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1
Bryant, William Barton. « Caspases and caspase regulators in Lepidoptera and Diptera ». Diss., Manhattan, Kan. : Kansas State University, 2009. http://hdl.handle.net/2097/2612.
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2
Monteiro, Paulo André de Moura. « Estratégias terapêuticas baseadas na modulação da atividade enzimática das caspases ». Master's thesis, [s.n.], 2014. http://hdl.handle.net/10284/4637.
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Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências FarmacêuticasA morte celular é um processo geneticamente determinado e importante em organismos multicelulares. Esta pode ocorrer através de vários mecanismos moleculares sendo a apoptose o mais conhecido. Na apoptose, os executores da morte celular são proteínas designadas por caspases. Estas enzimas são endoproteases, mais especificamente proteases de cisteína que atuam a seguir a um resíduo de ácido aspártico. De acordo com a sua função, podem ser classificadas em três grupos: caspases inflamatórias, caspases iniciadoras da apoptose e caspases efetoras da apoptose. Nos últimos anos, vários estudos têm demonstrado a importância da modulação da atividade enzimática das caspases para fisiopatologia celular. Um inibidor ideal de caspases deverá ser altamente seletivo, possuir uma boa biodisponibilidade e ser farmacologicamente ativo. Entre os inibidores das caspases foram descritos inibidores ortostéricos, inibidores alostéricos, inibidores peptidomiméticos, pequenas moléculas inibidoras não peptídicas e inibidores naturais. Em doenças associadas a uma desregulação do processo apoptótico, tais como as doenças oncológicas, as doenças neurodegenerativas ou doenças inflamatórias, a inibição/ativação da apoptose através da modulação da atividade enzimática das caspases representa uma estratégia terapêutica promissora. Este facto tem contribuído para o desenvolvimento da investigação sobre a modulação da actividade enzimática das caspases e, subsequentemente, para a descoberta e caracterização de novas moléculas inibidoras e ativadoras das caspases. O presente trabalho de revisão bibliográfica foi desenvolvido com o objetivo de rever e integrar esta informação. Cell death is a genetically determined process, which is important for multicellular organisms. This process occurs through several molecular mechanisms among which the best known is called apoptosis. In apoptosis the cell death executors are proteins, the caspases. These enzymes are endoproteases, more specifically cysteine proteases that cleave proteins after a residue of aspartic acid. According their function, caspases can be classified into three groups: inflammatory, initiators and effectors of apoptosis. In the last years, several studies have demonstrated the importance of the modulation of the enzymatic activity of caspases for cell pathophysiology. An ideal inhibitor should have high selectivity and bioavailability, and be pharmacologically active in vivo. Several caspase inhibitors have been described including ortosteric inhibitors, allosteric inhibitors, peptidomimetic inhibitors, non-peptide small molecule inhibitors and natural inhibitors. In diseases associated with dysregulation of the apoptotic process, such as oncologic diseases, neurodegenerative diseases or inflammatory diseases, the inhibition/activation of apoptosis through the modulation of the enzymatic activity of the caspases is likely to represent a promising therapeutic approach. This notion led to new research developments on the modulation of capase’s cell activity and, subsequently, to the identification and characterization of novel drugs acting as enzyme inhibitors or activators. The present work reviews the main findings published in the literature about this topic.
3
Houri, Tarek. « Rôle des caspases au cours de la photodégénérescence rétinienne ». Thesis, Clermont-Ferrand 1, 2012. http://www.theses.fr/2012CLF1PP04/document.
Texte intégralRésumé :
Quelque soit le type de dégénérescences rétiniennes, les cellules photoréceptrices à l'origine de la genèse du signal lumineux, meurent par un mécanisme commun : l'apoptose. Au laboratoire, nous avons mis en évidence que l'inhibition de la caspase-3, une caspase effectrice de l'apoptose, permet de réduire l'apoptose des cellules photoréceptrices (Perche et al. 2007). Dans la continuité de ces résultats, le but de nos travaux de thèse est d'identifier les molécules impliquées en amont de la caspase-3. Pour mener à bien notre projet, nous avons utilisées un modèle expérimentale de dégénérescence rétinienne induite par une exposition à la lumière (modèle de photodégénérescence rétinienne). Les atteintes rétiniennes sont quantifiées par : l'électrorétinographie in-vivo permettant d'évaluer la fonction rétinienne, l'histologie pour l'analyse morphométrique de la rétine aux quelles sont associés des dosages enzymatiques. Ainsi, nous avons montré que l'injection d'un inhibiteur de la caspase-12 à 0,4 ou à 0,8 mM, de la caspase-9 à 0,2 ou à 0,4 mM, ou de la caspase-8 à 0,2 mM, injecté dans le vitré n'a aucun effet toxique sur la rétine et n'a aucun effet protecteur contre l'apoptose des cellules photoréceptrices induites par la lumière. Ces résultats suggèrent que les caspases-8, 9 et 12 ne sont pas impliquées dans l'activation de la caspase-3 et donc dans l'initiation de l'apoptose des photorécepteurs induite par la lumière. Toutefois, après injection dans le vitré, les inhibiteurs inhibent leur cible respective uniquement transitoirement. Par conséquent, pour pouvoir conclure sur le rôle de ces caspases dans le processus dégénératif, il faudrait pouvoir inhiber les caspases de façon plus persistante. Il serait donc intéressant de reproduire des expérimentations similaires en augmentant la concentration de l'inhibiteur injecté ou en réduisant le délai entre l'injection de l'inhibiteur et l'induction du stress. De plus, la caspase-3 peut être activée indépendamment des caspases initiatrices, comme par exemple : les céramides, les cathepsines et les calpaïnesNo abstract available
4
Chereau, David. « Fonctionnalité, activation, régulation allostérique des caspases, les effecteurs de l'apoptose : création de nouveaux inhibiteurs de caspases ». Aix-Marseille 1, 2003. http://www.theses.fr/2003AIX11033.
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Depuis sa découverte, l'apoptose, ou mort cellulaire programmée, a suscité un intérêt croissant de la part de la communauté scientifique internationale. Suivant un stimulus, le signal apoptotique est transmis et amplifié au sein de la cellule par une famille de protéases à cystéine appelée caspase. L'implication de l'apoptose dans un grand nombre de maladies humaines en a fait un sujet de recherche majeur. L'objectif de cette thèse de recherche est d'étudier les caspases, dans le but de créer une nouvelle génération de molécules thérapeutiques. Chaque caspase reconnaît spécifiquement une séquence tetrapeptidique donnée. Les divergences entre les sites actifs des différentes caspases reflètent leur sélectivité de substrat. A partir des structures tridimensionnelles de 4 caspases, les modèles structuraux de 7 autres caspases ont été créés. L'utilisation de paires d'inhibiteurs tetrapeptidiques a permis d'effectuer une étude fonctionnelle approfondie de chaque sous-site composant le site actif des caspases. Le lien entre ces analyses structurelle et fonctionnelle a mis en évidence les principales caractéristiques des sites actifs des caspases et devrait permettre d'améliorer le développement d'inhibiteurs compétitifs plus sélectifs. Le mécanisme d'activation des caspases sera également discuté. Finalement, l'identification d'un site de fixation des nucléotides dans caspase-9 sera traité. Cette enzyme est activée par sa fixation à Apaf-1, formant un complexe protéique appelé apoptosome. Ce site de fixation serait impliqué dans l'inhibition de l'activité de l'apoptosome par les nucléotides. L'implication au niveau cellulaire de ce phénomène sera discutée en détail ainsi que l'éventuelle utilisation d'analogues de nucléotides à des fins thérapeutiques. La concentration en nucléotides jouerait un rôle majeur dans la régulation de l'apoptose.
5
Deng, Meihong. « Proteolytic cleavage of FOXM1 by caspases / ». View the Table of Contents & ; Abstract, 2006. http://sunzi.lib.hku.hk/hkuto/record/B36396503.
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Deng, Meihong, et 邓美虹. « Proteolytic cleavage of FOXM1 by caspases ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B45010675.
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Dallaire, LeBlanc Philippe. « Novel functions of the inflammatory caspases ». Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=121336.
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Innate immunity stands at the front line of host defense and effects protection through constitutive and inducible means. Central to the host response to infection and injury is inflammation, a process initiated by various sensors of danger such as the NOD-like receptors (NLRs), a subfamily of cytosolic Pattern-Recognition Receptors (PRRs). NLRs are activated through oligomerization and assembly of cytosolic signaling platforms, including nodosomes and inflammasomes. While nodosomes activate inflammatory transcriptional pathways, inflammasomes interact with a subfamily of cytosolic enzymes called the inflammatory caspases. This thesis focuses on the functions of the inflammatory caspases within the context of the host response to infection. Expression of caspase-12, a member of the inflammatory caspase family that inhibits inflammasome signaling, is confined to a subset of individuals with African ancestry. This geographic restriction is thought to be related to an increased susceptibility to bacterial infection and sepsis lethality in individuals that express caspase-12. We found that caspase-12 dampened the mucosal immune response to the enteric attaching and effacing pathogen Citrobacter rodentium independently of its effects on the inflammasome. These effects were due to caspase-12 disrupting Nod signalosome assembly and downstream induction of antimicrobial effectors. We also show that High-mobility-group-box 1 (HMGB1), a previously identified mediator of sepsis lethality, is processed and activated by the inflammatory caspase-1. This processing releases two HMGB1 fragments with antagonistic activities that can modulate dendritic cell immunogenicity through the Rage and Tlr4 receptors in response to the tolerogenic signals transmitted by apoptotic cells. In a murine model of sepsis, we show that tolerance to a secondary infection and associated mortality can be regulated by adoptive transfer of dendritic cells treated with the caspase-1 generated HMGB1 fragments. This thesis therefore identifies novel functions of the inflammatory caspases and contributes to our understanding of inflammatory disease.L'immunité innée se retrouve à la ligne de front des défenses de l'hôte. Ses protections sont conférées par l'entremise de défenses constitutives et inductibles. Centrale à la réponse de l'hôte à l'infection et aux stresses tissulaires est l'inflammation, un processus initié par différents capteurs cellulaires de dangers tels que les NLRs (NOD-like receptors), une sous-famille cytosolique de PRRs (Pattern-recognition receptors). Les NLRs sont activés par oligomerization et l'assemblage de plates-formes de signalisation cytoplasmiques, incluant les nodosomes et inflammasomes. Les nodosomes induisent l'activation de voies de transcription inflammatoires alors que les inflammasomes interagissent avec une sous-famille d'enzymes cytosoliques nommées les caspases inflammatoires. Cette thèse étudie les fonctions des caspases inflammatoires dans le cadre de la réponse de l'hôte à l'infection, l'inflammation et la mort cellulaire. Caspase-12, une caspase inflammatoire qui inhibe l'inflammasome, est exprimée uniquement dans un sous-ensemble de personnes d'ascendance africaine. Cette restriction géographique est crue être reliée à une susceptibilité accrue aux infections bactériennes et la septicémie chez les individus qui expriment cette enzyme. Nous avons constaté que la caspase-12 régule la réponse immunitaire au pathogène entérique Citrobacter rodentium indépendamment de ses effets sur l'inflammasome en diminuant la production de peptides antimicrobiens dans l'intestin. Ces effets sont dus à un assemblage défectueux du nodosome causé par la caspase-12 en aval de l'activation de NF-κB. Nous démontrons également que High-mobility-group-box-1 (HMGB1), un facteur cellulaire contribuant à la mortalité lors de la septicémie, est clivé et activé par la caspase inflammatoire caspase-1. Ce clivage libère deux fragments ayant des activités antagonistes pouvant moduler l'immunogénicité des cellules dendritiques par les récepteurs Rage et Tlr4 en réponse aux signaux tolérogènes transmis par les cellules apoptotiques. Dans un modèle murin de septicémie, nous démontrons que la tolérance à une infection secondaire ainsi que son taux de mortalité peuvent être réglementés par transfert adoptif de cellules dendritiques traitées avec les fragments HMGB1 produits par la caspase-1. Cette thèse contribue donc au savoir scientifique en identifiant des fonctions préalablement inconnues des caspases inflammatoires.
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Henzing, Alexander John. « Chemical & ; biochemical studies of Caspases ». Thesis, University of Edinburgh, 2000. http://hdl.handle.net/1842/15007.
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Caspases are cysteine-dependent aspartate-directed proteases responsible for the proteolysis of a plethora of substrates during programmed cell death. These include structural proteins of the cytoplasm and nucleus, components of the DNA repair machinery, protein kinases, signalling proteins and regulatory proteins. Caspases are synthesised as relatively inactive zymogens, that become activated by scaffold-mediated transactivation or via cleavage by upstream proteases in an intracellular cascade. The resulting heterotetrameric enzymes possess a unique absolute requirement for aspartate at the substrate cleavage site, and recognise a tetrameric sequence within the substrate. In order to assess the role of caspases in apoptotic execution, I set out to evaluate the synthesis of novel caspase inhibitors, which would enable the detection of active caspases from apoptotic whole cell extracts. First a 2,4-dinitrophenyl probe was designed for the affinity tagging of caspases in two-dimensional gel electrophoresis. Second, biotinylated peptidylaldehydes were prepared which will enable the affinity purification of caspases from apoptotic cytosolic extracts under non-denaturing conditions. To enable biochemical studies of caspases, I developed a method, which permits the affinity purification of caspases. Apoptotic chicken hepatoma cell-line extracts were purified over an avidin column using a biotinylated probe. Finally, to permit the appraisal of the caspase proteomic variability between different cell types, and methods of apoptotic induction, and the identification of post-translational modifications of caspases, I developed a reproducible system for the identification of caspases by two-dimensional gel electrophoresis.
9
Hotti, Anneli. « Caspases in c-Myc-induced apoptosis ». Helsinki : University of Helsinki, 2000. http://ethesis.helsinki.fi/julkaisut/laa/haart/vk/hotti/.
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Boatright, Kelly M. « Activation of initiator caspases in apoptosis / ». Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2004. http://wwwlib.umi.com/cr/ucsd/fullcit?p3144323.
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Rébé, Cédric. « Rôle des caspases dans la différenciation macrophagique ». Dijon, 2005. http://www.theses.fr/2005DIJOMU06.
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Les caspases sont activées au cours de la différenciation des monocytes du sang périphérique en macrophages mais pas au cours de leur différenciation en cellules dendritiques. Elles sont également activées dans les cellules leucémiques monocytaires U937 différenciées par les esters de phorbol. Cette activation survient en l'absence d'apoptose et est nécessaire à la différenciation puisque l'inhibition des caspases (par Bcl-2, p35 ou l'inhibiteur peptidique z-VAD-fmk) bloque la différenciation. L'activation de la caspase-8 est nécessaire à la différenciation puisque l'expression d'une caspase-8 mutée inhibe la différenciation. Elles est activée au sein d'un complexe atypique formé par FADD en l'absence des récepteurs à domaines de mort. Dans ce complexe les protéines RIP et FLIP sont recrutées et clivées par la caspase-8. Les conséquences du clivage de RIP par les caspases seraient de moduler l'activité du facteur de transcription NF-kB au cours de la différenciation macrophagique.
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Nhan, Thomas Q. « Physiologic functions of activated caspases in macrophages / ». Thesis, Connect to this title online ; UW restricted, 2008. http://hdl.handle.net/1773/6311.
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Droin, Nathalie. « Identification des caspases impliquées dans l'apoptose des cellules leucémiques humaines : Rôle et fonction des isoformes de la caspase-2 ». Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0018/NQ56468.pdf.
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Deheuninck, Julien. « Le récepteur MET, une cible fonctionnelle des caspases ». Lille 1, 2006. https://pepite-depot.univ-lille.fr/LIBRE/Th_Num/2006/50376-2006-Deheuninck.pdf.
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L' hépatocyte growth factor/scatter factor (HGF/SF) est le ligand du récepteur tyrosine kinase MET, qui favorise les capacités de survie, prolifération, motilité et morphogenèse des cellules épithéIiales. La signalisation de l' HGF/SF-MET est essentieIle au cours du développement et sa dérégulation peut conduire au développement tumoral et à la progression métastatique. La surexpression du récepteur et/ou du ligaud est associée à de nombreux cancers et est souvent corrélée à un mauvais pronostic. De plus, un lien causatif entre MET et le cancer est établi depuis l'identification de mutations activatrices de MET dans le cancer papillaire rénal héréditaire. L'activation du récepteur MET par l'HGF/SF est classiquement associé à la survie cellulaire, en réponse à des stress variés. Cependant, nos travaux nous ont amené à montrer qu'en absence d'HGF/SF, ces même stress peuvent convertir le récepteur MET en facteur pro-apoptotique. En effet, nous avons montré que le récepteur est clivé par les caspases dans sa région juxtamembranaire, permettant la génération de deux fragments fonctionnels : un fragment transmembranaire, p100 MET, correspondant à un récepteur-leurre, et un fragment p40 MET, cytosolique, possédant des capacités pro-apoptotiques. Nous avons également montré que le clivage juxtamembranaire est régulé négativement par l'activation du récepteur, par la phosphorylation d'un résidu tyrosine juxtaposé au site de clivage par les caspases. Ces travaux révèlent que MET est une cible fonctionnelle des caspases et mettent en évidence que l'HGF/SF et MET participent à la balance survie/apoptose.
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Deheuninck, Julien Fafeur Véronique. « Le récepteur MET, une cible fonctionnelle des caspases ». Villeneuve d'Ascq : Université des sciences et technologies de Lille, 2009. https://iris.univ-lille1.fr/dspace/handle/1908/1224.
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Reproduction de : Thèse de doctorat : Sciences de la vie et de la santé : Lille 1 : 2006.N° d'ordre (Lille 1) : 3867. Articles en anglais reproduits dans le texte et en annexe. Résumé en français et en anglais. Titre provenant de la page de titre du document numérisé. Bibliogr. p. 73-109.
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Villars, Alexis. « Orchestration of epithelial cell elimination by effector caspases ». Electronic Thesis or Diss., Sorbonne université, 2022. http://www.theses.fr/2022SORUS567.
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Les épithéliums sont des tissus constitués de cellules très adhérentes les unes aux autres. Grâce à cela, les épithéliums agissent comme une barrière et protègent les organes qu'ils enveloppent des dangers extérieurs tels que les infections. Cependant, les épithéliums sont loin d'être statiques et présentent des taux élevés de renouvellement cellulaire par division et mort cellulaire. C'est un défi pour le tissu car la fragmentation des cellules mourantes peut entraîner une perte d'étanchéité du tissu et donc mettre en danger les organes qu'ils protègent. Pour pallier cela, les cellules apoptotiques sont expulsées des épithéliums par une séquence d'événements de remodelage qui contractent la cellule tout en rapprochant ses voisines. Ce processus, appelé extrusion cellulaire, contribue à maintenir l'étanchéité des tissus pendant la mort cellulaire. Cependant, la façon dont la cellule prend la décision d'extruder, et les mécanismes qui conduisent à sa contraction sont mal connus. Pour étudier ce phénomène, nous utilisons l'épithélium monocouche du notum de la pupe de drosophile. Dans ce tissu, l'activation des caspases précède et est nécessaire à l'extrusion cellulaire. L'extrusion cellulaire a été principalement analysée à travers l'étude de la régulation de l'actomyosine. Cependant, la relation entre l'activation des caspases et l'extrusion cellulaire est encore mal comprise. Nous avons montré que, contrairement à ce qui était anticipé, l'initiation de l'extrusion cellulaire et la constriction apicale ne sont pas associées à la modulation de la concentration ou de la dynamique de l'actomyosine. Au contraire, la constriction apicale des cellules est initiée par le désassemblage d'un réseau médio-apical de microtubules par l’action des caspases effectrices. Il est important de noter que la déplétion des microtubules est suffisante pour passer outre le besoin de caspases pour l'extrusion cellulaire. De plus, la stabilisation des microtubules nuit fortement à l'extrusion cellulaire. Ces résultats démontrent pour la première fois que le désassemblage des microtubules par les caspases est une importante étape limitante de l’extrusion. En outre, elle met en évidence une fonction plus générale des microtubules dans la stabilisation de la forme des cellules épithéliales. En outre, comme les caspases clivent une grande quantité de substrat, l'activation des caspases a longtemps été considérée comme un point de non-retour conduisant irréversiblement à l'apoptose. Cependant, des études récentes ont montré des fonctions non apoptotiques des caspases. Ces fonctions sont vastes et impliquées dans la différenciation cellulaire, la prolifération, le maintien de la pluripotence et bien d'autres. De même, plusieurs travaux montrent des événements d'activation transitoire des caspases. Par conséquent, ce qui établit la balance entre les niveaux de caspase non létaux et l'engagement dans l'apoptose reste peu clair. Il a été proposé que les cellules survivent jusqu'à un seuil d'activation des caspases, mais cela n'a jamais été testé. Si un tel seuil existe, la manière dont sa valeur est fixée et est modulée n'est pas claire. Pour quantifier l’engagement des cellules dans l’extrusion, nous avons utilisé un rapporteur live de caspase et systématiquement segmenté et suivi les cellules du notum. Par régression logistique, nous avons montré qu'il n'y a pas de seuil commun d'activité des caspases effectrices menant à l'extrusion. Au contraire, les niveaux de caspases sont corrélés linéairement avec la probabilité d’engagement dans l'extrusion. De plus, par statistique bayésienne, nous avons pu identifier des paramètres prédictifs de la sensibilité des cellules aux caspases. Par exemple l'activation antérieure des caspases semble être associée à l'engagement dans l'extrusion à un niveau de caspase inférieur. Ceci est la première analyse quantitative du processus d'engagement dans l'extrusion ou l'apoptose in vivo et au niveau de la cellule uniqueEpithelia are tissues made up of cells that are highly adherent to each other. Thanks to this property, epithelia act as a barrier and protect the organs they encase from external dangers such as infections. However, epithelia are far from static and exhibit high rates of cell turnover through cell division and death. This is a challenge for the tissue because the fragmentation of dying cells can result in a loss of tissue sealing and thus potentially endanger the organs they protect. To address this problem, apoptotic cells are expelled from the epithelia by a sequence of remodelling events that contract the cell while bringing its neighbours together. This process is called cell extrusion and it helps maintain tissue sealing during cell death. However, how the cell makes the decision to extrude and what are the mechanisms that lead to its contraction are not well known. To study this phenomenon, we use the monolayer epithelium of the Drosophila pupa notum. In this tissue, caspase activation precedes and is necessary for cell extrusion. Cell extrusion has been mostly analysed through the study of actomyosin regulation. Yet, the mechanistic relationship between caspase activation and cell extrusion is still poorly understood. We showed that the initiation of cell extrusion and apical constriction are surprisingly not associated with the modulation of actomyosin concentration and dynamics. Instead, cell apical constriction is initiated by the disassembly of a medio-apical mesh of microtubules driven by effector caspases. Importantly, the depletion of microtubules is sufficient to bypass the requirement of caspases for cell extrusion. Additionally, microtubule stabilisation strongly impairs cell extrusion. This demonstrates for the first time that microtubules disassembly by caspases is an important rate-limiting step of extrusion. Moreover, it outlines a more general function of microtubules in epithelial cell shape stabilisation. Additionally, because caspase cleave a large amount of substrate, caspase activation was long seen as a point of no-return irreversibly leading to apoptosis. However, recent studies showed non-apoptotic functions of caspases. These non-apoptotic functions are broad and involved for instance in cell differentiation, proliferation, maintenance of pluripotency and many others. Similarly, our work and other’s showed events of transient caspase activation. Therefore, what sets the balance between non-lethal caspase levels and the irreversible commitment in apoptosis remains unclear. It has been proposed that cells can survive up to a certain threshold of caspase activation but was never tested. If such threshold indeed exists, how its value is set and modulated is unclear. We used a live caspase reporter and systematic segmentation of cells in the notum to quantify the engagement of cell in extrusion. Using logistic regression, we showed that there is no common threshold of effector caspase activity leading to extrusion. Rather, caspases levels correlate linearly with the probability to engage in extrusion. Furthermore, using Bayesian statistical analysis we were able to identify parameters predictive of cell sensitivity to caspase. We showed for instance that past caspase activation seems to be associated with the engagement in extrusion at a lower caspase level. This is the first quantitative analysis of the engagement process in extrusion or apoptotis in vivo and at the single cell level
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Rodriguez-Enfedaque, Aida. « Régulation de l'apoptose mitochondriale par le facteur de survie FGF1 et l'inhibiteur de caspases zVAD-fmk ». Versailles-St Quentin en Yvelines, 2009. http://www.theses.fr/2009VERS0038.
Texte intégralRésumé :
L’apoptose est un processus physiologique de mort cellulaire essentiel à la survie des organismes pluricellulaires. L’objectif de ce travail a été d’étudier les effets de deux molécules : le facteur de survie FGF1 et l’inhibiteur des caspases zVAD-fmk sur l’apoptose dépendante de p53, un oncosuppresseur, régulateur clé de l’apoptose. Dans un premier temps, nous nous sommes intéressés à l’effet du FGF1 sur l’apoptose dépendante de p53 dans un modèle de cellules neuronales : les cellules PC12. Les résultats obtenus lors de ma thèse montrent que : (1) les FGF1 exogène et endogène (intracellulaire et nucléaire) inhibent l’apoptose dans les cellules PC12 en diminuant la phosphorylation et la stabilisation de p53, (2) la protéine FGF1 inhibe l’activité transcriptionnelle de p53 vis-à-vis de ses gènes cibles pro-apoptotiques puma et noxa, (3) le FGF1 inhibe l’activation de la caspase-3, effecteur de l’apoptose (4) pour la majorité des activités du FGF1 endogène, la présence de sa séquence de nucléarisation est déterminante. Dans un second temps, nous avons étudié l’effet de l’inhibiteur de caspases zVAD-fmk sur la voie mitochondriale de l’apoptose dans des fibroblastes embryonnaires de rongeurs. Les résultats obtenus montrent que : (1) le zVAD-fmk accélère l’apoptose dépendante de p53 et du TNF dans ces cellules, (2) les protéines Bax et Bak et la dépolarisation des membranes mitochondriales sont nécessaires pour cette accélération, (3) le zVAD-fmk inhibe classiquement les caspases executrices-3/7 et (4) de façon surprenante, le zVAD-fmk induit une augmentation du clivage et de l’activité de la caspase-9 et ne semble pas inhiber la caspase-8Apoptosis is a physiological cell death in multicellular organisms that is required for embryogenesis, metamorphosis, homeostasis and elimination of cells that are potentially detrimental to organism. Deregulations of apoptosis have been implicated in many pathologies. The main aim of this work is the study of the Fibroblasts Growth Factor I (FGFI) and the caspase inhibitor zVAD-fmk effects in p53-dependent apoptosis. First, we study the effect of FGF1 in p53-dependent apoptosis. As both factors have been involved in neuronal apoptosis, we realized our study in PC12 cells, a neuronal cellular model. Our results show that: (1) exogenous and endogenous (intracellular and nuclear) FGF1 inhibit p53 phosphorylation and stabilization and thus p53-dependent apoptosis, (2) FGF1 inhibits puma and noxa trans-activation induced by p53, (3) FGF1 inhibits caspases-3 cleavage and (4) the nuclear localization of endogenous FGF1 is required for its anti-apoptotic activities. Second, we study the effect of pancaspase inhibitor zVAD-fmk in mitochondrial apoptosis in rodent embryonic fibroblasts. Our results show that: (1) zVAD-fmk increases p53- and TNF-dependent apoptosis, (2) this acceleration of apoptosis by zVAD-fmk involved mitochondrial events (3) Bax and/or Bak are required for p53- and TNF-dependent apoptosis and for zVAD-fmk induced apoptosis acceleration, (4) zVAD-fmk inhibits caspases-3/7 activity and (5) surprisingly, zVAD-fmk increases caspases-9 cleavage and activity and does not seems to inhibit caspases-8
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Teshima, Tathyane Harumi Nakajima. « Investigação da atividade apoptótica na abertura luminal dos ductos das glândulas salivares : análise comparativa entre modelo animal e humano ». Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/23/23139/tde-24052016-164518/.
Texte intégralRésumé :
As glândulas salivares são estruturas essenciais para a manutenção da homeostase da cavidade oral pela síntese e secreção do fluido salivar. A disfunção ou perda permanente das glândulas salivares causadas por radioterapia, doenças inflamatórias ou desordens congênitas elevam principalmente o risco de infecções da mucosa oral e de estruturas dentárias, além de potencialmente prejudicar funções fisiológicas como fala, mastigação e paladar, diretamente interferindo na qualidade de vida dos indivíduos afetados. Os tratamentos atualmente disponíveis são apenas paliativos, ressaltando a necessidade de se compreender melhor os processos embriogênicos a fim de desenvolver novas estratégias terapêuticas capazes de regenerar as glândulas salivares. O princípio da formação das glândulas salivares baseia-se na coordenação de diversos processos morfogenéticos, e este trabalho foca particularmente em investigar a formação do espaço luminal do sistema de ductos, uma vez que a adequada abertura dos lumens é um processo essencial para a secreção salivar. Relata-se que a remoção das células centrais dos cordões sólidos epiteliais por morte celular apoptótica é o principal mecanismo de abertura do espaço luminal dos futuros ductos glandulares em camundongos. Porém, pouco se sabe sobre o controle temporal da apoptose durante o desenvolvimento glandular e sobre seu comportamento em glândulas salivares humanas. Neste trabalho, o perfil de expressão de diversas proteínas envolvidas na cascata apoptótica em glândulas salivares fetais humanas foi analisado de acordo com cada estágio morfogenético por imunoistoquímica (Bax, Bak, Bad, Bid, Bcl-2, Bcl-x, Bcl-xL, caspase-3 clivada, caspases-6, -7 e -9, apaf-1, survivina e citocromo c). As análises semi-qualitativas resultaram em negatividade apenas para as proteínas Bcl-2, Bad, Bid e caspase-3 clivada em todas as fases de desenvolvimento. A expressão nuclear de Bax e Bak foi identificada em presumidos espaços luminais em estágios precoces, enquanto Bcl-xL foi o fator antiapoptótico da família Bcl-2 que exibiu expressão nuclear mais importante. Caspases-6, -7 e -9 foram positivas em todas as fases, e a ausência de caspase-3 clivada sugere caspase-7 como principal caspase efetora da apoptose em desenvolvimento de glândulas salivares humanas. Ambos os componentes do complexo apoptossomo foram positivos durante o desenvolvimento glandular, e o inibidor survivina demonstrou mais positividade nuclear em estágios mais avançados. Ao observar a expressão de reguladores apoptóticos durante o desenvolvimento glandular humano, foram realizados experimentos funcionais com culturas de tecido glandular de camundongos para avaliar o papel das caspases durante a formação desta estrutura. Inicialmente detectou-se a atividade apoptótica em glândulas salivares de camundongos albinos no centro dos cordões epiteliais primários a partir de estágios precoces de desenvolvimento através de TUNEL e caspase-3 clivada. A partir disso, foi realizada a inibição apoptótica funcional in vitro durante o mesmo período, que resultou em ductos significativamente mais amplos e em defeitos morfológicos importantes nas estruturas luminal e acinar. Este trabalho evidenciou portanto atividade apoptótica durante a formação de glândulas salivares humanas e de camundongo, expressando-se em fases mais precoces do que reportadas anteriormente. Além disso, a ausência de Bad e Bid indica que a via intrínseca está mais ativa que a extrínseca, e distintos perfis de expressão da maioria das moléculas sugere adicionais funções não-apoptóticas durante a morfogênese glandular.Salivary glands are essential structures for the maintenance of homeostasis of the oral cavity by synthesizing and secreting saliva. Permanent dysfunction or loss of salivary glands caused by radiotherapies, inflammatory diseases or congenital disorders increase mainly the risk of infections of the oral mucosa and tooth surface, also impairing physiological functions as speech, mastication and taste, directly interfering in quality of life. Current treatments are only palliative-based, which highlights the need of having a better understanding of embryonic processes to develop therefore new therapeutic strategies able to regenerate salivary glands. The development of glandular secretory units and ductal system involves the coordination of several morphogenetic processes, and this study particularly focuses in investigating the formation of the lumenal space of the ductal system, as the proper lumen opening is an essential step for the salivary secretion. The clearance of the central cells of developing solid epithelial stalks by apoptotic cell death is the main mechanism of lumen space opening within presumptive ducts in mouse salivary glands. However little is known about its temporal regulation and its function in human salivary glands. Here we analysed the profile expression of several apoptosis-related proteins during human salivary gland development in correlation to each morphogenetic stage by immunohistochemistry (Bax, Bak, Bad, Bid, Bcl-2, Bclx, Bcl-xL, cleaved caspase-3, caspases-6, -7 e -9, apaf-1, survivin e citocromo c). Immunohistochemical results were analysed semi-qualitatively, and proteins Bcl-2, Bad, Bid and cleaved caspase-3 were considered completely negative at all stages of development. The nuclear expression of Bax and Bak were observed within the presumptive luminal spaces at early stages, while Bcl-xL was the antiapoptotic factor of Bcl-2 family that showed more prominent nuclear expression. Caspases-6, -7 and -9 were positive at all stages, and the absence of cleaved caspase-3 suggests caspase-7 as the main effector caspase during human salivary gland development. Both components of the apoptosome complex were also positive through all development, and the inhibitor of apoptosis survivin has shown more nuclear positivity at later stages. As the expression of apoptotic regulators was observed during human salivary gland development, functional experiments were then performed in mouse salivary gland cultures to determine the apoptotic activity of during the glandular formation. Initially, the apoptotic activity was detected in mouse salivary glands within the centre of primary epithelial stalks from early stages of development by TUNEL and cleaved caspase-3. Thus the in vitro apoptotic inhibition was performed at the same stages, which resulted in significant wider ducts and important morphological defects within luminal and acinar structures. This work has therefore evidenced the existence of apoptotic role in salivary gland lumen formation of both human and mouse models, having an earlier start point as reported before. Moreover, the absence of Bad and Bid indicates that the intrinsic pathway is more active than the extrinsic during human development, and the distinct subcellular expression of most molecules suggests additional non-apoptotic functions.
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Amara-Benmerabet, Souheila. « Étude de l'apoptose dans deux modèles murins : (i) excès d'apoptose dans les azoospermies chez l'homme et dans un modèle d'arrêt de la spermatogenèse chez le rat et (ii) défaut dans l'adénocarcinome du rectum de patients mauvais répondeurs à la radiothérapie ». Lyon 1, 2007. http://www.theses.fr/2007LYO10100.
Texte intégralRésumé :
L'apoptose est le processus de mort cellulaire programmée, nécessaire au développement et à la survie des organismes. La destabilisation de ce processus provoque différentes pathologies humaines comme le cancer quand le processus fait défaut ou bien des pathologies de perte cellulaire associée à une perte de fonction quand le processus est en excès. Nous nous sommes concentrés sur l'étude des modifications de la phase exécutrice de l'apoptose à travers trois familles de molécules (i) les caspases effectrices (-3, -6 et -7) qui sont responsables de la mort des cellules ; (ii) les inhibiteurs d'apoptose (IAPs) qui inhibent l'activation ou l'action des caspases ; (iii) les inhibiteurs d'IAPs représentés par Smac/DIABLO. Nous avons étudié le processus d'excès d'apoptose dans le testicule humain pathologique (azoospermie) et dans deux modèles expérimentaux où nous avons induit l'apoptose des cellules germinales testiculaires (par un éther de glycol, par utilisation de radio-chimiothérapies). Nous avons étudié le processus de défaut d'apoptose un modèle de carcinogenèse (adénocarcinome rectal) présentant une résistance à la radiothérapie, nous avons cherché à modifier la cascade apoptotique pour lever cette résistanceApoptosis is a programmed cell death process useful for the development and the survival of organisms. Alteration in this process induces several human diseases such as cancer when apoptosis is decreased and diseases characterized by a loss of function when apoptosis is increase. We focuses our work on the study of alterations of the executor step of apoptosis through three families of molecules : (i) effector caspases (-3, -6 and -7) that induced cell death ; (ii) inhibitor of apoptosis proteins (IAPs) that inhibit caspase activation or action and (iii) IAPs inhibitors such as Smac/DIABLO. We studied increased apotosis in human azoospermia and a model of induced testicular germ cell death by glycol ether (EGME), ionizing radiations or platinum derivative (oxaliplatin) administration. We studied decrease apoptosis in biopsies of rectal adenocarcinoma from patients radiosensitive or radioresistant. Moreover, we tried to manipulate a model of radiosensitive and radioresitant cell lines to overcome the resistance to apoptotic in the radioresistant cell line
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Baritaud, Mathieu. « Etude de la dualité d’AIF, dans la mort cellulaire programmée indépendante des caspases via son partenaire yH2AX et dans la phosphorylation oxydative via les complexes et supercomplexes mitochondriaux ». Paris 6, 2013. http://www.theses.fr/2013PA066289.
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L’apoptosis inducing factor (AIF) est une flavoprotéine mitochondriale à deux visages, à travers sa fonction vitale dans la phoshorylation oxydative et sa fonction apoptotique lors de la mort cellulaire programmée (MCP). Suite à un stimulus de mort cellulaire, AIF est relarguée de la mitochondrie vers le noyau, et forme un complexe de dégradation de l’ADN avec l’histone H2AX et la DNase Cyclophiline A. Ce dégradosome est crucial pour l’exécution de la MCP indépendante des caspases aussi appelée nécroptose. Ce travail de thèse détermine l’implication de la forme activée d’H2AX par phosphorylation sur la sérine 139, γH2AX dans le dégradosome lors de la nécroptose induite par l’agent alkylant de l’ADN, MNNG. La transduction de fibroblastes embryonnaires murins (MEF) H2AX-/- avec la forme non-phosphorylable ou phosphomimétique d’H2AX pour la sérine 139, a permis de démontrer que γH2AX joue un rôle conformationnel dans l’activation du dégradosome et l’exécution de la nécroptose. De plus, nous avons démontré que les kinases, activées suite aux dommages de l’ADN, ATM et DNA-PK contrôlent la nécroptose via l’activation d’H2AX. D’autre part, nous avons étudié la fonction d’AIF dans la mitochondrie en utilisant un modèle de MEF inductible pour la délétion d’AIF. L’analyse de l’activité de la phosphorylation oxydative dans ce système in vitro inédit nous a permis de suivre les conséquences progressives de la perte d’AIF. Ainsi, nous avons confirmé qu’AIF est essentiel pour le fonctionnement de ce mécanisme énergétique mitochondrial. Et pour la première fois, le rôle vital de cette protéine mitochondriale n’est pas seulement associé au complexe I mais aussi aux supercomplexesApoptosis inducing factor (AIF) is a mitochondrial protein with two faces: a vital role in mitochondrial oxidative phosphorylation and a death function in programmed cell death (PCD). On one hand, after cell death triggering, AIF is released from mitochondria and involved in a DNA degradation complex (degradosome) with histone H2AX and DNAse cyclophilin A. This complex is crucial in caspase-independent PCD mediated by DNA damage, named necroptosis. H2AX and its activated form γH2AX, phosphorylated on serine 139, had often been described in DNA repair. In this thesis work, we characterized this activated form in necroptosis induced by alkylating agent MNNG (N-methyl-N'-nitro-N-nitrosoguanidine). Transduction of H2AX KO embryonic murine fibrobasts (MEF), with mutant forms of H2AX for serine 139 - non phosphorylable or phosphomimetic - demonstrated that γH2AX have a conformational role for degradosome activation and MNNG-induced necroptosis execution. With pharmacological and cellular approaches, we also demonstrated that kinases usually involved in DNA damage response also controlled necroptosis via H2AX activation by serine 139 phosphorylation. On the other hand, by using an innovative in vitro model of inducible MEF for AIF deletion, and many techniques as native electrophoresis, in-gel activity, oxygraphy, we confirmed the implication of AIF in mitochondrial oxidative phosphorylation. For the first time, we also described the role of this mitochondrial flavoprotein, not only for complex I but also for mitochondrial supercomplexes formation
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Cathelin, Séverine. « Rôle des caspases dans la différenciation de cellules hématopeïtiques ». Dijon, 2006. http://www.theses.fr/2006DIJOMU08.
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Les caspases sont des protéases spécifiquement activées au cours de la différenciation des monocytes en macrophages. Cette activation des caspases survient en absence d’apoptose et est nécessaire à la différenciation macrophagique. Les voies d’activation et les cibles des caspases au cours de la différenciation des monocytes en macrophages étaient inconnues. J’ai contribué à montrer l’importance de l’activation de la caspase-8 dans la différenciation macrophagique. La caspase-8 est activée au sein d’un complexe atypique formé notamment par FADD en absence des récepteurs à domaines de mort. Dans ce complexe, les protéines RIP et FLIPL et S sont recrutées et clivées par la caspase-8. Le clivage de RIP par les caspases module l’activation du facteur de transcription NF-B au cours de la différenciation macrophagique. J’ai identifié des cibles des caspases au cours de la différenciation macrophagique par une approche protéomique comparative. J’ai participé à montrer que HSP70 régule l’érythropoïèse en protégeant le facteur de transcription GATA-1 du clivage par les caspases au cours de la différenciation érythrocytaire terminaleCaspases are proteases with a specific activation in the macrophage differentiation of human monocytes. Caspase activation is required for macrophage differentiation and is not related to apoptosis. Activation pathways and substrates of caspases during macrophage differentiation were unknown. I contributed to show the importance of the activation of the caspase-8 in macrophage differentiation. Caspase-8 is activated within an atypical complex formed in particular by FADD in absence of death receptor. In this complex, the proteins RIP and FLIPL and S are recruited and cleaved by caspase-8. Cleavage of RIP by caspases controls the activation of transcription factor NF-B during macrophage differentiation. I identified targets of caspases during macrophage differentiation by a comparative proteomic approach on differentiated cells expressing or not a caspase inhibitor. I took part in showing that HSP70 controls the erythropoiesis by protection GATA-1 from cleavage by caspases during terminal erythroid differentiation
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Caution, Kyle J. « Legionella pneumophila and caspases : modulation of the actin cytoskeleton ». The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1449147516.
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kapoor, varun. « Mechanism of Reversal of Alzheimer’s Disease A-beta Induced Neuronal Degeneration in Cultured Human SHSY Cells Using A Neurotrophic Ependymin Mimetic ». Digital WPI, 2007. https://digitalcommons.wpi.edu/etd-theses/908.
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"Alzheimer’s disease (AD) is a neurodegenerative disorder that leads to dementia in adults. The mechanism of neurodegeneration is thought to involve the extracellular production of a highly toxic A-beta peptide that engages cell surface receptors to induce cellular oxidative stress and apoptosis, but the signal transduction pathways that lead to A-beta induced cell death are unknown. We previously showed that a human ependymin neurotrophic peptide mimetic (hEPN-1) can promote cell survival in an in vitro AD model system. This initial observation was extended in this thesis by investigating the mechanism of A-beta induced apoptosis and hEPN-1 induced survival. Immunoblots were used to assay the total cellular levels of specific caspase proteins. The results show that A-beta induced apoptosis uses an extrinsic caspase pathway involving caspases-2 and -3, and that hEPN-1 treatment can reduce those caspase levels. A caspase activity assay showed that A-beta increased caspase-3/7 activity, while hEPN-1 treatment lowered it. Moreover, in vivo studies with AD transgenic mice showed that hEPN-1 treatment increased antioxidative superoxide dismutase levels in brain. Thus, hEPN-1 holds potential as a therapeutic to treat the underlying neurodegenerative cause of AD, not merely its symptoms as with other currently approved AD drugs."
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Milhas, Delphine. « Rôle des caspases et des sphingolipides dans la signalisation cytotoxique du récepteur FAS dans les lymphocytes T ». Toulouse 3, 2007. http://thesesups.ups-tlse.fr/70/.
Texte intégralRésumé :
Le récepteur Fas (CD95) et son ligand FasL (CD95-L) jouent un rôle clé dans la mort des lymphocytes T. Alors que la caspase-8 a été montrée comme essentielle dans l'apoptose induite par la stimulation de Fas, des travaux récents suggèrent l'existence de voies de signalisation indépendantes de la caspase-8. Le céramide, un sphingolipide bioactif, joue un rôle potentiel dans l'induction de la mort cellulaire. L'objectif de notre travail a été de clarifier le rôle des caspases et du céramide dans la mort de lymphocytes T induite par FasL. Nous montrons que la caspase-10 est capable de se substituer à la caspase-8 dans la signalisation apoptotique de Fas, en clivant Bid (Bcl-2 interacting domain) et en activant la cascade des caspases dans des cellules Jurkat. De plus, les caspases-8 et -10 jouent un rôle dans l'induction d'une mort nécrotique, indépendamment de leur activité catalytique. Une inhibition de l'activité de la sphingomyéline synthase (SMS), une enzyme qui convertit le céramide en sphingomyéline, est détectée en réponse à FasL. L'inhibition préalable de la SMS, par approche pharmacologique ou épigénétique (siRNA), favorise l'augmentation du taux intracellulaire de céramide et la mort induite par FasL. L'incubation de cellules Jurkat en présence d'analogues exogènes de céramide s'accompagne d'une toxicité, suggérant un rôle du céramide dans la signalisation cytotoxique de Fas. Nos résultats mettent en évidence le rôle essentiel des caspases-8 et -10 dans la mort apoptotique et nécrotique des lymphocytes T induite par FasL. Interférer avec l'activité de la SMS pourrait représenter une nouvelle stratégie thérapeutique pour sensibiliser les lymphocytes T à FasLFas (CD95) engagement by FasL (CD95L) plays a crucial function in T lymphocytes cell death. In contrast to caspase-8, controversy exists as to the ability of caspase-10 to mediate apoptosis in response to FasL. The ceramide, a bioactive sphingolipid, plays a potential role in cell death. The aim of our study was to clarify the role of caspases and ceramide in FasL-induced T lymphocyte death. Ours results indicate that caspase-10 can substitute to caspase-8 as an initiator caspase in Fas signaling leading to Bid (Bcl-2 interating protein) processing, caspase cascade activation, and apoptosis of human leukemia Jurkat T cells. Moreover, initiator caspases-8 and -10 can trigger cell death independently of their catalytic activities, and are absolutely required for FasL-induced ceramide production and cell death, including necrosis. The ceramide is converted to sphingomyelin (SM) by SM synthase (SMS). In Jurkat cells, FasL treatment inhibits SMS activity in a dose- and time-dependent manner. The inhibition of ceramide conversion to SM, by pharmacological approach or by siRNA, enhances FasL-induced death of Jurkat and activated T cells. Novel ceramide analogs elevate endogenous ceramide content and promote Jurkat cell death, suggesting a role of ceramide in cytotoxic Fas signaling. Altogether our results highlight the essential role of caspases-8 and -10 in FasL-induced apoptotic and necrotic leukemia cell death. Moreover the inhibition of SM synthesis may facilitate FasL-induced ceramide increase and lymphocytes death. Inhibiting SMS activity may represent an interesting therapeutic strategy to sensitize T lymphocytes to FasL
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Bhandary, Binny. « Characterization of caspases in the apoptotic pathway of Aedes aegypti ». Thesis, Kansas State University, 2016. http://hdl.handle.net/2097/32597.
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Master of ScienceDivision of Biology
Rollie J. Clem
Caspases are a conserved family of cysteine proteases that play important roles in apoptosis and innate immunity as well as other cellular processes. Eleven caspase genes have been annotated in the mosquito Aedes aegypti. Amongst these, previous studies have demonstrated functional roles for AeDronc, CASPS7 and CASPS8 in the Ae. aegypti apoptosis pathway, while CASPS18 and CASPS19 have also been functionally characterized. A previous study from our research group showed that AeIAP1 has preferential binding for CASPS7 compared to CASPS8. In this study, it was confirmed that AeIAP1 has a higher capacity to inhibit CASPS7 than CASPS8. Furthermore, five of the remaining Ae. aegypti caspases, namely CASPS15, CASPS16, CASPS17, CASPS20 and CASPS21, were characterized. An attempt was made to classify these caspases as initiator or effector caspases, based on factors such as the length of their prodomain, sequence similarity to known Drosophila initiator and effector caspases, and their substrate specificity. The functions of these caspases in apoptosis was examined in the Ae. aegypti cell line Aag2, by using RNA interference to reduce their expression and test the effect on apoptosis. Recombinant CASPS16, 17, 20 and 21 were produced in bacteria and the abilities of these recombinant proteins to cleave different caspase substrates were examined. From the resulting data, it was concluded that CASPS17 and CASPS21 are likely to be effector caspases since they preferred a effector caspase substrate. When considering the prodomain length, CASPS17 has a short prodomain, but CASPS21 has a long prodomain, which is normally associated with initiator caspases. CASPS20 did not show preference for any specific substrate and has a short prodomain. Since it did not have a specific preference of substrate, it is likely to be an effector caspase based on prodomain length. CASPS16 showed a slightly higher preference for the initiator caspase substrate WEHD, and has a long prodomain. Based on these results, CASPS16 is likely an initiator caspase. To examine the potential roles of CASPS15, 16, 17, 20 and 21 in apoptosis, their expression in Aag2 cells was knocked down using RNA interference. Successful knockdown was verified by qRT-PCR. After silencing specific caspases, the cells were exposed to two different apoptotic stimuli, ultraviolet radiation (UV) or the RNA synthesis inhibitor actinomycin D (ActD). Following apoptotic treatment, apoptosis was measured by two methods; caspase activity was measured using an effector caspase substrate, and phosphatidyl serine exposure on the outer leaflet of the plasma membrane, which occurs in apoptotic cells, was measured by Annexin V staining and flow cytometry. In cells where CASPS15, 16, 17, 20 or 21 had been knocked down and the cells were then treated with UV or ActD, it was observed that effector caspase activity and Annexin V staining were both significantly lower than in UV- or ActD-treated cells that had received control double-stranded RNA. Together these results suggest that all of these caspases are involved in apoptosis in Aag2 cells. This study serves as a starting point for further research on Ae. aegypti caspases and their roles in specific cellular processes.
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Bérard, Marion. « Mécanisme et rôle de l'apoptose induite via le récepteur de l'antigène des lymphocytes B matures chez l'homme ». Lyon 1, 2000. http://www.theses.fr/2000LYO1T015.
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Ekici, Ozlem Dogan. « Design, synthesis, and evaluation of novel irreversible inhibitors for caspases ». Diss., Georgia Institute of Technology, 2003. http://hdl.handle.net/1853/5333.
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Fletcher, G. C. « The role of caspases in the death of sympathetic neurons ». Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599084.
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Primary neurons from the rat superior cervical ganglion (SCG) are dependent on nerve growth factor (NGF) for their survival both in vivo and in vitro and die by apoptosis after NGF withdrawal. This study examines the involvement of caspases in SCG neuronal death and the circumstances under which caspase inhibitors both prevent apoptosis and allow the functional recovery of SCG neurons. Firstly, the effects of three caspase inhibitors on NGF-deprivation-induced apoptosis were tested. The most effective inhibitor at non-toxic concentrations was BOC-aspartyl(O-methyl) fluoromethylketone (BAF), which was further characterised in assays examining caspase activity during SCG neuronal apoptosis. The long-term survival of cells in which BAF treatment had prevented apoptosis was followed and it was found that newly-isolated cells could not survive after the readdition of NGF, in contrast to established neuronal cultures. The reasons to account for the lack of long-term survival of the newly-isolated NGF-deprived, BAF-treated neurons were examined. The most striking observation was the increased autophagic activity at the time of NGF addition and the selective loss of mitochondria three days later. Thus, newly-isolated cultures appear to become committed to death as a result of mitochondrial damage upstream of caspase activation. In contrast established neuronal cultures, which were rescued after caspase inhibition had prevented apoptosis, appear to become committed to death coincident with caspase activation. The data presented here suggest that the mechanism that commits neurons to die must be established before it can be predicted whether survival factors can rescue neurons when death has been prevented by caspase inhibition.
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Longthorne, Vanessa L. « Caspases and the molecular control of apoptosis in leukaemic cells ». Thesis, Keele University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242284.
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Ekici, Özlem Doğan. « Design, synthesis, and evaluation of novel irreversible inhibitors for caspases ». Available online, Georgia Institute of Technology, 2004:, 2003. http://etd.gatech.edu/theses/available/etd-04062004-164633/unrestricted/ekici%5Fozlem%5Fd%5F200312%5Fphd.pdf.
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Teruya, Roberto [UNIFESP]. « Estudo de aspectos morfológicos e funcionais de ratos submetidos a isquemia e repercussão de músculo esquelético, sob a ação da pentoxifilina ». Universidade Federal de São Paulo (UNIFESP), 2006. http://repositorio.unifesp.br/handle/11600/21513.
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Previous issue date: 2006Objetivos: estudar os aspectos morfológicos e funcionais do rim de ratos relacionados com a isquemia e reperfusão de musculatura esquelética e o uso da pentoxifilina. Métodos: Ratos Wistar EPM-I (n=60) foram submetidos à isquemia do membro posterior pelo clampeamento da artéria ilíaca comum esquerda por um período de seis horas e observados por quatro (OA) ou vinte e quatro horas (OB) após a reperfusão. Outro grupo, GS(n=6), foi submetido a anestesia e procedimentos operatórios sem a obstrução arterial. A pentoxifilina (PTX ¬4Omg.Kg-1) não foi aplicada (OAI e OB1) ou foi aplicada no início da reperfusão (0A2 e GB2) ou no início da isquemia e início da reperfusão (OA3 e OB3). A eutanásia ocorreu ao término do período de reperfusão correspondente em cada grupo de animais, quando foram coletadas amostras de sangue para análise bioquímica da creatinofosfoquinase, uréia, creatinina, sódio e potássio séricos. Na seqüência foi realizada a nefrectomia esquerda para estudo histológico das alterações morfológicas dos nefrons e túbulos renais, assim como a imuno-histoquímica para apoptose pela expressão da caspase-3. Foram aplicados os testes de Mann-Whitney e Kruskal-Wallis (p≤ 0,05). Resultados: Ocorreu aumento significativo da uréia (90,5±30,96 mg.dL-1), creatinina (2,28≤0,54 mg.dL-1) e potássio (16± 3,66 mmohiL-¬1) no grupo B3 onde o mesângio também mostrou-se significativamente espessado (0,97± 0,42). Houve diminuição do número de túbulos renais comprometidos (0,70±0,14) no grupo B2. A expressão de caspase-3 foi maior nos grupos B2 (16,35±1,65 por cento) e B3 (15,57±2,54 por cento) que em GS (9,8±1,98 por cento). Conclusão: A isquemia e reperfusão de músculo esquelético de ratos produzem lesões à distância em tecido renal e a pentoxifilina tem algum efeito protetor sobre estas lesões na fase precoce de observação (até quatro horas). Na fase tardia (até vinte e quatro horas) esta proteção não se faz evidente e até exerce papel antagônico, agravando as lesões quando aplicada nos períodos de isquemia e reperfusão e dependente da dose usada.
Objectives: to study morphologic and functional aspects of the kidney of rats related with the ischemia and reperfusion of skeletal musculature and pentoxifylline. Methods: Wistar EPM-1 rats (n=60) were submitted to the ischemia of the posterior limb by clamping the left common iliac artery for a period of six hours and observed by four (GA) or twenty-four hours (GB) after the reperfusion. Another group, GS(n=6), was submitted to the anesthesia and surgical procedures without the arterial obstruction. The pentoxifylline (PTX - 40mg.Kg-1) it was not applied (GA1 and GB1) or it was applied in the beginning of the reperfusion (GA2 and GB2) or in the beginning of the ischemia and in the beginning of the reperfusion (GA3 and GB3). The euthanasia was done at the end of the period of corresponding reperfusion in each group of animals, when samples of blood were collected for biochemistry analysis of the creatinofosfoquinase, urea, creatinine, sodium and potassium. In the sequence the left nefrectomy was accomplished for histological study of the morphologic alterations of the nefrons and renal tubules, as well as the imuno-histochemistry test for apoptose by the expression of the caspase-3. They were applied the tests of Mann-Whitney and KruskalWallis (p≤ 0,05). Results: it were significant increase of the urea (90,5 ± 30,96 mg.dL-1), creatinine (2,28 ± 0,54 mg.dL-1) and potassium (16 ± 3,66 mmol.dL-1) in the group B3 where the mesangium was also shown significantly thickened (0,97 ± 0,42). There was decrease of the number of renal tubules injured (0,70 ± 0,14) in the group B2. The caspase-3 expression was larger in the groups B2 (16,35 ± 1,65%) and B3 (15,57 ± 2,54%) that in GS (9,8 ± 1,98%). Conclusions: the ischemia and reperfusion of skeletal muscle of rats produce long distance lesions in renal tissue and the pentoxifylline has some protecting effect on these lesions in the precocious phase of observation (up to four hours). In the late phase (up to twenty-four hours) this protection is not made evident and until it exercises antagonistic dosedependent effects, worsening the lesions when applied in the ischemia and reperfusion periods.
BV UNIFESP: Teses e dissertações
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Östman, Johan. « Mechanisms involved in amyloid induced cytotoxicity / ». Umeå : Dept. of Molecular Biology, Univ, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-541.
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Souza, Denise Silvia de. « Indução artificial da apoptose como medida de segurança em terapia genica ». [s.n.], 2005. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311960.
Texte intégralRésumé :
Orientador: Sara T. O. SaadDeissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Para que a terapia gênica seja aplicada à terapêutica clínica, é necessário o desenvolvimento de um sistema que permita a eficácia biológica e segurança no caso de efeitos tóxicos. O gene da eritropoetina (EPO) pode ser utilizado para o tratamento de anemias crônicas, porém estudos in vivo têm demonstrado que efeitos tóxicos, como trombose e policitemia fatal, são freqüentes devido ao descontrole da expressão da EPO e alta elevação do hematócrito (Hct). O objetivo deste estudo foi buscar um sistema capaz de induzir a apoptose de células transformadas com o gene da EPO, baseado na ativação artificial da caspase9, através de indutores químicos de dimerização (CIO), comparando este sistema ao do Tet-Off. Duas construções foram utilizadas: a primeira contendo o cDNA da EPO murina (pBS-mEpoD) sob o controle do sistema Tet-off (ptetTA) e o segundo contendo o cDNA da caspase9 ligado a duas moléculas de FKBP em tandem (iCasp9). As moléculas de FKBP contêm uma mutação F36V que permite a ligação específica do indutor químico de dimerização (CIO) AP20187, gentilmente cedido pela ARIAD Pharmaceutics (Cambridge, MA). Estudos in vitro mostraram que, em células murinas C2C12 transfectadas estavelmente, o vetor icasp9 apresentou expressão adequada e 90% das células entraram em apoptose após a administração do AP 20187. Os ensaios in vivo foram realizados, inicialmente, com 3 grupos de camundongos (11/grupo), que receberam '5mu¿p pBS-mEpoD , '0,5mu¿g ptet-tTA e diferentes concentrações de iCasp9: grupo 1: zero, grupo 2= '6mu¿g e grupo 3= '10mu¿ g. As injeções intramusculares foram seguidas de eletroporação (8 pulsos, 30mseg , 200V/cm, 1Hz). Após cinco semanas, os animais apresentaram aumento no Hct de 33% (Student T test p=0.0013), 36.8% (p=0.0004) e 12.8% (p=0.0374) nos grupos 1,2 e 3 respectivamente, sugerindo que a administração de '6mu¿g de icasp9 não altera a expressão do vetor pBSmEpoD, enquanto que '10mu¿g de iCasp9 reduz sua eficiência. Novo experimento foi realizado, onde 49 animais participaram do estudo, sendo que treze destes receberam as concentrações administradas ao grupo 1, acima descrito, e 36 receberam as concentrações do grupo 2. Através deste experimento, foi possível verificar a eficiência do sistema na elevação e sustentação do hematócrito, assim como comparar os sistemas iCasp9/AP20187 e Tet-Off, no controle da expressão da eritropoetina. ... Observação: O resumo, na íntegra, poderá ser visualizado no texto completo da tese digital
Abstract: In order to apply gene therapy to clinical practice, it is necessary to develop a system establishing biological efficiency and safety in case of toxic effects.The erythropoietin gene (EPO) can be used in the treatment of chronic anemia, however in vivo studies have revealed that toxic effects, such as thrombosis and fatal polycythemia, are frequent due to uncontrolled EPO expression and a high increase in the hematocrit (Hct) levels.The aim of this study was to search for a system capable of inducing apoptosis in cells transformed by the EPO gene, based on the artificial activation of caspase-9, using chemical inducers of dimerization (CIO), comparing this system to Tet-Off. Two constructions were used: the first one containing the cONA of murine EPO (pBSmEpoO) under Tet-Off system (ptet-tTA) control and the second containing the cONA of caspase-9 connected to two FKBP molecules in tandem (iCasp9). The FKBP molecules contain a F36V mutation that permits a specific connection to the chemical inducer of dimerization (CIO) AP20187, kindly provided by ARIAO Pharmaceutics (Cambridge, MA). Studies in vitro demonstrated that, in stably transfected murine cells C2C12,the icasp9 vector presented and adequate expression and 90% of the cells entered apoptosis after AP20187 administration. The in vivo assays were performed, initially, with 3 groups of mice (11/group) that received '0,5mu¿g pBS-mEpoO, '0,5mu¿g ptet-tTA and different concentrations of iCasp9: group 1: zero, group 2='6mu¿g, and group 3='10mu¿g.The intramuscular injections were followed by electroporation (8 pulses, 30mseg, 200V/cm, 1Hz). After five weeks, the animais demonstrated a 33% increase in Hct (Student T test p=0.0013), 36.8% (p=0.OO04)and 12.8% (p=0.0374) in groups 1, 2, and 3 respectively, suggesting that the administration of '6mu¿g of icasp9 does not alter the pBS-mEpoO vector expression, although '10mu¿g of iCasp9 reduces its efficiency. A new assay was performed, the study involved 49 animais, thirteen of which received the same concentrations administered in group 1, described above, and 36 received the same concentrations as group 2. ... Note: The complete abstract is available with the full electronic digital thesis or dissertations
Mestrado
Biologia Estrutural, Celular, Molecular e do Desenvolvimento
Mestre em Fisiopatologia Médica
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Li, Wenjing. « The role of PML and executioner caspases in mammary gland development ». Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609289.
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Daugas, Eric. « Role de l'aif au cours des voies d'apoptose independantes des caspases ». Paris 6, 2001. http://www.theses.fr/2001PA066283.
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La permeabilisation des membranes mitochondriales joue un role precoce et central au cours de l'apoptose dans la majorite des systemes etudies. Elle provoque la liberation par les mitochondries de proteines solubles dont l'apoptosis inducing factor (aif), le cytochrome c, les procaspases 2 et 9, smac/diablo. Cette liberation est suffisante pour l'activation d'hydrolases cataboliques extramitochondriales responsables des degradations cellulaires observees. Ce travail de these consacre a l'etude fonctionnelle de l'aif a montre : _qu'aif est une proteine mitochondriale d'expression ubiquitaire, _qu'aif est relocalise des mitochondries au noyau au cours de l'apoptose induite par de nombreux inducteurs, _que la liberation d'aif par les mitochondries est inhibee par bcl-2, _que l'expression cytosolique d'aif suffit a induire les modifications apoptotiques nucleaires, _qu'aif joue un role preponderant au cours de la phase de degradation de l'apoptose avec un role direct sur le noyau : condensation de la chromatine et clivage de l'adn, _qu'aif exerce ses effets pro-apoptotiques independamment des caspases, _qu'aif initie une voie d'apoptose nucleaire independante de celle initiee par la liberation du cytochrome c par les mitochondries, _qu'aif, a lui seul, peut rendre compte des modifications nucleaires survenant au cours de modeles d'apoptose independante des caspases, _qu'aif est le principal effecteur dans certains modeles d'apoptose et notamment l'induction de celle-ci par la deprivation en serum, _qu'aif est essentiel a l'apoptose provoquant la cavitation des embryons murins, premiere vague d'apoptose au cours du developpement embryonnaire. Cette etude a permis de preciser le role d'aif au cours de l'apoptose. De plus, elle a confirme, in vivo, l'importance fonctionnelle des voies d'apoptose independantes des caspases en leur attribuant aif comme seul effecteur moleculaire essentiel decrit a ce jour.
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Yang, Rui. « Interaction between caspases and their substrates in the inflammasome signaling pathway ». Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1559917811566556.
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Yang, Jie. « STRUCTURE, FUNCTION, AND REGULATION OF INFLAMMATORY CASPASES IN INFLAMMATION AND PYROPTOSIS ». Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1560267566637531.
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Cardona, Colom Maria. « Identificació de la funció de les caspases executores en el desenvolupament cardíac, basada en l’estudi de la deleció de les caspases 3 i 7 en els cardiomiòcits ». Doctoral thesis, Universitat de Lleida, 2014. http://hdl.handle.net/10803/285433.
Texte intégralRésumé :
Diversos estudis demostren com les caspases són silenciades durant el desenvolupament cardíac,
aquest fet indica que la funció que porten a terme les caspases en el cor té importància durant el
desenvolupament.En aquest treball hem generat una soca de ratolins amb una deleció cardíacespecífica
de les caspases executores 3 i 7 (DKO) per tal d’esbrinar quina és la funció d’aquestes
caspases en el desenvolupament del cor. Mentre que la manca global de les caspases 3 i 7
comporta una mort prematura i un desenvolupament cardíac anormal, la seva manca específica en
el miocardi no suposa problemes de supervivència i el cor té una morfologia normal, demostrant
que el fenotip cardíac que presenta el KO global és un efecte secundari de la manca de les
caspases en un altre teixit. Aquest estudi descriu com la manca d’aquestes caspases
específicament en el miocardi suposa una disminució en la proliferació, que comporta un inferior
nombre de cardiomiòcits, que acaba desenvolupant un cor més petit. A més, els nostres resultats
demostren com els cors DKO compensen el dèficit de cardiomiòcits desenvolupant una
hipertròfia lleu; el desenvolupament d’aquesta hipertròfia va associat a un canvi en la tendència
de l’expressió dels gens de diversos grups funcionals, demostrant un canvi adaptatiu d’aquests
cors amb l’edat. El fet desencadenant del problema proliferatiu en els DKO sembla tenir relació
amb un augment en la resposta inflamatòria, que podria estar induint l’expressió de gens
implicats en la desregulació de la proliferació, com Serpina3.Mitjançant la sobre-expressió de les
caspases amb el centre catalític mutat hem demostrat com aquesta funció no-apoptòtica de les
caspases és independent de la seva activitat catalíticaDistintos estudios demuestran como las caspasas son silenciadas durante el desarrollo cardíaco, este hecho indica que la función que llevan a cabo las caspasas en el corazón tiene importancia durante el desarrollo.En este trabajo hemos generado una cepa de ratones con una deleción cardíaco-específica de las caspasas ejecutoras 3 y 7 (DKO) con el fin de encontrar cuál es la función de dichas caspasas en el desarrollo del corazón. Mientras que la falta global de las caspasas conlleva una muerte prematura y un desarrollo cardíaco anormal, su manca específica en el miocardio no supone problemas de supervivencia y el corazón tiene una morfología normal, demostrando que el fenotipo cardíaco que presenta el KO global es un efecto secundario de la falta de las caspasas en otro tejido. Este estudio describe como la falta de estas caspasas específicamente en el miocardio supone una disminución en la proliferación, que conlleva un inferior número de cardiomiocitos, que acaba desarrollando un corazón más pequeño. Además, nuestros estudios demuestran como los corazones DKO compensan el déficit de cardiomiocitos desarrollando una hipertrofia leve; el desarrollo de esta hipertrofia va asociado a un cambio en la tendencia de la expresión de los genes de distintos grupos funcionales, demostrando un cambio adaptativo de estos corazones con la edad. El hecho desencadenante del problema proliferativo en los DKO parece tener relación con un aumento en la respuesta inflamatoria, que podría estar induciendo la expresión de genes implicados en la desregulación de la proliferación, como Serpina3. Mediante la sobre-expresión de las caspasas con el centro catalítico mutado hemos demostrado como esta función no-apoptótica de las caspasas es independiente de su actividad catalítica.
Several studies demonstrate that caspases are silenced during cardiac development, this fact indicates that the function that caspases carry out in the heart is important during heart development. In the present work we generated a mice strain with a cardiac-specific deletion of the executioner caspases 3 and 7 (DKO) in order to investigate the function of these caspases during heart development. While the global lack of caspases 3 and 7 causes a premature death and an abnormal cardiac development, their specific lack in the myocardium does not cause survival problems and the heart has a normal morphology, demonstrating that the cardiac phenotype of the global KO is a secondary effect of the lack of caspases in another tissue. This study describes how the lack of caspases specifically in the myocardium supposes a reduction in proliferation, which implies an inferior number of cardiomyocytes, which finally forms a smaller heart. Moreover, our results demonstrate that DKO mice compensate the deficit of cardiomyocytes by developing a mild hypertrophy; the development of this hypertrophy is accompanied by a change in gene expression tendency, showing an adaptive change of these hearts with age. It seems that the proliferative problem in the DKO hearts is related to an increase in the inflammatory response, which could be inducing the expression of genes implicated in the deregulation of proliferation, like Serpina3. By means of the over-expression of non-catalytic caspases we demonstrated that this non-apoptotic function of the caspases is independent of their catalytic activity.
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Blázquez, Vilas Susana. « Estudi immunohistoquímic de les caspases en el càncer de mama. Relació amb altres factors pronòstics ». Doctoral thesis, Universitat Rovira i Virgili, 2005. http://hdl.handle.net/10803/8714.
Texte intégralRésumé :
El càncer de mama és, actualment, el tumor més freqüent en dones i correspon al 22% de tots els càncers que es produeixen en aquest sexe.En les comarques de Tarragona, es diagnostiquen uns 280 nous casos amb una taxa d'increment anual del 2,2%.
Fins fa una dècada la mortalitat per aquest tipus de càncer era molt elevada, actualment ha disminuït gràcies sobretot als programes de cribatge i detecció precoç.
Es coneixen múltiples factors de risc que intervenen en el desenvolupament del càncer de mama, en els quals s'hi inclouen factors dietètics i determinats estils de vida, alteracions genètiques, principalment en dos gens coneguts com són el BRCA1 i el BRCA2, i també factors hormonals.
Tots ells han estat estudiats àmpliament per tal de poder evitar que es produeixi el carcinoma, però tot hi així es continua desenvolupant el tumor i encara, avui en dia moltes dones en moren per la seva causa.
Un cop el càncer de mama s'ha produït cal veure'n quin en serà el seu pronòstic en funció de determinats paràmetres. Des d'aquesta vessant, s'han estudiat els diferents factors pronòstics per poder preveure quin en serà el curs i evolució de la malaltia i veure si es pot aplicar algun tipus de tractament específic en cada cas concret. En l'estudi de les relacions entre els factors pronòstics com la trobada de nous, en el què es basa la tesi.
S'ha vist, tal i com moltes publicacions han confirmat, que els càncers de mama que tenen més apoptosi (mort cel·lular programada) tenen pitjor pronòstic. Això és degut a què aquests tumors presenten, concomitantment, un índex de proliferació cel·lular molt més elevat i per tant són més agressius. En el procés de l'apoptosi hi intervenen una sèrie de proteases de la cisteïna conegudes com a CASPASES que, activades de forma seqüencial, desencadenen l'apoptosi.
En el treball s'han valorat dues de les més de deu caspases conegudes (la caspasa 3 i la caspasa 6) per veure si intervenen el en pronòstic de les pacients amb càncer de mama. A més a més s'han valorat d'altres factors com són l'índex de proliferació cel·lular (ki-67) i el percentatge de cèl·lules apoptòtiques, mitjançant la tècnica de TUNEL.
L'estudi s'ha realitzat sobre 210 casos de Carcinoma Ductal Infiltrant (CDI) de mama en estadis operables quirúrgicament (pT1-pT2), diagnosticats en l'Hospital Universitari Joan XXIII de Tarragona en el període comprès entre 1988 i 2001.
De cada cas s'han recollit dades del tumor com la mida tumoral, el grau de diferenciació histològica, la presència de metàstasis als ganglis limfàtics del buidament de l'aixella i la presència de necrosi tumoral en el component infiltrant.
També s'ha realitzat de cada cas, la tècnica de TUNEL per calcular el percentatge de cèl·lules i/o cossos apoptòtics i les tincions immunohistoquímiques tant per valorar les caspases com l'índex de proliferació cel·lular. El total de cèl·lules que expressaven aquests marcadors s'han especificat en percentatges.
Els resultats obtinguts en el nostre estudi mostren que, en l'anàlisi multivariat, l'estat dels ganglis limfàtics i l'atipia cel·lular són factors pronòstics independents tant per la recidiva com per la mortalitat, mentre que la mida del tumor només és factor pronòstic independent per la recidiva tumoral.
A més a més, en aquest treball, l'índex apoptòtic i l'expressió immunohistoquímica tant de les caspases com de l'índex de proliferació cel·lular no han esdevingut factors pronòstics independents ni per la recidiva tumoral ni per la mortalitat de la pacient.
Aquests resultats mostren que continuen essent els coneguts clàssicament com a factors pronòstics els que tenen importància en el pronòstic de les pacients.
Així doncs, s'amplia la línia d'investigació de l'apoptosi i els diferents elements que intervenen en tot el procés, i seran necessaris d'altres estudis per poder conèixer completament el comportament de les caspases i veure si modificant la seva actuació podem canviar el decurs de la malaltia.
Nowadays, breast cancer is the most common cancer in women and it corresponds to 22% of all cancers in females. In the Tarragona area, nearly 280 new cases are diagnosed with an annual increase tax of 2.2%.
During the last decade, mortality due to this cancer was very high, at present it has decreased specially by screening programs and an early detection.
There are some risk factors involved in breast cancer development such as diet factors and some life styles, genetic alterations, mainly in two genes known as BRCA1 and BRCA2, and hormonal factors.
All of them have been widely studied to avoid a cancer progression, however, new breast cancers cases continue appearing and many women died by its fault.
Once the breast cancer has appeared, it is important to know which will be its prognosis which depends on some intrinsic and extrinsic tumour features. From this point of view, some different prognostic factors have been studied in order to predict the course and the evolution of this tumour and to see if we could do any special treatment in each case. In this important aspect is based the present study.
Many publications have proved that breast cancers with a high apoptosis index (programmed cell death) have a better prognosis compared with the same type of cancer with less or any apoptosis. This feature seems to be related to the high proliferation index that breast cancer with high apoptosis have, so consequently, its behaviour is worst.
Many elements take part in the apoptotic process, some of them are the Caspases, cisteine proteases which are activated sequentially and are the main point in the apoptotic process..
In this work two from more than ten caspases have been studied (caspase 3 and caspase 6) to see if they have any paper in breast cancer prognosis. We have evaluated some other factors such as cell proliferation index (ki67) and the average of apoptotic cells done by TUNEL technique.
The study includes 210 cases of Ductal breast cancer in operable stages (pT1 - pT2) which were diagnosed in Joan XXIII Hospital in Tarragona between 1988 - 2001.
We have collected some information from each cases such as tumour size, histological differentiation degree, the presence or absence of lymph node metastasis and the presence or absence of tumoral necrosis in the infiltrating component.
We have evaluated from each case, the number of apoptotic cells or bodies by TUNEL technique and we have done immunohistochemical studies to evaluate the caspases' expression as the proliferation index. The results have been expressed on percentage.
In the multivariate analysis our results show that lymph node status and cell atipism are independent prognostic factors for recurrence and mortality. On the other hand, the tumour size is only independent prognostic factor for recurrence.
Moreover, in this study, the apoptotic index and the immunohistochemical expression of caspases and cell proliferation index have not turned out to be an independent prognostic factors neither recurrence nor mortality.
These results show that classic prognostic factors known until now are the most important factors to predict the evolution of the illness.
More studies will be necessary more studies in this field to know completely the caspases behaviour and to see if changing its functions, the course of the breast cancer could change.
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Abulafia, Denise P. « Inflammatory Mechanisms After Thromboembolic Ischemic Stroke in Mice ». Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_dissertations/122.
Texte intégralRésumé :
Stroke induces multiple pathological sequelae directly affecting neuronal survival and eliciting short and long-term deficits in behavioral outcome. Most of stroke models utilized to investigate these pathological consequences are based on pure cerebral ischemia models. However, human thromboembolic stroke is characterized by a complex multifactorial response that involves the activation of the cerebral microcirculation by the occluding thrombus. Here, we have characterized a novel mouse model of tromboembolic stroke that mimics most of the clinical aspects of the human pathology. The common carotid artery thrombosis (CCAT) model produces consistent and reproducible infarcts and triggers an inflammatory response comparable to other well established models of stroke. Several of the pathological consequences of cerebral ischemia are triggered by focal inflammatory processes that occur early after the ischemic event. Cerebral inflammation is initiated by an early release of pro-inflammatory cytokines. These active cytokines promote the recruitment of inflammatory cells from the blood cerebral circulation into the brain parenchyma and subsequent release of additional amounts of inflammatory cytokines. This exacerbated cytokine response result in further irreversible neuronal and histopathological damage. Cytokines interleukyne-1 beta (IL-1 beta) and interleukyne-18 (IL-18) maturation requires the presence of active caspase-1. Activation of caspase-1 in the peripheral immune response involves the recruitment of several caspase-1 molecules into a macromolecular complex termed the inflammasome. Cerebral ischemia triggers the synthesis and activation of caspase-1. However, the cellular mechanisms associated to the activation of caspase-1 in the ischemic brain remain to be elucidated. In this study, we demonstrate that the NLRP1-inflammasome composed by capase-1, ASC (apoptosis-associated speck-like protein containing a caspase-activating recruitment domain) and NLRP1 (NLR (nucleotide binding, leucine-rich repeat) is assembled following the ischemic event. Moreover, we have characterized the cellular distribution of the inflammasome proteins in the normal and the ischemic brain. Data from this investigation suggest that six to twenty four hours following CCAT the inflammasome complex is assembled in neurons while microglia, macrophages and astrocytes form this complex at 7 days following cerebral ischemia. On the basis of these findings we next investigated whether inhibition of the inflammasome complex reduces the inflammatory response after ischemia. Neutralization of NLRP1 utilizing a specific antibody, revealed decreased activation of caspase-1 and IL-1 beta and reduced histopathological damage within the ischemic brain. Thus, the inflammasome complex is a major contributor of the inflammatory response following cerebral ischemia and inhibition of this complex may be a novel therapeutic target for reducing the pathological consequences of stroke.
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Vakkala, née Mustonen M. (Merja). « Apoptosis in breast lesions ». Doctoral thesis, University of Oulu, 2000. http://urn.fi/urn:isbn:9514256506.
Texte intégralRésumé :
Abstract
In this work the extent of apoptosis was studied in a set of 504 benign and malignant breast lesions to elucidate its role in breast tumor development and progression. Also the correlation of apoptosis with estrogen and progesterone receptor positivity, cell proliferation and patients' prognosis was studied. The breast lesions were also analyzed immunohistochemically with antibodies to apoptosis regulating proteins bcl-2 and bax, and caspases 3, 6 and 8. In addition, the immunohistochemical expression of NO• synthesizing enzyme iNOS in relation to apoptosis and angiogenesis was studied. Furthermore, the expression of the antioxidative enzyme MnSOD was studied in relation to apoptosis and cell proliferation.
According to the results, the apoptotic index was lowest in benign breast lesions. It was higher in in situ carcinomas, where a gradual increase in the extent of apoptosis from grade I to III in situ carcinoma was seen. The apoptotic index in invasive carcinomas was higher than in in situ carcinomas, and also in invasive carcinomas there was a gradual increase in apoptosis from grade I to III carcinomas. The apoptotic index was highest in recurrent carcinomas.
Strong bcl-2 expression was usually found in benign breast lesions but the immunoreactivity decreased in in situ and invasive carcinomas. There was a significant inverse association between bcl-2 immunoreactivity and the extent of apoptosis. Low bcl-2 immunoreactivity also associated with estrogen- or progesterone receptor negativity. In contrast, bax expression did not show any significant association with apoptosis, hormone receptors or the histologic types of tumors. Strong cytoplasmic caspase 3, 6 and 8 immunoreactivity was found in most carcinomas. It was weaker in in situ carcinomas and only weak immunoreactivity could be seen in benign breast lesions. There was a significant association between the extent of apoptosis and caspase immunoreactivity.
iNOS expression was found in both tumor and stromal cells. iNOS expression in tumor cells was more frequently found in invasive than in in situ carcinomas. Its expression correlated significantly with a high apoptotic index and high vascularization of the lesion. There was significantly less MnSOD immunoreactivity in invasive breast carcinomas compared to in situ carcinomas or benign hyperplasias. MnSOD immunoreactivity did not associate with the extent of apoptosis, but there was a marginal inverse association between cell proliferation and MnSOD expression.
Increased apoptosis was significantly associated with a high cell proliferation, and inversely associated with a positive estrogen status. A high apoptotic index (< 0.50%) was associated with a decreased survival of the patients.
The results of this study show that apoptosis plays a decisive role in the development and progression of breast carcinoma. It is influenced not only by apoptosis regulating proteins, such as bcl-2 and caspases, but also by the estrogen receptor status. Apoptosis was also associated with iNOS positivity, the effect of which is mediated through increased NO• production. In line with the suggested role of MnSOD as a tumor suppressor gene, its expression was downregulated in invasive breast carcinoma. In conclusion, the association of apoptosis with patient survival in breast carcinoma may be secondary to its association with tumor cell proliferation and high tumor grade, not necessarily suggesting any causal association between apoptosis and survival.
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Kapoor, Varun. « Mechanism of reversal of Alzheimer's disease A-beta induced neuronal degeneration in cultured human SHSY cells using a neurotrophic ependymin mimetic ». Link to electronic thesis, 2007. http://www.wpi.edu/Pubs/ETD/Available/etd-071607-181533/.
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Fortunato, Franco. « CHRONIC ETHANOL CONSUMPTION INHIBITS MULTIPLE APOPTOTIC PATHWAYS IN THE RAT PANCREATIC ACINAR CELL ». UKnowledge, 2003. http://uknowledge.uky.edu/gradschool_diss/257.
Texte intégralRésumé :
Multiple lines of experimental evidence demonstrate that chronic alcoholconsumption causes mitochondrial injury, as well as acinar cell oxidative and metabolicstress. Alcoholics are more susceptible to acute and chronic pancreatitis. Despite alcoholrelatedacinar cell injury, apoptosis, or programmed cell death, appears to be reduced inacinar cells rather than increased, as is seen in the liver.This work describes the possible mechanisms through which alcohol affects theacinar cell apoptosis pathways in the rat pancreas. Two apoptotic pathways wereinvestigated: (1) receptor-mediated apoptosis via Fas/FasL and caspase-8, and (2)mitochondrial-mediated apoptosis via Bcl-2/Bax and caspase-9. Both pathways canactivate the final apoptosis executer caspase-3. Using the Lieber-DeCarli alcohol/controldiet, rats fed alcohol for 14 weeks had a significant decrease of key mediators of theFas/Fas ligand receptor-mediated pathway, while the mitochondria-associated apoptoticpathway is inappropriately deactivated. In addition, this study describes the mRNAexpression of inflammatory cytokines, such as IL-1??, IL-6, TNF??, IL-18 and TGF??,which are reported to influence inflammation and apoptosis. The anti-inflammatoryeffects of alcohol were confirmed with decreased expression of regulatory cytokinesincluding IL-1??, IL-18, TGF?? and IL-6 in alcohol-fed rats.Alcohol appears to block apoptosis in the pancreas through multiple mechanisms.Activity of the Fas/Fas ligand receptor-mediated pathway appears to be suppressed at thelevel of caspase-8, with further inhibition by down-regulation of caspase-3. Despiteknown acinar cell stress and mitochondria injury, the mitochondria-mediated apoptoticpathway was not activated. This data suggest that alcohol consumption suppresses theremoval of mitochondria injured acinar cells, promoting apoptosis resistance, and mayincrease the susceptibility to pancreatitis. The increased susceptibility to pancreatic injurywas further investigated by using lipopolysaccharide (LPS). Alcohol exacerbates LPSinducedpancreatoxicity by enhanced pancreatic apoptosis. The attenuation of apoptosisby ethanol increased the threshold of apoptosis in response to LPS and acceleratesapoptosis. Here it is hypothesized that alcoholics are more susceptible to endotoxinmediatedacute pancreatitis and the response is more severe than in non-alcoholics.
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Boujrad, Hanan. « Mort cellulaire programmée indépendante des caspases médiée par AIF : rôle de l'histone H2AX et de sa forme phosphorylée γ-H2AX ». Paris 6, 2011. http://www.theses.fr/2011PA066457.
Texte intégralRésumé :
La mort cellulaire programmée (MCP) est un processus fondamental au sein des organismes. Des dérégulations de la MCP sont impliquées dans diverses pathologies dont les cancers. L'apoptose, caractérisée par l'activation de protéases spécifiques, les caspases, était considérée au départ comme l'unique mode de MCP. Néanmoins, depuis une quinzaine d'années, de nouveaux types de MCP indépendants des caspases ont été décrits. Ces voies alternatives de MCP constituent un intérêt clinique potentiel afin de contourner la résistance tumorale aux traitements ciblant la voie caspase-dépendante. Au sein du laboratoire, nous étudions une voie de mort cellulaire indépendante des caspases et de la protéine p53 (mutée dans de nombreux cancers) et associée au dommage à l'ADN induit par le N-methyl-N'-nitro-N-nitrosoguanidine, un agent alkylant de l'ADN. La protéine AIF (Apoptosis-Inducing Factor) est un des acteurs essentiels de cette voie. Lors du processus de mort cellulaire, AIF, ancrée dans la mitochondrie, est transloquée au niveau du cytosol puis redistribuée au noyau où elle induit la fragmentation de l'ADN. Mon travail de thèse a consisté en l'élucidation des mécanismes moléculaires impliquant AIF, qui est dépourvue d'activité nucléase, dans le processus de chromatinolyse. Ainsi, nous avons pu démontrer la formation d'un complexe entre l'histone H2AX, AIF et l'endonucléase cyclophiline A, capable de dégrader l'ADN des cellules mourantes. La phosphorylation de H2AX au niveau de la sérine 139 (gamma-H2AX) est rapide et essentielle au processus de mort. En conséquence, la dernière partie de ma thèse a été consacrée à l'identification des kinases responsables de cette phosphorylation.
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Dorstyn, Loretta Esterina. « The identification and characterisation of two novel Drosophila caspases, DRONC and DECAY ». Title page, contents and abstract only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phd718.pdf.
Texte intégralRésumé :
Includes a list of publications co-authored by the author during the preparation of this thesis. Thesis amendments in back leaf. Includes bibliographical references (leaves 123-168). The studies described concentrate on the cloning and characterisation of the two Drosophila caspases, DRONC and DECAY
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Sané, Alain-Théophile. « Rôle et fonction des caspases lors de l'apoptose induite par la chimiothérapie ». Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0023/NQ51970.pdf.
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Dillon, Christopher P. « Elucidating the role of effector caspases in immune development using lentiviral RNAi ». Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/34196.
Texte intégralRésumé :
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2006.Includes bibliographical references.
Caspases play an important role in apoptosis, or programmed cell death. In particular, three highly related effector caspases, caspases-3, -6, and -7, translate upstream death signals into the physical manifestations of apoptosis by proteolytically cleaving structural and enzymatic targets. However, it is not clear what specific role each individual caspase plays in apoptosis or whether interaction between them is important. We used RNA interference (RNAi) to examine their roles in immune cells. RNAi has revolutionized the field of mammalian genetics by expediting the interrogation of gene function. Endogenous genes are targeted for silencing by the introduction of double stranded RNAs, known as short interfering RNAs (siRNAs), through a mechanism that is well conserved across many species. While this technique has been used successfully in tissue culture experiments, our studies focused on extending the use of RNAi into immune cells. Our initial experiments demonstrated that primary T cells were capable of RNAi-based gene silencing, but were difficult to introduce siRNAs into. Therefore, more robust techniques for the stable and efficient introduction of siRNAs into primary immune cells and animal models were required.
(cont.) Viral vectors, which can infect a wide variety of cell types and drive consistent transgene expression, provide a potential delivery vehicle for short hairpin RNAs (shRNAs), an alternative form of double stranded RNA produced within the target cell. Thus, we designed a lentiviral vector system for delivering shRNAs and used the vector to generate transgenic knockdown animals. Further experiments enhanced this vector system by enabling tissue- or temporal-specific transgene or shRNA expression as well as reducing variegated viral expression. Using these lentiviral RNAi vectors, we began to assess the role of effector caspases in the immune system. We generated T cell lines in which the effector caspases were ablated individually or simultaneously by RNAi and tested whether these cells were resistant to apoptosis. Of the three effector caspases, only silencing of caspase-3 protected against cell death in T cells, whereas simultaneous knockdown of caspase-6 or caspase-7 with caspase-3 provided no additional protective effect against apoptosis. We also generated transgenic caspase-7 knockdown animals and found that this caspase might influence B cell development.
by Christopher P. Dillon.
Ph.D.
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Lawrence, Clare Patricia. « The role and regulation of caspases during T cell activation and proliferation ». Thesis, University of Leicester, 2006. http://hdl.handle.net/2381/30779.
Texte intégralRésumé :
In the present study, the effects of two caspase inhibitors, z-VAD-FMK and z-IETD-FMK, on T cell activation and proliferation were compared to the negative control, z-FA-FMK. All three compounds inhibited T cell proliferation, blast formation, CD25 expression, IL-2 signalling and nuclear translocation of the NF-kappaB subunit, p65. However, unlike z-VAD-FMK and z-IETD-FMK, z-FA-FMK inhibited IL-2 and IFN-gamma secretion and blocked cell cycle entry. Furthermore, although both z-VAD-FMK and z-IETD-FMK inhibited Fas-induced caspase activation, they had no effect on caspase-8 and -3 processing during T cell activation. In contrast, z-FA-FMK, which did not inhibit caspase processing during apoptosis, blocked caspase-8 and -3 processing in activated T cells. This suggests that peptidyl-fluoromethylketones have pleiotropic immunosuppressive properties which may not involve the processing of caspase-8 or -3. In addition, these data suggest that the processing of caspases is regulated differently during T cell activation compared to apoptosis. To further characterise the role of caspase-8 during T cell activation, an activation-induced cell death (AICD) model using caspase-8-/- Jurkat T cells was examined. In addition, the involvement of FADD, the docking protein for caspase-8, was also investigated. Caspase-8-/- Jurkat T cells were resistant to AICD induced by PMA and ionomycin, whereas FADD-/- Jurkat T cells underwent TNF-alpha-mediated necrosis. These data suggest that caspase-8 but not FADD is required for the T cell activation signalling pathway and also implicate TNF-alpha in AICD in the absence of the Fas-signalling pathway. In conclusion, the results suggest that non-specific effects of caspase inhibitors are involved in the inhibition of T cell activation and proliferation and that the regulation of caspases during T cell activation is different from that during apoptosis.
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Lafont, Élodie. « Rôles des caspases initiatrices et des sphingomyéline synthases dans l'apoptose induite par CD95L et TRAIL ». Toulouse 3, 2011. http://thesesups.ups-tlse.fr/1353/.
Texte intégralRésumé :
La mort cellulaire par apoptose est un mécanisme effecteur de la réponse immunitaire anti-tumorale. La liaison de ligands, dont TRAIL et CD95L, produits par des cellules immunitaires, sur des récepteurs de mort (DR pour Death Receptor), exprimés par les cellules tumorales, permet l'induction de l'apoptose. Ceci met en jeu différents événements dont la formation du DISC (Death Inducing Signalling Complex) et l'activation des caspases. De plus, le taux intracellulaire de céramide, un sphingolipide pro-apoptotique, augmente au cours de cette signalisation. L'objectif de cette thèse a été de clarifier le rôle des caspases initiatrices et du céramide dans l'apoptose induite par CD95L et TRAIL. Le rôle causal de la caspase 10, caspase initiatrice, dans l'induction de mort par CD95L est controversé. Nos travaux indiquent que cette protéase est impliquée dans la mort induite par CD95L en présence ou non de zVAD-fmk, un inhibiteur des caspases. Par ailleurs, nous montrons que la sphingomyéline synthase 1 (SMS1), qui synthétise de la sphingomyéline à partir de céramide, est inhibée de façon caspase-dépendante dans la signalisation de CD95. La SMS1 module l'induction de l'apoptose en réponse à CD95L et TRAIL. Ainsi, la surexpression de la SMS1 confère une protection vis-à-vis de la mort induite par ces ligands, tandis que la diminution de son expression sensibilise des cellules cancéreuses. Ce rôle protecteur dépendrait de la modulation de la formation du DISC et de la voie apoptotique mitochondriale. L'inhibition de cette enzyme pourrait donc permettre de sensibiliser des cellules cancéreuses à la mort induite par des agonistes des DR en modulant plusieurs étapes de l'apoptoseApoptotic cell death is an effector mechanism involved in immune responses, and, particularly in anti-tumoral immune response. Binding of ligands, such as TRAIL and CD95L, which are produced by immune cells, on DR (Death Receptors) expressed by tumor cells, induces apoptosis. This involves, in particular, DISC (Death Inducing Signalling Complex) formation and caspases activation. Moreover, an increase of intracellular level of ceramide, a pro-apoptotic sphingolipid, has been observed during this signalling and might be involved in cell death induction. The aim of this PhD was to clarify initiator caspases and ceramide roles in CD95L and TRAIL induced apoptosis. Initiator caspase 10 involvement in CD95L-induced cell death is still controversed. Our results indicate that this protease is indeed involved in CD95L-induced cell death as well as in CD95L induced cell death in the presence of zVAD-fmk, a caspase inhibitor. Moreover, we show that sphingomyelin synthase 1 (SMS1), which is responsible for the synthesis of sphingomyelin from ceramide, is inhibited in CD95 signalling, in a caspase-dependent way, and more precisely in a caspase-8-dependent way. SMS1 could modulate CD95L- and TRAIL-induced cell death. Indeed, SMS1 overexpression is protective against CD95L- and TRAIL- induced cell death, whereas down-regulating SMS1 by RNA interference sensitizes cancer cells. Our results point out that SMS1 protective role might depend on DISC formation and apoptotic mitochondrial pathway modulations. Sphingomyelin synthesis inhibition might therefore be an original way to sensitize cancer cells towards DR agonists via putative apoptotic signalling modulations at several steps
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Wang, Hong. « The proto-oncogene c-Kit inhibits tumor growth by behaving as a dependence receptor ». Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1172/document.
Texte intégralRésumé :
C-Kit est généralement considéré comme un récepteur à tyrosine kinase et comme un proto-oncogène, dont la surexpression et la mutation conduisent à une progression tumorale médiée par son activité kinase. En clinique, les traitements ciblant l’activité kinase de c-Kit, comme l’Imatinib (Gleevec), ont été largement utilisés pour traiter les patients atteints de maladies liées à c-Kit. Alors que le rôle de c-Kit comme proto-oncogène ne fait aucun doute, certaines études et analyses de bases de données diffèrent avec l’idée d’un rôle pro-tumoral de c-Kit, laissant penser à un rôle différent de c-Kit dans le cancer. Ici, nous montrons que c-Kit appartient à la famille des récepteurs à dépendance, de la même façon que d’autres récepteurs de la famille des tyrosine kinases tel que MET, RET et TrkC. En absence de son ligand Stem Cell Factor (SCF), au lieu de rester inactif, c-Kit déclenche l’apoptose, qui peut être renforcée par l’invalidation de son activité kinase. En parallèle, nous montrons que c-Kit est capable de se lier à la caspase-9 et de l’activer. De plus, à la manière d’autres récepteurs à dépendance, c-Kit est aussi clivé par des protéases de type caspase sur son résidu acide aspartique D816, qui est nécessaire à son activité pro-apoptotique. La mutation du site D816 inhibe l’interaction entre c-kit et la caspase-9 et invalide l’activité pro-apoptotique de c-Kit. De façon intéressante, la mutation D816 est l’une des mutations les plus communes de ce récepteur dans la plupart des cancers liés à c-Kit, et cette mutation favorise la résistance au traitement Gleevec. Nous montrons aussi que la surexpression de c-Kit invalidé pour son activité kinase est capable d’inhiber la croissance tumorale dans des modèles animaux, alors que la mutation du site D816 empêche son effet suppresseur de tumeur. En outre, nous avons développé un outil permettant de bloquer l’interaction entre SCF et c-Kit, déclenchant l’activité pro-apoptotique de c-Kit dans les cancers positifs pour ce récepteur. En utilisant l’activité pro-apoptotique de c-Kit, en combinaison avec des inhibiteurs de kinases comme le Gleevec, nous proposons une nouvelle stratégie thérapeutique. En conclusion, nous démontrons que c-Kit est un membre de la famille des récepteurs à dépendance, présentant une activité pro-apoptotique, et pouvant être utilisé comme un outil alternatif dans le cadre d’un traitement contre le cancerC-Kit has been generally considered as a receptor tyrosine kinase and a proto-oncogene, whose upregulation and mutation lead to tumor progression through its kinase activity. Clinically, drugs targeting the kinase activity of c-Kit, such as Imatinib (Gleevec), have been wildly used to treat patients with c-Kit related diseases. While the role of c-Kit as a proto-oncogene is of no doubt, some research reports and database analysis do not fit well the tumor promoting role of c-Kit, indicating a possible different role of c-Kit in cancer. Here, we show that c-Kit belongs to the dependence receptor family, similarly to other receptor tyrosine kinases such as MET, RET and TrkC. In the absent of its ligand SCF (stem cell factor), instead of staying inactive, c-Kit triggers apoptosis, which can be enhanced by silencing its kinase activity. Besides, we have shown that c-Kit is able to bind and activate caspase-9. Moreover, similarly to other dependence receptors, c-Kit is also cleaved by caspases-like protease at aspartic acid residue D816, which is crucial for its pro-apoptotic activity. The mutation of D816 site inhibits the c-Kit/caspase-9 binding and silences the pro-apoptotic activity of c-Kit. Of interest, c-Kit D816 mutation is one of the most common mutation of this receptor in many c-Kit related cancers and it promotes resistance against Gleevec treatment. We also show that overexpression of kinase mutated c-Kit is able to inhibit tumor growth in animal models, while the mutation of D816 site impairs the tumor suppressing activity. Furthermore, we develop a tool to block the SCF/c-Kit interaction, which unleashes the pro-apoptotic activity of c-Kit in cancers expressing this receptor. By using the pro-apoptotic activity of c-Kit, in combination with kinase inhibitors like Gleevec, we propose a novel therapeutic strategy. In conclusion, we demonstrate that c-Kit is a member of dependence receptor family, harboring intrinsic pro-apoptotic activity, which can be used as an alternative tool in cancer treatment