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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

P53-mediated control of mRNA translation during Endoplasmic Reticulum stress : mechanisms and physiological implications / Contrôle de la traduction des ARNm médiée par P53 au cours du stress du réticulum endoplasmique : mécanismes et implications physiologiques

López, Ignacio 05 September 2016 (has links)
Des fluctuations physiologiques lors de la production et du repliement des protéines, ainsi que des processus pathologiques comme l’infection virale, le vieillissement et les cancers peuvent conduire à un stress du Réticulum Endoplasmique (RE). Il s’agit d’un état caractérisé par l’accumulation de protéines non/mal repliées dans la lumière du RE, qui déclenche la réponse aux protéines dépliées, dite UPR (Unfolded Protein Response). Pour rétablir l’équilibre protéique, la réponse UPR va inhiber la synthèse protéique globale cap-dépendante et favoriser la production de protéases et de chaperonnes associées au RE, notamment la protéine BiP qui joue également le rôle de senseur principal de l’UPR. Notre groupe a précédemment montré que lors d’un stress du RE, une isoforme particulière du suppresseur de tumeur p53, l’isoforme p53ΔN40 (également connue sous le nom de p53/47, Δ40p53, ΔNp53 ou p47) est induite sélectivement par PERK pour conduire à l’arrêt de la division cellulaire en G2 et que ceci dépend de la suppression de l’expression de p21CDKN1A par l’isoforme longue de p53 (p53FL) avec p53ΔN40 agissant notamment au niveau transcriptionnel et traductionnel.Le sujet principal de mon travail a été de comprendre comment p53 induit l’apoptose en cas de stress prolongé du RE. J’ai pu montrer que ceci dépend de la diminution de l'expression de BiP, via une interaction directe de la protéine p53 avec une petite région de la séquence codante de l'ARNm de BIP. Cette trans-suppression de BiP est médiée par un domaine de 7 acides aminés présent dans p53FL et aussi dans p53ΔN40. Cette inhibition de l'expression de BiP pendant les tress du RE conduit à une augmentation de l'apoptose par l'activation de la protéine BIK ainsi libérée d’une interaction répressive avec BiP. De plus, BIK est également activée pendant le stress du RE par p53FL et/ou p53ΔN40 au niveau transcriptionnel. Mes résultats établissent pour la première fois un lien entre la capacité de liaison à l'ARNm de p53 et le contrôle de la traduction de cet ARNm avec une réponse cellulaire particulière.Ce travail montre également que p53 contrôle la traduction de deux ARNm supplémentaires par ce qui semble être deux mécanismes d’action différents. Ces deux mécanismes reposent sur des séquences présentes dans l'ARNm, mais diffèrent sur la nécessité d'une interaction directe avec la protéine p53. Comme montré pour BiP, la capacité de liaison à l'ARNm de p53 bloque la traduction des ARNm de FGF-2 et de p53. Dans cette catégorie, nous pouvons maintenant également inclure l'ARNm de MDMX. D’un autre côté, la suppression de la traduction de p21CDKN1An'a pas été associée à une interaction avec p53, ce qui est aussi le cas pour la suppression de l’expression de MDM2. Les implications physiologiques des suppressions d’expression de MDM2et de MDMX sont discutées.Ces résultats montrent que la suppression de la traduction de l'ARNm médiée par p53 joueun rôle physiologique majeur lors de l'UPR et soutient le rôle spécifique de la p53ΔN40 en réponse à du stress du RE. / Physiological fluctuations of protein production/folding and pathological processes like viralinfection, aging and cancers can lead to Endoplasmic Reticulum (ER) stress. It is a statecharacterized by the accumulation of unfolded or misfolded proteins in the ER lumen that triggers the Unfolded Protein Response. In restoring ER proteostasis, the UPR inhibits global capdependent protein synthesis and promotes proteases and ER chaperons, notably BiP, which also functions as the main UPR sensor. Our group has previously shown that during ER stress, a selective induction of the p53 tumour suppressor protein isoform p53ΔN40 (also known as p53/47, Δ40p53, ΔNp53, p47) by PERK leads to G2 arrest, and that this depends on a suppression of p21CDKN1A expression by p53 full-length (p53FL) and p53ΔN40 acting at transcription and translation. The main topic of my work has been to understand how p53 promotes apoptosis during prolonged ER stress. I could show that this depends on the down regulation of BiP expression via a direct interaction between a restricted region of the bip mRNA's coding sequence and p53 protein. The trans-suppression is mediated by a 7-aa domain of the p53 protein present in both p53FL and p53ΔN40. The inhibition of BiP expression during ER stress leads to an increase in apoptosis via activation of the BH3-only BIK protein by liberating it from a repressive interaction with BiP. Moreover, BIK is further activated during ER stress by transcription induction mediated by p53FL and/or p53ΔN40. These results links for the first time the RNA-binding capacity of p53 and the control of mRNA translation with a particular cellular response. The work also shows that p53 controls the translation of two additional mRNAs in what appears to be two different mechanisms. Both mechanisms rely on sequences present in the mRNAs but differ in the requirement of a direct interaction with the p53 protein. Like with BiP, the RNA-binding capacity of p53 shuts down the translation of fgf-2 and p53 mRNAs. To this category we can now also include the mdmx mRNA. On the other hand, suppression of p21CDKN1A translation was not shown to require an interaction with p53 and this is also the case for suppression of MDM2. The physiological implications of MDMX and MDM2 suppression are discussed. These data illustrate that p53-mediated mRNA translation suppression plays a physiological role during the UPR and further supports the specific role of the p53ΔN40 during ER stress.
2

'Nostalgia' and 'Panic' in Huang Biyun's Fiction Huang Biyun xiao shuo de "huai jiu" yu "kong huang" /

Au, Siu-lung. January 2008 (has links)
Thesis (M.A.)--University of Hong Kong, 2008. / Includes bibliographical references (p. 98-103)
3

Targeting Autophagy in Multiple Myeloma

Dai, Yun 01 January 2015 (has links)
Apoptosis (Type I) and autophagy (Type II) represent two major forms of programmed cell death. Numerous anticancer agents employed in standard chemotherapy or novel targeted therapy induce both apoptosis and autophagy. Of note, a cytoprotective autophagic response often counteracts apoptosis triggered by such agents, potentially contributing to drug-resistance. Mechanistically, autophagy and apoptosis share molecular regulatory mechanisms primarily governed by the Bcl-2 family proteins. However, since autophagy acts as the double-edge sword in cancer, whether autophagy should be inhibited or activated in cancer treatment remains the subject of debate. Here we report a) a novel autophagy-targeted strategy that targeting the adaptor SQSTM1/p62 induces “inefficient” autophagy due to cargo-loading failure and converts cytoprotective autophagic response to apoptosis via the BH3-only protein NBK/Bik (Part 1); and b) a new mechanism for acquired drug-resistance in which the BH3-only protein Bim acts as a dual-agent regulating both autophagy and apoptosis (Part 2).
4

Osteopontin-Stimulated Apoptosis in Cardiac Myocytes Involves Oxidative Stress and Mitochondrial Death Pathway: Role of a Pro-Apoptotic Protein Bik

Dalal, Suman, Zha, Qinqin, Singh, Mahipal, Singh, Krishna 01 July 2016 (has links)
Increased osteopontin (OPN) expression in the heart, specifically in myocytes, associates with increased myocyte apoptosis and myocardial dysfunction. Recently, we provided evidence that OPN interacts with CD44 receptor, and induces myocyte apoptosis via the involvement of endoplasmic reticulum stress and mitochondrial death pathways. Here we tested the hypothesis that OPN induces oxidative stress in myocytes and the heart via the involvement of mitochondria and NADPH oxidase-4 (NOX-4). Treatment of adult rat ventricular myocytes (ARVMs) with OPN (20 nM) increased oxidative stress as analyzed by protein carbonylation, and intracellular reactive oxygen species (ROS) levels as analyzed by ROS detection kit and dichlorohydrofluorescein diacetate staining. Pretreatment with NAC (antioxidant), apocynin (NOX inhibitor), MnTBAP (superoxide dismutase mimetic), and mitochondrial KATP channel blockers (glibenclamide and 5-hydroxydecanoate) decreased OPN-stimulated ROS production, cytosolic cytochrome c levels, and apoptosis. OPN increased NOX-4 expression, while decreasing SOD-2 expression. OPN decreased mitochondrial membrane potential as measured by JC-1 staining, and induced mitochondrial abnormalities including swelling and reorganization of cristae as observed using transmission electron microscopy. OPN increased expression of BIK, a pro-apoptotic protein involved in reorganization of mitochondrial cristae. Expression of dominant-negative BIK decreased OPN-stimulated apoptosis. In vivo, OPN expression in cardiac myocyte-specific manner associated with increased protein carbonylation, and expression of NOX-4 and BIK. Thus, OPN induces oxidative stress via the involvement of mitochondria and NOX-4. It may affect mitochondrial morphology and integrity, at least in part, via the involvement of BIK.
5

THE SUPPORT OF GENE EXPRESSION IN UNDERSTANDING SECONDARY METABOLITE PRODUCTION AND ECOLOGY IN FUSARIUM VERTICILLIOIDES

LAZZARO, IRENE 23 February 2012 (has links)
Il tema principale di questa tesi di dottorato verte sul metabolismo secondario di F. verticillioides, con particolare interesse alla via biosintetica, produzione e mascheramento delle fumonisine B (FB), fumonisine A (FA), fumonisine C (FC) e bikaverina, studiati in relazione all’ecologia fungina. E’ stato osservato che l’acqua libera (aw) esercita un effetto significativo maggiore rispetto alla temperatura sul metabolismo secondario di F. verticillioides. Alti valori di aw favoriscono l’espressione dei geni FUM ed una maggiore sintesi delle FB, FA e FC. Inoltre la produzione di bikaverina e l’espressione di BIK1 sono influenzate dall’ aw nello stesso modo che la produzione di FB e l’espressione dei geni FUM. Anche il tempo di incubazione è un fattore critico per la produzione di FB in F. verticillioides, così come per F. proliferatum: la produzione di FB, FA e FC aumenta nel tempo fino a 30 giorni, periodo dopo il quale si notano differenze tra le due specie fungine. Riguardo le fumonisine nascoste, queste sono state ritrovate in colture sia di F. verticillioides che di F. proliferatum. Non è stata registrata sintesi alcuna in colture cresciute su substrato di crescita sintetico, ma al contrario solo su colture cresciute su substrato a base di mais. / The main topic of this PhD thesis is F. verticillioides secondary metabolism, with regard to fumonisin B (FB), fumonisin A (FA), fumonisin C (FC) and bikaverin biosynthetic pathways and production and masking, studied in relation to fungal ecology. What we found is that water activity (aw) has a more significant effect than temperature on F. verticillioides secondary metabolism. Moreover bikaverin production and BIK1 expression are influenced by aw in the same way as FB production and FUM gene expression respectively. High aw levels favour FUM gene expression and allow the highest synthesis of FB, FA and FC. Incubation time is also critical for FB production both for F. verticillioides and F. proliferatum: the general trend is that FB, FA and FC production increases with time, up to 30 days, period after which differences can be noticed between F. verticillioides and F. proliferatum. As regard masked fumonisins, they are recovered in F. verticillioides and also F. proliferatum cultures, furthermore no synthesis is observed on cultures grown on synthetic medium, but only in those grown on maize-based substrates.
6

L’oncogène Src et les protéines de la famille Bcl-2 : une coopération coupable : implication de la protéine Bik dans la résistance à l’apoptose de cellules transformées par l’oncogène Src / The src oncogene and the Bcl-2 family proteins : a guilty cooperation : Implication of the Bik protein in the resistance to apoptosis of Src-transformed cells

Lopez, Jonathan 04 May 2010 (has links)
La protéine tyrosine kinase c-Src est surexprimée et activée dans de nombreux cancers. De manière remarquable, Src est activé dans plus de 80% des adénocarcinomes coliques où il joue un rôle dans la carcinogenèse et la progression vers un phénotype métastatique. c-Src et son homologue viral v-Src activent un grand nombre de voies cellulaires permettant à la tumeur de proliférer, de résister à la mort cellulaire et d’acquérir des capacités accrues de migration et d’angiogenèse. Au cours de ma thèse nous avons mis en évidence un mécanisme inattendu d’échappement à l’apoptose de fibroblastes murins surexprimant de manière stable v-Src et de plusieurs lignées tumorales humaines (coliques en particulier) présentant une activité c-Src dérégulée. Nous avons montré que Src stimule la dégradation protéasomedépendantede la protéine Bik, un membre pro-apoptotique de la famille Bcl-2, connu pour être un suppresseur de tumeurs. Cette régulation post-traductionnelle du niveau d’expression de Bik est à l’origine d’une forte résistance de la voie mitochondriale de l’apoptose. L’inhibition de l’activité kinase de Src ou le blocage de la dégradation de Bik par le protéasome permettent de restaurer des concentrations normales de la protéine Bik dans les cellules transformées et de les restaurer efficacement l’apoptose. En revanche, l’inhibition des protéines anti-apoptotiques de la famille Bcl-2 par l’ABT-737 semble moins efficace. Par ailleurs, nous avons également contribué à mettre en évidence le rôle anti-migratoire et anti-invasif du lithium sur des cellules transformées par Src. Le mécanisme moléculaire mis en jeu implique l’activation redox des protéines tyrosine phosphatases cellulaires. Enfin, nous avons participé à l’étude de peptides mimant les hélices centrales d’insertion de Bax, Bcl-xL et Bid, représentant les trois sous-groupes de protéines de la famille Bcl-2. Nous avons comparé leur comportement vis-à-vis d’une monocouche lipidique mimant la membrane mitochondriale externe ainsi que leur capacité à perméabiliser des mitochondries isolées. Nos résultats nous ont permis de proposer que les fragments centraux d’insertion membranaire des protéines Bcl-2 seraient directement impliqués dans la divergence fonctionnelle des différents sous groupes qui composent la famille / C-Src tyrosine kinase is overexpressed and activated in a number of cancers. Remarkably, Src is deregulated in more than 80% of colorectal adenocarcinoma, playing a role in carcinogenesis and progression toward a metastatic phenotype. c-Src and v-Src activate a large number of intracellular pathways which allow the tumor to proliferate, to evade the cell death machinery and to acquired enhanced migratory and angiogenic abilities. During my PhD, we discovered an unknown mechanism to evade apoptosis developed by murine fibroblasts stably overexpressing v-Src and by some human tumor cell lines with c-Srcb deregulation. We have shown that Src stimulate the proteasomal degradation of the Bik protein, a proapoptotic member of the Bcl-2 family proteins known to act as a tumor suppressor. This post-translationnal regulation of the Bik protein expression level leads to a strong resistance of the mitochondrial pathway of apoptosis. Inhibition of the Src kinase activity or of the Bik proteasome-dependent degradation restore normal levels of the Bik protein and efficiently resensitize these cells to apoptosis. Inhibition of the antiapoptotic Bcl-2 proteins by ABT737 seems to be less efficient in these cells. We also contribute to show that lithium suppresses motility and invasivity of v-Src transformed cells. The molecular mechanism involve a redox activation of the protein tyrosine phosphatases. Finally, we compared the membrane behavior and the ability to permeabilize mitochondria of synthetic peptides derived from the central helical hairpin of Bax,Bcl-xL and Bid. We showed that these structurally analogous domains have distinct membrane behavior which could account for the functional divergence between the Bcl-2 family members

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