identified the selective recruitment of the AP-1A subunits and interacting molecules (clathrin, g-synergin), Arf1 and Arf1 effectors (Big2, Git1), Rac1 including Rac1 effectors (b-PIX, RhoGEF7) and a Rac1 dependent actin nucleation machinery (Wave/Scar complex, Arp2/3 complex, associated effectors) as well as members of a Rab machinery (Rab11, Rab14). This finding was further supported by in vivo colocalization studies of the AP-1A cargo CI-MPR with CYFIP2, a protein of the Wave/Scar complex, and the localization of Big2 and Git1 on Rab11 positive membranes (Matafora et al., 2001; Shin et al., 2004). The biochemical characterization revealed that the stabilization of AP-1A coats, most probably driven by cargo molecules that stabilize AP-1A and Arf1 on membranes, leads as well to the stabilization of the two other machineries. Thus, the results support the notion that cargo sorting, vesicular movement and membrane fusion are coordinated during early steps of vesicular traffic. In analogy, the proteomic screens on AP-3 coated structures identified as well ≈40 selectively recruited proteins, which constituted a similar supramolecular network of protein machineries involved in coat formation, action nucleation and membrane fusion via Rab proteins. Thus, beside the AP-3 coat including the AP-3 subunits, Arf1 and Arf effectors (Big1, ARAP1, AGAP1), members of the septin family involved in actin rearrangements and most of the already described effectors of Rab5 microdomains (EEA1, Rabaptin-5, Rabex-5, Vps45) involved in early endosomal dynamics were selectively recruited together with Rab5 and Rab7. Thus, the proteomic analysis of AP-1A and AP-3 coated structures suggest that both AP coats use similar principles - coats, actin nucleation devices and Rab fusion machineries - to assemble supramolecular structures needed for membrane traffic. Although we do not have the ultimate proves yet, it seems as AP-1A and AP-3 use different members of subcomplexes, hence different GTPase effectors, different actin nucleation machineries and different Rab GTPases, to regulate their specific transport pathways and to link the different protein machineries. The proteomic analysis revealed for example that they probably use different Arf and Rho GTPase effectors to link the coat with actin nucleation. However, this has to be proven experimentally. In order to understand the networks of protein interactions, bioinformatic tools were used as a first approach. Even though some clues about the overall organization of the supramolecular protein complexes were provided, the direct links to the Rab machinery are still elusive. Maybe the proteins with thus far unknown functions could be involved. The biochemical analysis, especially the role of PIPs, and the Rab GTPases identified in the context of AP-1A and AP-3, provide indications about AP-1A and AP-3 function in vivo. The results could be interpreted in a way that AP-1A functions either in traffic from PI-4P positive membranes towards Rab11/Rab14 positive membranes or AP-1A coats assemble on PI-4P and Rab11 or Rab14 positive membranes, hence, TGN to endosomes traffic. The same holds true for AP-3, the results either suggest AP-3 mediates traffic from PI-3P positive towards Rab5/Rab7 positive membranes or they could be interpreted in a way that AP-3 assembles on PI-3P and Rab5 positive membranes for subsequent transport to Rab7 positive membranes, thus traffic from early to late endosomes. Overall, the results of this thesis research provided important insight into the formation of AP-1A and AP-3 coated structures and the potential interconnection between AP coats, actin nucleation and membrane fusion machineries. Alconada, A., U. Bauer, and B. Hoflack. 1996. A tyrosine-based motif and a casein kinase II phosphorylation site regulate the intracellular trafficking of the varicella-zoster virus glycoprotein I, a protein localized in the trans-Golgi network. Embo J. 15:6096-110. Bonifacino, J.S., and B.S. Glick. 2004. The mechanisms of vesicle budding and fusion. Cell. 116:153-66. Eskelinen, E.L., Y. Tanaka, and P. Saftig. 2003. At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol. 13:137-45. Ghosh, P., N.M. Dahms, and S. Kornfeld. 2003. Mannose 6-phosphate receptors: new twists in the tale. Nat Rev Mol Cell Biol. 4:202-12. Matafora, V., S. Paris, S. Dariozzi, and I. de Curtis. 2001. Molecular mechanisms regulating the subcellular localization of p95-APP1 between the endosomal recycling compartment and sites of actin organization at the cell surface. J Cell Sci. 114:4509-20. Owen, D.J., B.M. Collins, and P.R. Evans. 2004. Adaptors for clathrin coats: structure and function. Annu Rev Cell Dev Biol. 20:153-91. Shin, H.W., N. Morinaga, M. Noda, and K. Nakayama. 2004. BIG2, a guanine nucleotide exchange factor for ADP-ribosylation factors: its localization to recycling endosomes and implication in the endosome integrity. Mol Biol Cell. 15:5283-94.

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32

Castro, Arce Johanna de. "RAR beta trans-repression of AP-1 transcription factor in HeLa cervical cancer cells consequences on transcription of viral and cellular AP-1 controlled genes /." [S.l. : s.n.], 2003. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB10806332.

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33

Vogt, Markus. "Untersuchungen zu Mutation, Expression und Regulation des potenziellen Tumorsuppressor-Gens APM-1 in menschlichen Tumorzellen." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=962871044.

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34

Magampa, Philemon Podile. "Electrochemical studies of the ligand 1-hydroxyl-3-aminopropilydenediphoshonic acid (APD) towards bone cancer therapy." Pretoria : [s.n.], 2006. http://upetd.up.ac.za/thesis/available/etd-08222007-162845.

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35

Arabi, Derkawi Riad. "Regulation de la nadph oxydase phagocytaire par la pat1 " protein interacting with app tail 1." Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00739376.

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Ce travail montre qu'une protéine non encore décrite dans les phagocytes, la PAT1 " Protein interacting with APP Tail 1 ", interagit avec la partie cytosolique de la p22phox (composant du cytochrome b558 membranaire de la NADPH oxydase). Nous avons utilisé différentes approches pour montrer cette interaction : le système double hybride, la technique de GST-pull down, la microscopie confocale et la technique de co-immunoprécipitation. De plus, nous avons montré que la PAT1a recombinante augmente l'activité de la NADPH oxydase, in vitro dans un système acellulaire reconstitué, et dans les cellules intactes (monocytes et cellules COS-phox). Cette nouvelle interaction régule donc l'activation de la NADPH oxydase et la production des FRO. Par ailleurs, la liaison de PAT1 aux microtubules pourrait favoriser l'assemblage du complexe NADPH oxydase pendant son activation. Ceci pourrait conduire à l'identification de nouvelles cibles thérapeutiques qui préviennent la survenue des lésions tissulaires dans les maladies inflammatoires.

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36

Magampa, Philemon Podile. "Electrochemical studies of the ligand 1-hydroxyl-3-aminopropilydenephosphonic acid (APD) towards bone cancer therapy." Diss., University of Pretoria, 2006. http://hdl.handle.net/2263/27457.

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The stability constants for the ligand 1-hydroxyl-3-aminopropilydene diphosphonic acid (APD) or Pamidronate with metal ions CdII, PbII and ZnII were established in this work by sampled direct current polarography (DCTAST). Due to precipitation of the metal-ligand complexes in the pH range about 4.0 to 5.0 at typical glass electrode potentiometric conditions, these systems could not be studied by glass electrode potentiometry (GEP). The concept of Virtual Potentiometry (VP) was used in the modelling of the metal-ligand system and refinement of stability constants to evaluate further the metal-ligand models derived from DCTAST. Virtual potentiometry uses virtual potentials to refine polarographic data by employing dedicated potentiometric software, ESTA. The structure of the metal complexes determined in this work is also proposed and compared to the reported crystal structures of the metal complexes of the ligand APD. The Linear Free Energy Relationship, LFER (log KML′ vs. log KM(OH) ) for the ligand APD is derived here for the first time using the log KML′ values from literature as well as the values for CdII, PbII and ZnII determined in this work. The log KML′ values of 153SmIII–APD and 166HoIII–APD, which cannot be determined by these two techniques (GEP and DCTAST), were predicted in this work using the LFER methodology.
Dissertation (MSc (Chemistry))--University of Pretoria, 2006.
Chemistry
MSc
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37

Vandenhoudt, Nathalie. "Etude du rôle des sites de liaison AP-1 intragéniques dans la régulation de l'expression du HIV-1 (Human Immunodeficiency Virus type 1)." Doctoral thesis, Universite Libre de Bruxelles, 2009. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210317.

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La vitesse de réplication du HIV-1(Human Immunodeficiency Virus type 1), qui semble corrélée de manière directe à la vitesse de progression de la maladie vers le stade SIDA, est essentiellement contrôlée au niveau transcriptionnel. La transcription du HIV-1 est régulée par la structure chromatinienne, des éléments agissant en cis localisés dans les LTRs, des facteurs de transcription agissant en trans et par la protéine virale trans-activatrice Tat (revu dans Quivy et al. 2007, Bisgrove et al. 2005, Rohr et al. 2003, Rabson and Graves 1997). En plus de l’enhancer localisé dans le LTR5’ du HIV-1, un enhancer intragénique, localisé dans le gène pol du HIV-1, inductible par le phorbol 12-myristate 13-acétate (PMA) a été identifié. La localisation progressive de l’activité enhancer a permis de définir deux domaines distincts et indépendants dans cet enhancer intragénique :les fragments 5103 et 5105 localisés respectivement dans la partie centrale du gène pol et dans une région couvrant la fin du gène pol, le gène vif, le gène vpr et le premier exon codant des gènes tat et rev (Verdin et al. 1990). Les fragments 5103 et 5105 se comportent tous deux comme des enhancers inductibles par le PMA lorsqu’ils sont clonés en amont du promoteur de la thymidine kinase dans un vecteur rapporteur en cellules HeLa. Notre laboratoire a précédemment identifié trois sites de liaison pour les facteurs de transcription AP-1 dans le fragment 5103 (Van Lint et al. 1991).

Au cours de notre thèse, nous avons poursuivi la caractérisation de ces sites de liaison AP-1 et avons montré que les facteurs c Fos, JunB et JunD interagissent in vitro avec ces motifs. Pour chaque site, nous avons identifié des mutations qui abolissent la liaison des facteurs AP-1 sans altérer la séquence en acides aminés sous-jacente de la transcriptase inverse. Par des expériences de transfection transitoire, nous avons démontré que les sites AP 1 intragéniques sont entièrement responsables de l’activité enhancer PMA-dépendante du fragment 5103. De plus, l’activité PMA-inductible du fragment 5103 est inhibée par le mutant dominant négatif A-Fos à condition que les sites ne soient pas mutés. A l’inverse, l’expression ectopique de dimères forcés AP-1 affecte positivement l’activité enhancer du fragment 5103. Enfin, nous avons étudié le rôle biologique des sites AP-1 intragéniques dans la réplication virale et avons montré que ces sites contribuent positivement à l’infectivité du virus.

Durant la seconde partie de notre thèse, nous avons entamé la caractérisation physique et fonctionnelle du fragment 5105. Nos résultats de transfection transitoire montrent que l’activité PMA inductible du fragment 5105 est localisée dans le dernier tiers de ce dernier :le sous fragment 5105.3. L’analyse bioinformatique de cette région a permis de mettre en évidence un site de liaison pour les facteurs AP-1 in vitro. Des mutations ponctuelles permettent d’abolir la liaison des facteurs à leur site mais altèrent la séquence en acides aminés sous-jacente codant pour les protéines Tat et Rev. Nous avons montré que ce site est impliqué dans l’activité transcriptionnelle de ce fragment. L’expression ectopique du mutant dominant négatif A-Fos inhibe l’activité transcriptionnelle PMA-inductible du fragment 5105. Une analyse bioinformatique plus large nous a ensuite permis d’identifier in vitro, par retard de migration sur gel, 5 sites de liaison pour le facteur YY1 et 2 sites de liaison pour le facteur PU.1 dont les implications pour le virus restent encore à déterminer.

Doctorat en Sciences
info:eu-repo/semantics/nonPublished

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Véliz, Mendoza Leonardo César. "Evaluación de una tubería a presión de acero de bajo carbono dañada por fuego, mediante la norma API 579-1/ASME FFS-1." Bachelor's thesis, Pontificia Universidad Católica del Perú, 2016. http://tesis.pucp.edu.pe/repositorio/handle/123456789/6868.

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A nivel mundial es común el uso de tuberías de acero de bajo carbono para contener o transportar diferentes fluidos a presión en el sector industrial. Estos componentes a presión no están libres de sufrir algún daño por fuego o calor radiante, los cuales causan paros inesperados y pérdidas económicas a las industrias, por ello realizar una evaluación de las aptitudes de servicio a los componentes que han sufrido daño por fuego da la posibilidad de evaluar si el componente puede seguir funcionando en las mismas condiciones de trabajo, diferentes o ser retirados de servicio. El objetivo del presente trabajo es evaluar la integridad de una tubería de acero de bajo carbono que ha sido intencionalmente dañada por fuego en el laboratorio, mediante el estudio y aplicación de la metodología del API 579-1/ASME FFS-1, además del uso del grado de daño de Neubabuer para evaluar el daño microestructural, con la finalidad de mostrar de forma practica el uso de la metodología y determinar si la tubería puede continuar en servicio. Con este fin, primero se preparó una tubería de acero de bajo carbono para someterla a diferentes temperaturas y tiempos de exposición al calor con la intención de ocasionar un daño por fuego. Luego, se siguió la metodología de forma experimental usando diferentes tipos de ensayos como inspección visual, ensayo de dureza y metalografía, en base a normas ASTM (American Society for Testing of Materials). Los resultados obtenidos fueron analizados para determinar qué cambios ocurrieron en la microestructura y propiedades mecánicas, después se determinó una nueva máxima presión admisible de trabajo en función a los resultados de las pruebas evaluadas de la tubería dañada por fuego, finalmente se corroboro con una prueba hidrostática en el laboratorio. Esta tesis, proporciona de forma práctica el análisis de componentes a presión como tuberías que han sufrido daño por fuego. En base a la evaluación se puede concluir por ejemplo que la tubería analizada a pesar de estar dañada por fuego puede seguir operando con una nueva presión de operación de 817 psi (presión de diseño 1180 psi) y no es necesario repararla o reemplazarla.
Tesis

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39

Borowiak, Malgorzata. "HBZ-induced functional deregulation of menin - new insights into the mechanism of telomerase activation during HTLV-1-mediated leukemogenesis." Phd thesis, Ecole normale supérieure de lyon - ENS LYON, 2013. http://tel.archives-ouvertes.fr/tel-00860179.

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Adult T-cell leukemia (ATL) is an aggressive lymphoproliferative disorder associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Reactivation of telomerase, a critical event in tumor progression observed in late phases of ATL development, has been shown to be caused by HBZ (HTLV-1 bZIP factor), a regulatory protein encoded by the negative strand of the HTLV-1 genome. The HBZ-mediated up-regulation of the telomerase catalytic subunit is dependent on JunD, which in the cellular context occurs in the complex with menin, the product of the MEN-1 tumor suppressor gene. Interaction with menin represses JunD-dependent transcription and converts JunD into a growth suppressor, whereas it acts as a growth promoter in the absence of menin. My results demonstrate that the viral protein HBZ abrogates tumor suppressor function of menin, resulting in the activation of JunD transcriptional activity and finally in the up-regulation of its target gene, the human telomerase reverse transcriptase (hTERT). I showed that HBZ, JunD and menin can coexist in the same protein complex and that HBZ and menin exert opposite effects on JunD transcriptional activity. Moreover menin inhibits the JunD-mediated activation of the hTERT proximal promoter and HBZ is able to counteract this effect. Finally, I proposed that HBZ, by recruiting p300 histone acetyltransferase, reverses the histone deacetylation conducted by menin-recruited HDACs and therefore up-regulates the expression of the hTERT gene. Altogether, my work led to the identification of the molecular mechanism leading to the functional impairment of the menin tumor suppressor, which results in the deregulation of AP-1 signaling in HTLV-1 infected cells. Finally this work gave new insights into the mechanism of the transcriptional up-regulation of the hTERT gene upon HTLV-1 infection, being a key event during the development of Adult T-cell leukemia and a necessary step towards the progression into more aggressive courses.

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Douceron, Estelle. "Découverte et caractérisation de la protéine APH-2 codée par le brin antisens du HTLV-2." Thesis, Lyon, École normale supérieure, 2011. http://www.theses.fr/2011ENSL0645.

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Bien que très proches dans leur organisation génomique, le rétrovirus HTLV-1 est impliqué dans le développement de la leucémie à cellule T de l’adulte (ATL) alors que l’infection par HTLV-2 n’a jamais été associée à des désordres hématologiques malins. La transformation des cellules infectées par HTLV-1 a longtemps été attribuée uniquement à la protéine virale transactivatrice Tax (Tax-1). Cependant, son expression est très faible dans les cellules ATL. La protéine HBZ a été découverte en 2002. Elle est traduite à partir d'un ARNm transcrit à partir du LTR 3' d'HTLV-1 et est exprimée par les cellules infectées issues de tous les patients HTLV-1 quel que soit leur statut clinique. HBZ participe au maintien du phénotype tumoral en stimulant la prolifération des cellules leucémiques et intervient dans l'échappement du virus au système immunitaire. Des analyses in silico nous avaient permis de détecter un cadre ouvert de lecture sur le brin complémentaire de l’ARN génomique d’HTLV-2. Mon travail de thèse a consisté à amplifier et caractériser d’une part le transcrit APH-2 et d’autre part la protéine qui en est issue. Nous avons démontré dans un premier temps que la transcription d’APH-2 était initié dans le LTR 3’ et que le transcrit APH-2 était épissé et poly-adénylé. Nous avons ensuite mis en évidence l’expression d’APH-2 dans les lignées infectées par HTLV-2, ainsi que dans des cultures de lymphocytes issus de deux porteurs sains africains. La mise au point d’une technique quantitative de RT-PCR nous a permis de détecter APH-2 ex vivo chez 94% des individus d’une série de 51 porteurs sains américains. Nous avons aussi montré que l'expression de cet ARNm était proportionnelle à la charge provirale. APH-2 code une protéine de 183 acides aminés dont nous avons mis en évidence l’expression dans la lignée MO. Mes travaux ont aussi permis de démontrer le rôle inhibiteur d’APH-2 sur la transcription virale malgré l’absence d’un domaine bZip classique, ainsi que son interaction avec le facteur de transcription CREB. Par immunofluorescence, nous avons établi la localisation nucléaire d’APH-2. La protéine semble associée aux corps PML grâce à une région de six arginines comprise entre les résidus 78 et 92. Cependant, contrairement à HBZ, nous n’avons pas observé d’interactions entre APH-2 et les facteurs cJun, JunD ou le cofacteur de transcription CBP/p300. De plus nous avons observé qu’APH-2 était incapable d’induire la prolifération des lymphocytes in vitro alors qu’une lymphocytose est souvent observée chez les porteurs d’HTLV-2. Grâce à une approche comparative, mes travaux ont ainsi permis d’apporter des éléments nouveaux dans la compréhension de la différence de pathogénicité qu’il existe entre HTLV-1 et HTLV-2
Although they are very similar in their genomic organization, the HTLV-1 retrovirus is involved in the development of adult T cell leukaemia (ATL) while HTLV-2 has not been associated to any malignant haematological disorders. The tumoral transformation of infected cells was widely associated to the viral transactivactor protein Tax (Tax-1), which modulates many cellular functions. However, its expression is slightly in ATL cells. In 2002, the HBZ protein was discovered, encoded from the 3’ LTR by the complementary strand of HTLV-1 and expressed by all HTLV-1 infected people. HBZ participates in the maintenance of the tumoral phenotype by stimulating leukemic cells proliferation and is involved in the immune system escape. We recently detected a coding region by an in silico analysis in the complementary strand of HTLV-2. My work consisted in the characterization of the APH-2 transcript, and in a second part, of the associated protein. At first, we characterized the APH-2 transcription initiation in the 3’LTR and that transcript was spliced and poly-adenylated and demonstrated that the APH-2 expression in all HTLV-2 cell lines and in short cultured lymphocytes from African healthy carriers. We used a quantitative RT-PCR on uncultured cells from 51 American HTLV-2 healthy carriers and we we detected APH-2 expression in 94% of them. We then showed that APH-2 RNA expression is correlated to the HTLV-2 proviral load. The APH-2 transcript encoded a 183 amino acid protein that was shown to be expressed in the HTLV-2 infected Mo cell line. Our work demonstrated the inhibitory functions of APH-2 in the viral transcription and its interaction with the transcriptional cofactor CREB despite the lack of a bZip domain. By an immunofluorescence approach we established the nuclear localisation of APH-2, which is in particular in the PML nuclear bodies. We demonstrated that six arginines in the 78-92 amino acids region is involved in this PML colocalization. Contrary to HBZ, we didn’t observe any interaction with between APH-2 and cJun or JunD factors nor with the transcriptional cofactor CBP/p300. Furthermore we showed that APH-2 is not involved in lymphocyte proliferation in vitro although a lymphocytosis is often observed in HTLV-2 carriers. According to this comparative approach, my work allowed us to better understand the difference of pathogenicity existing between HTLV-1 and HTLV-2

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41

Tran, Phuong My. "Anthrapyrazole cysteinyl peptides as inhibitors of AP-1 transcription factor binding." Thesis, De Montfort University, 1998. http://hdl.handle.net/2086/10703.

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Synthesis of peptides anchored to DNA by intercalating chromophores can incorporate the design principle of the naturally occurring peptide based antibiotics. This work is concerned with the synthesis of DNA anchored cysteinyl peptides designed to be potentially nucleotide sequence specific with possible affinity for the AP-l transcription site. Previous work has shown that anthraquinones and anthrapyrazoles (APZs) substituted with cationic side groups are excellent DNA intercalating agents. In this work a series of APZ analogues has been synthesised which are coupled onto the amino terminus of varying peptide sequences. Three derivatives of APZs were prepared namely 2-, 2,5- and 2,7-substituted. Eight short polypeptides (see below), all varying slightly in sequence but all containing the KCR motif (with one exception where a Cys was replaced with Ser) were combined with the APZ chromophore to give a series of intercalator-peptide molecules. Peptides were synthesised using the Fmoc strategy on a solid phase peptide synthesizer (SPPS). The peptides were then isolated by reversed-phase HPLC using a water: acetonitrile gradient. Characterisation of the peptides was carried out by matrix assisted laser desorption ionisation (MALDI) mass spectrometry and two dimensional nmr (i.e. COSY and NOESy). Anthraquinone linked peptide ligands were also synthesised using similar synthetic routes, and tested for their activity. Coupling of the two components was achieved via activation of the carboxylic acid group using PyBOP or via formation of a reactive aziridinium ion. All intercalator-peptides prepared were examined for their DNA binding properties. The methods included the effect of intercalator-peptides on the thermal denaturation of DNA and the competitive displacement of ethidium by fluorimetry. It was shown that the APZ binds to DNA by intercalation. Peptides prepared were: H2N-A-K-C-R-A-C02H; H2N-A-K-C-R-A-CONH2; H2N-A-K-S-R-A-CONH2; H2N-A-K-C-R-N-A-CONH2; H2N-A-K-C-R-K-A-CONH2; H2N-A-K-C-R-N-R-A-CONH2; H2N-A-K-C-R-K-R-ACONH2; H2N-A-A-K-C-R-A-A-CONH2. The biological activities of the intercalatorpeptides were then investigated using an electrophoretic mobility shift assay (EMSA), making use of cell nuclear extracts rich in AP-l and also c-Jun homodimer recombinant proteins. It was shown that most of the intercalatorpeptides were capable of inhibiting AP-l (fos/jun) heterodimer protein from binding to the AP-l DNA consensus sequence. Importantly, the intercalatorpeptides showed superior activity over the intercalator or peptide moieties alone. The order of binding affinity was intercalator-peptide> intercalator» peptide.

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42

Gorman, Michael Anthony. "Crystal structure of the human DNA repair enzyme AP endonuclease 1." Thesis, Open University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242493.

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43

Basuyaux, Jean-Philippe. "Etude des interactions entre les facteurs de transcription ETS et AP-1 dans la régulation de la collagénase-1 et de la stromélysine-1." Lille 1, 1997. http://www.theses.fr/1997LIL10093.

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La collagenase-1 et la stromelysine-1 sont des métalloprotéases de la matrice (MMPS) qui dégradent différents composants des membranes basales et de la matrice extracellulaire. Les MMPS jouent un rôle critique dans le développement des cancers (invasion tumorale, angiogénèse, métastases). Les familles de facteurs de transcription fos-jun et ETS sont constituées d'oncoprotéines impliquées dans la génération de plusieurs cancers. C-fos et c-jun forment un dimère qui lie le site ap-1. L'induction via ap-1 est le mécanisme transcriptionnel majeur de l'expression de plusieurs MMPS. Toutefois, ap-1 n'agit pas seul. Les facteurs ETS lient des sites appelés EBS et coopèrent avec les facteurs ap-1. Nous montrons que erg est recrute sur un site EBS (-89) de la collagenase-1 par le dimère c-fos/c-jun lie au site ap-1 voisin (-72). Au contraire, erg n'induit pas la stromelysine-1 et il inhibe l'induction par ETS2 via un tandem EBS inverse (-216,-208) distant du site ap-1 (-70). Pour comprendre au niveau moléculaire la régulation de la transcription de la collagenase-1 et de la stromelysine-1, nous avons étudié les interactions protéiques directes entre ces facteurs de transcription. Nous montrons que erg et le complexe c-fos/c-jun lient ETS2. L'utilisation de protéines ETS2 tronquées indique que erg lie la région transactivatrice n-terminale de ETS2 et sa région c-terminale liant l'ADN. Le complexe c-fos/c-jun lie uniquement la région c-terminale de ETS2. De plus, l'interaction entre c-fos/c-jun et ETS2 est favorisée par un fragment présentant les deux sites EBS du promoteur de la stromelysine-1. Ces résultats suggèrent que des interactions protéiques entre des facteurs de transcription peuvent moduler différemment l'expression de gènes ayant des motifs semblables, mais organises différemment, comme pour la collagenase-1 et la stromelysine-1.

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44

Xu, Feng, Satoko Ito, Michinari Hamaguchi, and Takeshi Senga. "Disruption of Cell Spreading by the Activation of MEK/ERK Pathway is Dependent on AP-1 Activity." Nagoya University School of Medicine, 2010. http://hdl.handle.net/2237/14175.

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45

Cherry, Cortnie Lauren. "Mechanisms of Depolarization Induced Dendritic Growth of Drosophila Motor Neurons." Diss., The University of Arizona, 2006. http://hdl.handle.net/10150/195475.

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MECHANISMS OF DEPOLARIZATION INDUCED DENDRITIC GROWTH OF DROSOPHILA MOTOR NEURONS Cortnie Lauren Cherry The University of Arizona, 2006 Director: Richard B. Levine The study of the cellular mechanisms underlying dendritic growth contributes to our understanding of nervous system development, function and disease. Electrical activity is a fundamental property of neurons, and this property is utilized to influence the mechanisms involved in dendrite formation and maturation. Here we employ the Drosophila transgenic system to quantify dendritic growth of identified motor neurons using both in vitro and in vivo techniques. Two novel techniques are introduced: one a system to visualize and measure dendritic outgrowth in cultured neurons using reporter proteins, and the other using 3D reconstruction to measure the arborization of identified motor neurons in vivo. Both transgenic manipulation of K+ channel function and depolarizing concentrations of K+ in the culture medium result in an acceleration of dendritic outgrowth. Depolarization induced outgrowth is dependent on Plectreurys Toxin (PLTX)-sensitive voltage-gated calcium current and protein synthesis in cultured motor neurons. Depolarization leads to direct induction of fos, a protein that heterodimerizes with jun to make the functional transcription factor, AP-1. Fos, but not jun, is necessary for basal levels of dendritic growth, while both are necessary for depolarization induced outgrowth. Over-expression of AP-1 in control cells is sufficient to cause dendritic outgrowth. The transcription factor Adf-1 is also necessary for basal and depolarization induced growth, but unlike AP-1 is not sufficient to cause outgrowth when over-expressed. Another transcription factor CREB, on the other hand, is not necessary for basal levels of dendritic growth, but is necessary for depolarization induced dendritic growth. Over-expression of CREB, like Adf-1, is not sufficient to cause dendritic outgrowth. These findings present exciting new techniques for the study of the field of dendritic regulation and contribute to our understanding of the cellular mechanisms underlying dendritic growth.

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46

Calicchio, Rosamaria. "High-throughput transcriptional analysis of the endothelial alterations in preeclampsia identifies JDP2 (Jun dimerization protein 2) as a novel actor in hypoxia sensing." Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05T060/document.

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La prééclampsie est une maladie humaine qui affecte 3-8 % des grossesses dans le monde, cliniquement définie par l’apparition de novo d’une hypertension et d’une protéinurie. La cause initiale de la maladie semble être liée à un défaut de vascularisation placentaire, ce qui entraine des cycles d'hypoxie – ré-oxygénation, une ischémie placentaire et la libération de débris placentaires dans la circulation maternelle. Ces derniers sont responsables d'une activation endothéliale généralisée, exacerbée par un état pro-coagulant et pro-inflammatoire. Pour mieux caractériser la réponse des cellules endothéliales aux facteurs plasmatiques présent dans la circulation maternelle des femmes prééclamptiques , nous avons choisi une approche à l’échelle du génome entier pour évaluer le profil d'expression génique (grâce à des puces d’expression) de la lignée de cellules endothéliales humaines de la veine ombilicale (HUVEC) cultivée avec du plasma prééclamptique, comparée au profil de cellules cultivées avec du plasma humain provenant de grossesses normales. Cette étude nous a permis d'identifier différents gènes modulés dont celui codant la protéine de dimérisation Jun 2 (JDP2, diminué près de trois fois) qui pourrait être responsable d'une partie des modifications transcriptomiques trouvées. De façon intéressante en effet, inhiber JDP2 par une approche de siRNA régule significativement à la baisse (entre autres) l'expression du VEGF, imitant ainsi les effets du plasma prééclamptique sur les HUVEC. Dans la dernière partie de mon projet, nous nous sommes particulièrement concentrés sur l'impact de l’inhibition de JDP2 sur des gènes induits par l'hypoxie. La tension partielle basse en oxygène modifie l'expression génique par l'intermédiaire de la stabilisation du facteur de transcription HIF- 1a. En fait, dans un état hypoxique, HIF- 1a échappe à la dégradation par le protéasome, il forme alors des hétérodimères avec ARNT (HIF- 1ß) et induit l'expression de gènes ayant un élément de réponse à l’hypoxie (HRE) dans leur promoteur. L'induction de l'expression du VEGF dans des conditions d’hypoxie constitue un des premiers modèles de l’effet de l’hypoxie sur l’expression génique et c’est également un des mieux caractérisés. Afin d'évaluer le rôle de JDP2 sur l'expression du VEGF, et plus généralement sur des gènes cible de l’hypoxie, nous avons cultivé des cellules HUVEC dans des conditions de normoxie et d’hypoxie. Les mêmes conditions ont été utilisées en association avec la transfection de siRNA contre JDP2. En conclusion, dans des conditions d’hypoxie, l’inhibition de JDP2 a un impact négatif sur l'expression du VEGF. De plus, JDP2 semble être un médiateur essentiel de l'expression génique induite par l'hypoxie, car il est nécessaire à une activité complète de promoteur contenant des HRE (démontré dans des essais luciférase)
Preeclamspia is a unique human disorder which affects 3-8% of pregnancies worldwide, clinically defined as the new onset of hypertension and proteinuria. The root cause of the disease seems to be linked to a defect of placental vascularization, which enhances cycles of hypoxia –reoxygenantion, placental ischemia and the release of placental debris into maternal circulation. The latter ones are responsible for a widespread endothelial activation, exacerbated pro-coagulable and pro-inflammatory state. To best characterize the response of endothelial cells to the plasma factors present in maternal circulation of preeclamptic women, we chose a genome –wide approach in order to evaluate the gene expression profile of Human Umbilical Vein Endothelial Cells (HUVEC) line cultivated with preeclamptic plasma, compared to cells cultivated with human plasma coming from normal pregnancies. This study allows us to identify the gene Jun Dimerization Protein2 (JDP2) which could be responsible for part of transcriptomic modifications. Interestingly inhibiting JDP2 by the use of siRNA significantly down- regulates VEGF expression, thus mimicking the effects of preeclamptic plasma on HUVEC. In the last part of my project we focus specifically on the impact of JDP2 knock down on hypoxia- induced genes. Low oxygen tension modifies gene expression via the stabilization of the transcription factor HIF-1a. In fact under hypoxic condition, HIF-1a escapes from proteasomal degradation, it forms heterodimers with ARNT (HIF- 1ß) and induces the expression of genes having a Hypoxia Responsive Element (HRE) in their promoter. One of the first and best characterized models of the effect of hypoxia on gene expression is the induction of VEGF expression under hypoxic condition. In order to evaluate the contribution of JDP2 to VEGF expression, and more generally to hypoxia target genes, we cultivate HUVEC in normoxic and hypoxic condition. The same conditions were used in association with transfection of siRNA against JDP2. In conclusion, under hypoxic condition, JDP2 down- regulation has a negative impact on VEGF expression. Moreover, JDP2 seems to be an essential mediator of hypoxia –induced gene expression, since it is necessary for a full HRE promoter activity (demonstrated by Luciferase assays)

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47

Völkel, Meike [Verfasser]. "Einfluß des β-site-APP-cleaving enzyme 1 (BACE 1) auf die synaptische Transmission und das Entladungsverhalten von CA1-Pyramidenzellen des Hippocampus / Meike Völkel." Kiel : Universitätsbibliothek Kiel, 2012. http://d-nb.info/1022796291/34.

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48

Boos, Vinzenz [Verfasser]. "Aktivierung der Fas (Apo-1/CD95) Signaltransduktion durch Hyperoxie im neonatalen Gehirn von Nagetieren / Vinzenz Boos." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2008. http://d-nb.info/1023328127/34.

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49

Soric, Bessai Ivana. "The effect of tubercidin on the induction of AP-1 and NF-[kappa]B dependent genes by interleukin-1." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0019/MQ49760.pdf.

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50

Gangnuss, Samantha. "Characterization of AP-1 transcription factor activation by wounding in fetal skin." Title page, table of contents and abstract only, 2002. http://web4.library.adelaide.edu.au/theses/09PH/09phg1974.pdf.

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"June 2002" Bibliography: leaves 144-170. Fetal skin has a unique ability to re-epithelialize a wound in the absence of dermal substrata, although this capacity is lost between embryonic day 17 (E17) and day 19 of gestation (E19) in the rat. This study seeks to identify the molecular signalling events induced by wounding in E17 and E19 skin, as well as the role these events play in the prenatal switch in re-epithelialization mechanisms in fetal skin.

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Dissertations / Theses on the topic 'Apg-1'

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