Дисертації з теми "CDKIs"
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Henderson, Andrew. "Isosteres of sulfonamide inhibitors of cyclin-dependent kinases (CDKs)." Thesis, University of Newcastle Upon Tyne, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.512187.
Повний текст джерелаMarchetti, Francesco. "Structure-activity relationships for alkoxypirimidine inhibitors of cyclin-dependent kinases (CDK’s)." Thesis, University of Newcastle Upon Tyne, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.556141.
Повний текст джерелаLolli, Graziano. "Cdks at the interface of cell cycle and and transcription regulation." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426389.
Повний текст джерелаChiurato, Matteo. "Synthèse de tétrahydropyrido-[isoindolones/isoquinolones/indolizinones] pour l'élaboration d'inhibiteurs de CDks." Orléans, 2007. http://www.theses.fr/2007ORLE2069.
Повний текст джерелаDelmas, Christelle. "Modes de régulation de l'inhibiteur de CDKs, p27kip1, par les MAPKsp42/p44." Toulouse 3, 2003. http://www.theses.fr/2003TOU30006.
Повний текст джерелаBettayeb, Karima. "Optimisation et caractérisation de nouveaux inhibiteurs pharmacologiques de kinases cycline-dépendantes (CDKs)." Rennes 1, 2008. http://www.theses.fr/2008REN1S025.
Повний текст джерелаCyclin-dependent kinases (CDKs) are key regulators of cell division cycle (CDK1, 2, 3, 4, 6, 7), apoptosis (CDK1, 5), and transcription (CDK7, 9). Pharmacological inhibitors of CDKs constitute a new family of potential antitumor agents: ten are under clinical trials, among which roscovitine, was discovered in our laboratory. My thesis is about identification, optimisation and characterization of biochemical and cellular effects of three new kinase inhibitory classes: 7-bromo-indirubins (7BIO), meriolin and new analogs of roscovitine (N&N1 and C&R8). 7BIO induces non-apoptotic cell death through an unknown mechanism (no release of cytochrome C, nor caspase activation). On the other hand, meriolins and second generation roscovitine analogs induce a classical apoptosis due to CDK9 inhibition, thus leading to disappearance of the cell survival factor, Mcl-1. These three classes of chemicals display promising anti-proliferative and antitumor properties
Wołowiec, Dariusz. "Étude des CDKS et des cyclines dans le tissu lymphoïde normal et pathologique." Lyon 1, 1995. http://www.theses.fr/1995LYO1T147.
Повний текст джерелаAppleyard, Lindsey Jemma. "Overcoming financial exclusion : Community Development Finance Institutions (CDFIs) and the balancing of financial and social objectives." Thesis, University of Birmingham, 2008. http://etheses.bham.ac.uk//id/eprint/386/.
Повний текст джерелаBaïdi, Feriel. "Simplicity and complexity in cell cycle control." Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B021.
Повний текст джерелаThe cyclin-dependent protein kinases (CDKs) are at the core of cell cycle control. In fission yeast, cell proliferation is regulated by CDK1/Cdc2 in association with the four cyclins Cdc13, Cig1, Cig2 and Puc1 at different stages of the cell cycle. However, this complex endogenous system can be replaced by a minimal module consisting of a fusion between Cdc2 and Cdc13 in the absence of G1/S cyclins. Surprisingly, this minimal CDK network drives the entire cell cycle in a wild type manner. Since a number of aspects of cell cycle control in fission yeast appear to be dispensable, we asked why similarly simplified circuits were not selected over the complex endogenous network during evolution. This led us to investigate the limits of such minimal systems, in particular when challenged by different stresses. Unexpectedly, we uncovered that simplification of the CDK network confers resistance to replication stress. We showed that this phenotype is independent from the CDK inhibitor Rum1 and the existing checkpoint pathways. It solely relies on operating the entire cell cycle with a single cyclin, Cdc13, and is associated with reduced genome instability when replication is challenged. However, it is not the consequence of changes in replication organisation along the chromosomes. Our data suggest that G1/S cyclin-associated Cdc2 activity may represent an alternative as yet unknown means of modulating cellular response to DNA stress. We also took advantage of a derivative of the minimal cell cycle network, in which Cdc2 is made sensitive to specific chemical inhibition. As a result, CDK activity can be externally modulated and cell cycle phases can be precisely controlled. Using this system, we re-visited the interplay between CDK and periodic transcription, a highly conserved process that is critical for proper cell proliferation. In contrast with previous studies in budding yeast, we demonstrate that periodic transcription in fission yeast is not independent from cell cycle progression. On the contrary, our work reveals that cell cycle transcriptional oscillations rely on quantitative changes in CDK activity levels. We therefore propose a new model, in which cell cycle progression and periodic transcription are intimately coupled through their common dependency on a unique input, namely CDK activity levels
Tikad, Abdellatif. "Développement de nouvelles pyrido[3,2-d]pyrimidines polyfonctionnalisées : application à la synthèse d’inhibiteurs de CDKs." Orléans, 2008. http://www.theses.fr/2008ORLE2079.
Повний текст джерелаKim, Jin Ah. "Le rôle du MAPK (Mitogen-Activated Protein Kinase) et CDKs dans la phase G2/M." Université Joseph Fourier (Grenoble), 2008. http://www.theses.fr/2008GRE10172.
Повний текст джерелаCell cycle checkpoints ensure genomic stability by delaying cell cycle progression in response to stress or DNA damage. G2 checkpoint guards entry into mitosis while the spindle checkpoint prevents ce Ils from entering anaphase until ail chromosomes are properly aligned. Ln this reports, we studied the role of MAPKs (Mitogen-Activated Protein Kinases) and the cdk inhibitor, p21 in G2 and M phase. MAPKs are important mediators of cellular responses to a variety of extracellular stimuli. Previous reports have shown that MAPK cascade is essential for entry into mitosis. Our results show that three MAPK members have different effects on G2 and M phase. ERKs (extracelluar signal-regulated kinases) do not have an effect on G2 to M progression but they regulate the spindle checkpoint by inhibiting APC activity. We also found that p38 and JNKs (c¬ Jun N-terminal Kinases) regulate G2-M transition. P38 activation delays cells in G2. The G2 delay by p38 involves activation of MAPKAPK2 and inactivation of cdc2. The G2 delay by inhibition of JNKs involves cdk2 activation and cdc2 inactivation. Inhibition of JNK activity in G2 cells leads to genomic instability. Cells undergo multiple round of DNA replication without undergoing mitosis resulting in an increase in DNA ploidy. This is probably due to inappropriate loading of MCMs (minichromosome maintenance) on chromatin during G2. The presence of Cdk2 activity in G2 may lead polyploidy in JNK inhibited condition
Stott, Francesca Joanne. "Analysis of the INK4 family of cyclin dependent kinase inhibitors, in the mammalian cell cycle." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322001.
Повний текст джерелаCarter, Ayesha DonNell. "Loss of Chk1 Function and Exogenous Expression of Cyclin A1/Cdk2 Results in Apoptosis after the MBT in Early Xenopus laevis Embryos." Diss., Virginia Tech, 2005. http://hdl.handle.net/10919/27644.
Повний текст джерелаPh. D.
Banerjee, Monisha Debika. "An investigation into the biological role of Pak1 phosphorylation by Cdks in neurones and mitotic cells." Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413667.
Повний текст джерелаMartinez, Anne-Marie. "Etude fonctionnelle de la CAK, la kinase activatrice des complexes CDKs-cyclines, identifiée chez le Xénope." Montpellier 1, 1997. http://www.theses.fr/1997MON1T001.
Повний текст джерелаPetersen, Philippe Alexandre Divina. "Simulações computacionais da interação de kinases e ligantes derivados de oxindol." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/43/43134/tde-22012019-234658/.
Повний текст джерелаMolecular modeling studies of the interaction of oxindol based ligands (isaepy, isapn [Cu(isapn)]²,isaenim and SU9516) with Cyclin Dependent Kinases proteins (CDK1 and CDK2) are presented here. CDK1 and CDK2 catalyze the phosphorylation of specific groups in proteins and inhibition of its activities implies in induction of cancer cells apoptosis. The goal is to determine which ligands increase the inhibition of ATP (adenosine triphosphate) into ADP (adenosine diphosphate) synthesis which occurs inside the CDK1 and CDK2 active site. We analyze the influence of the Cu ion on increasing the inhibitory activity in isapn ([Cu(isapn)]² metal complex). Comparisons between the results obtained from studies of the isapn and [Cu(isapn)]² inserted into the ATP binding site of CDK1 with measurements of gel electrophoresis were performed. The hyperfine coupling at Cu ion in [Cu(isapn)]² in different chemical environments are here obtained and the results are compared with EPR measurements. This work aims to contribute to the development of new ligands which increase the inhibition of the synthesis of ATP into ADP in the CDKs moreover we aim to assist in the reduction of the costs of measurements that are based on trial and error aproaches.
Udayasankar, Subalekha. "Investigation of Automated Population and Maintenance of a Resource Database using Web-based Screen Scraping and Web Services." Miami University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=miami1177689101.
Повний текст джерелаRibas, i. Fortuny Judit. "Estudi de l'apoptosi induïda per inhibidors farmacològics de les CDKS. Caracterització dels sinergismes amb taxoides i nutlina-3." Doctoral thesis, Universitat de Lleida, 2005. http://hdl.handle.net/10803/8078.
Повний текст джерелаEn aquest treball, hem mostrat que la línia neuroblàstica de les SH-SY5Y i la promielocítica de les HL60, morien apoptòticament en resposta a ambdós fàrmacs. Una caracterització més extensa del procés, va evidenciar que la sobre expressió de Bcl-2 o Bcl-XL no conferien resistència. En canvi, la inhibició general de les caspases amb z-VAD-fmk, frenava parcialment la mort. En conseqüència, vam hipotetitzar que ens trobàvem davant d'una via extrínseca d'apoptosi, dependent de l'activació de la caspasa 8 (CASP8) o de la caspasa 10 (CASP10). Tanmateix, les CASP8/10 no s'expressen a les SH-SY5Y ja que els seus gens han estat metilats, i és més, no vam observar que es reexpressessin en resposta a l'olomoucina o la roscovitina. En conclusió, la implicació al nostre paradigma experimental d'una via extrínseca canònica d'apoptosi va ser descartada. D'altra banda, la inhibició de la síntesi de proteïnes protegia les SH-SY5Y de l'apoptosi. Curiosament, vam observar l'existència de sinergisme de rescat entre el z-VAD-fmk i ,per exemple, la cicloheximida, fet que suggeria l'existència de diferents vies apoptòtiques en diferents subpoblacions del cultiu cel·lular. La manca de toxicitat del tractament amb PD98059 o UO126, dos inhibidors de la via Erk1/2, anava en contra de que la inhibició de Erk1/Erk2 fos la causa de l'apoptosi. És més, el tractament amb olomoucina i roscovitina induïa la fosforilació i subseqüent activació de les Erk1/2. Sorprenentment, al nostre model, l'isoolomoucina, un isòmer inactiu de l'olomoucina, causava els mateixos efectes sobre les ERKs. Basant-nos en els resultats d'iso-olomoucina, vam concloure que la fosforilació de les ERKs i la seua subseqüent activació, no estaven implicats en els fenòmens d'apoptosi, proliferació i diferenciació. Finalment, vam mostrar que les SH-SY5Y diferenciades esdevenien resistents a l'olomoucina i a la roscovitina, fet que recolzava el paper de la inhibició de les CDKs en tant que esdeveniment iniciador de la cascada apoptòtica. D'altra banda, l'olomoucina i la roscovitina són cada cop més estudiats en el context de la teràpia combinatòria enfront del càncer. Als nostres treballs, hem utilitzat la R-roscovitina, un dels dos estereoisòmers de la roscovitina. La combinació amb el docetaxel (DTX) no era sinèrgica induint mort. En canvi, la R-roscovitina sensibilitzava les SH-SY5Y a l'apoptosi induïda per la nutlina-3, un nou i prometedor f-armac inductor de la via p53.
La olomoucina y la roscovitina son dos inhibidores de las cinasas dependientes de ciclinas (CDKs) cuyo mecanismo de acción es competir con el ATP por la unión a la enzima. Presentan una alta selectividad
"in vitro"ante la CDK1, 2, 5, 7, 9 y las ERKs. Este perfil inhibidor les confiere amplias perspectivas en la terapia antitumoral. En este trabajo, hemos mostrado que la línea de las SH-SY5Y, derivada de neuroblastoma, y la de las HL-60, derivada de una leucemia promielocítica, morían apoptoticamente en respuesta a ambos fármacos. Una caracterización más amplia del proceso apoptótico, evidenció que la expresión forzada de Bcl-2 o de Bcl-XL no conferían resistencia ante ninguna de nuestras drogas. En cambio, sí se hacían parcialmente más resistentes cuando eran tratadas con un inhibidor general de las caspasas (z-VAD-fmk). En consecuencia, nuestra hipótesis fue que nos hallábamos ante una apoptosis por vía extrínseca iniciada por la caspasa 8 (CASP8) y/o la caspasa 10 (CASP10). Curiosamente, dichas caspasas no se expresan en las SH-SY5Y debido a un proceso de metilación génica, y pudimos ver que el tratamiento tampoco inducía su reexpresión. En conclusión, descartamos que las SH-SY5Y iniciasen una vía extrínseca canónica en respuesta a nuestras drogas. Por otro lado, la inhibición de la síntesis proteica en nuestro modelo frenaba la apoptosis. Es más, el z-VAD-fmk junto con, por ejemplo, la cicloheximida, presentaban un sinergismo en el rescate. Esto sugería la coexistencia en nuestro cultivo de distintas subpoblaciones capaces de iniciar diferentes vías apoptóticas. El tratamiento con PD98059 o UO126, dos inhibidores de la via de Erk1/2, se mostró inocuo a la hora de inducir muerte, por lo cual descartamos que la inhibición de Erk1/2 fuera la responsable de la apoptosis. Sorprendentemente, el estudio del estado de fosforilación de Erk1/2, nos permitió constatar que éstas se activaban en respuesta a la olomoucina y la roscovitina. Más sorprende aún, resultó el hecho que la iso-olomoucina, un isómero inactivo de la olomoucina, causara los mismos efectos sobre Erk1/2. Esto nos permitió afirmar que no existía correlación entre la fosforilación de Erk1/2 y la inhibición de las CDKs. En base principalmente a los resultados de la iso-olomoucina, pudimos afirmar que la fosforilación de las ERKs y su subsiguiente activación, no se correlacionaban con la apoptosis, proliferación y diferenciación celular. Finalmente, evidenciamos que las SH-SY5Y diferenciadas se volvían resistentes a la olomoucina y a la roscovitina, hecho a favor de que la inhibición de las CDKs fuera el evento iniciador de la cascada apoptótica. Alternativamente, la olomoucina y la roscovitina están siendo cada vez más estudiadas en el contexto de la terapia combinatoria frente al cáncer. En nuestros experimentos, utilizamos también la R-roscovitina, uno de los dos estereoisómeros de la roscovitina. En su combinación con el docetaxel (DTX), no observamos sinergismo. El caso contrario sucedi´o cuando fue administrada junto a la nutlina-3, un nuevo y prometedor inductor de p53. Vimos como la R-roscovitina sensibilizaba las SH-SY5Y a la apoptosis inducida por la nutlina-3.
Olomoucine and roscovitine are two ATP-competing inhibitors of cyclin-dependent kinases (CDKs) displaying a promising profile as anticancer agents. They exhibit "in vitro"selectivity against CDK1, 2, 5, 7, 9 and ERKs. In this work, we have showed that SH-SY5Y neuroblastoma and HL-60 promielocytic cell lines died by apoptosis in response to both drugs. An extensive characterization of the process in SH-SY5Y cells has shown that neither Bcl-2 nor Bcl-XL overexpression conferred any resistance to both drugs. However, a partial protective effect was detected when cells were treated with a general inhibitor of caspases (z-VAD-fmk). Therefore, the involvement of an extrinsic pathway mediated by Caspase 8 (CASP8) or Caspase 10 (CASP10) could be hypothesised. CASP8/10 are known not to be expressed in SH-SY5Y because of gene silencing and we have found no re-expression was induced by either olomoucine or roscovitine. In conclusion, a canonical extrinsic pathway has been discarded in SH-SY5Y cells facing these drugs. On the other hand, protein synthesis inhibitors protected SH-SY5Y cells from apoptosis.
Interestingly, a synergism in cell protection was observed between z-VAD-fmk and, for instance cycloheximide. This suggested different apoptotic pathways occurring in distinct subpopulations of the cell culture. No lethality was found when cells were treated with either PD98059 or UO126 drugs, two inhibitors of the Erk1/2 pathway, thus discarding, this inhibition as the cause of apoptosis. Furthermore, olomoucine and roscovitine induced the phosphorylation and subsequent activation of Erk1/2 proteins.
Interestingly, iso-olomoucine, an inactive isomer of olomoucine, caused the same effect in our cell model.
Therefore, no correlation existed between Erk1/2 phosphorylation and CDK inhibition. Based mainly on the iso-olomoucine results, we concluded that phosphorylation and subsequent activation of Erk1/2 were not involved in apoptosis, proliferation and differentiation of the cells. Finally, we show that differentiated SH-SY5Y cells became resistant to either olomoucine or roscovitina, thus providing support for CDK inhibition as the initiating event of these apoptotic processes. Olomoucine and roscovitine are being increasingly studied in the context of combinatorial therapy for cancer. In our studies, we have also used R-roscovitine, the right stereoisomer of roscovitine. No synergism was found when combined with docetaxel (DTX). On the contrary, R-roscovitine sensitized SH-SY5Y cells to nutlin-3 induced apoptosis, being nutlin-3 a new promising inductor of the p53 functions.
Lólomoucine et la roscovitine sont deux inhibiteurs des kinases d´ependantes de cyclines (CDKs) qui agissent par inhibition competitive via le site d'union de l'ATP. Son profil inhibiteur est tr-es prometteur dans le traitement du cancer. Présentent une grande spécificité "in vitro"face aux CDK1, 2, 5, 7, 9 e aux ERKs. Dans ce travail, nous avons d´emontré que la lignée neuroblastique SH-SY5Y et la promyélocitique HL-60, mouraient apoptotiquement en réponse àces drogues. Une plus large caractérisation de l'apoptose dans les SH-SY5Y a mis enévidence que la surexpression de Bcl-2 ou de Bcl-XL ne se traduisait par une augmentation de la résistance au traitement. Cependant, le traitement avec un inhibiteur général des caspases (z-VAD-fmk) présentaient des effets protecteurs partiels. Au vu de ces résultats, notre hypothèse reposait sur límplication d'une voie extrinsèque d'apoptose qui d´ependait de l'activation de la caspase 8 (CASP8) ou de la caspase 10 (CASP10). Néanmoins, la m´ethylation des gènes des CASP8 et 10 dans les SH-SY5Y empèche l'expression de ces protéines et, plus encore, l'olomoucine et la roscovitine nínduiraient pas la réexpression de ces caspases. En conclusion, l'apoptose par une voie extrinsèque classique pouvait ètreécartée dans notre paradigme expérimental. D'un autre coté, les inhibiteurs de la synthèse des protéines protégeaient les SH-SY5Y de l'apoptose. De manière surprenante, on avait observé l'existence de synergie dans la protection avec z-VAD-fmk et, par exemple, le cycloheximide.
Ce fait suggérait la présence de différents sous-poupulations cellulaires dans les SH-SY5Y qui engageaient des voies apoptotiques distinctes. Le manque d'effets toxiques du PD98059 or UO126, deux inhibiteurs de la voie d'Erk1/2, avait écarté l'inhibition de Erk1/Erk2 comme la responsable de l'apoptose.
Plus encore, l'olomoucine et la roscovitine induisaient la phosphorylation et subséquente activation d'Erk1/Erk2. De manière surprenante, l'iso-olomoucine, un isomère inactif de l'olomoucine, induisait aussi la phosphorylation et l'activation dans notre modèle cellulaire. Sur base de ces résultats, nous avons conclu que la phosphorylation d'Erk1/Erk2 et son activation, n'avait pas un corr´elat avec l'apoptose, la prolifération et la différentiation cellulaire. Finalement, nous avons mis en évidence que les SH-SY5Y différentiées devenaient résistantes à l'olomoucine ou à la roscovitine. Ce fait suggérait que l'inhibition des CDKs avait un role dans le d´eclenchement de l'apoptose. Alternativement, l'olomoucine et la roscovitine sont de plus en plus étudiées dans le contexte de la th´erapie combinatoire face au cancer.
J'ai utilisé la R-roscovitine dans nos expériences, l'un des deux stéréoisomères de la roscovitine. La combinaison avec le docétaxel (DTX) n'avait pas des effets l´etaux synergiques, en revanche la R-roscovitine sensibilisait les SH-SY5Y à lápoptose par la nutline-3, un nouvel agent inducteur de la voie p53.
Ribas, i. Fortuny Judit. "Estudi de l'apoptotsi induïda per inhibidors farmacològics de les CDKS. Caracterització dels sinergismes amb taxoides i nutlina-3." Doctoral thesis, Universitat de Lleida, 2005. http://hdl.handle.net/10803/8078.
Повний текст джерелаLa olomoucina y la roscovitina son dos inhibidores de las cinasas dependientes de ciclinas (CDKs) cuyo mecanismo de acción es competir con el ATP por la unión a la enzima. Presentan una alta selectividad"in vitro"ante la CDK1, 2, 5, 7, 9 y las ERKs. Este perfil inhibidor les confiere amplias perspectivas en la terapia antitumoral. En este trabajo, hemos mostrado que la línea de las SH-SY5Y, derivada de neuroblastoma, y la de las HL-60, derivada de una leucemia promielocítica, morían apoptoticamente en respuesta a ambos fármacos. Una caracterización más amplia del proceso apoptótico, evidenció que la expresión forzada de Bcl-2 o de Bcl-XL no conferían resistencia ante ninguna de nuestras drogas. En cambio, sí se hacían parcialmente más resistentes cuando eran tratadas con un inhibidor general de las caspasas (z-VAD-fmk). En consecuencia, nuestra hipótesis fue que nos hallábamos ante una apoptosis por vía extrínseca iniciada por la caspasa 8 (CASP8) y/o la caspasa 10 (CASP10). Curiosamente, dichas caspasas no se expresan en las SH-SY5Y debido a un proceso de metilación génica, y pudimos ver que el tratamiento tampoco inducía su reexpresión. En conclusión, descartamos que las SH-SY5Y iniciasen una vía extrínseca canónica en respuesta a nuestras drogas. Por otro lado, la inhibición de la síntesis proteica en nuestro modelo frenaba la apoptosis. Es más, el z-VAD-fmk junto con, por ejemplo, la cicloheximida, presentaban un sinergismo en el rescate. Esto sugería la coexistencia en nuestro cultivo de distintas subpoblaciones capaces de iniciar diferentes vías apoptóticas. El tratamiento con PD98059 o UO126, dos inhibidores de la via de Erk1/2, se mostró inocuo a la hora de inducir muerte, por lo cual descartamos que la inhibición de Erk1/2 fuera la responsable de la apoptosis. Sorprendentemente, el estudio del estado de fosforilación de Erk1/2, nos permitió constatar que éstas se activaban en respuesta a la olomoucina y la roscovitina. Más sorprende aún, resultó el hecho que la iso-olomoucina, un isómero inactivo de la olomoucina, causara los mismos efectos sobre Erk1/2. Esto nos permitió afirmar que no existía correlación entre la fosforilación de Erk1/2 y la inhibición de las CDKs. En base principalmente a los resultados de la iso-olomoucina, pudimos afirmar que la fosforilación de las ERKs y su subsiguiente activación, no se correlacionaban con la apoptosis, proliferación y diferenciación celular. Finalmente, evidenciamos que las SH-SY5Y diferenciadas se volvían resistentes a la olomoucina y a la roscovitina, hecho a favor de que la inhibición de las CDKs fuera el evento iniciador de la cascada apoptótica. Alternativamente, la olomoucina y la roscovitina están siendo cada vez más estudiadas en el contexto de la terapia combinatoria frente al cáncer. En nuestros experimentos, utilizamos también la R-roscovitina, uno de los dos estereoisómeros de la roscovitina. En su combinación con el docetaxel (DTX), no observamos sinergismo. El caso contrario sucedi´o cuando fue administrada junto a la nutlina-3, un nuevo y prometedor inductor de p53. Vimos como la R-roscovitina sensibilizaba las SH-SY5Y a la apoptosis inducida por la nutlina-3.
Olomoucine and roscovitine are two ATP-competing inhibitors of cyclin-dependent kinases (CDKs) displaying a promising profile as anticancer agents. They exhibit "in vitro"selectivity against CDK1, 2, 5, 7, 9 and ERKs. In this work, we have showed that SH-SY5Y neuroblastoma and HL-60 promielocytic cell lines died by apoptosis in response to both drugs. An extensive characterization of the process in SH-SY5Y cells has shown that neither Bcl-2 nor Bcl-XL overexpression conferred any resistance to both drugs. However, a partial protective effect was detected when cells were treated with a general inhibitor of caspases (z-VAD-fmk). Therefore, the involvement of an extrinsic pathway mediated by Caspase 8 (CASP8) or Caspase 10 (CASP10) could be hypothesised. CASP8/10 are known not to be expressed in SH-SY5Y because of gene silencing and we have found no re-expression was induced by either olomoucine or roscovitine. In conclusion, a canonical extrinsic pathway has been discarded in SH-SY5Y cells facing these drugs. On the other hand, protein synthesis inhibitors protected SH-SY5Y cells from apoptosis.Interestingly, a synergism in cell protection was observed between z-VAD-fmk and, for instance cycloheximide. This suggested different apoptotic pathways occurring in distinct subpopulations of the cell culture. No lethality was found when cells were treated with either PD98059 or UO126 drugs, two inhibitors of the Erk1/2 pathway, thus discarding, this inhibition as the cause of apoptosis. Furthermore, olomoucine and roscovitine induced the phosphorylation and subsequent activation of Erk1/2 proteins.Interestingly, iso-olomoucine, an inactive isomer of olomoucine, caused the same effect in our cell model.Therefore, no correlation existed between Erk1/2 phosphorylation and CDK inhibition. Based mainly on the iso-olomoucine results, we concluded that phosphorylation and subsequent activation of Erk1/2 were not involved in apoptosis, proliferation and differentiation of the cells. Finally, we show that differentiated SH-SY5Y cells became resistant to either olomoucine or roscovitina, thus providing support for CDK inhibition as the initiating event of these apoptotic processes. Olomoucine and roscovitine are being increasingly studied in the context of combinatorial therapy for cancer. In our studies, we have also used R-roscovitine, the right stereoisomer of roscovitine. No synergism was found when combined with docetaxel (DTX). On the contrary, R-roscovitine sensitized SH-SY5Y cells to nutlin-3 induced apoptosis, being nutlin-3 a new promising inductor of the p53 functions.
Lólomoucine et la roscovitine sont deux inhibiteurs des kinases d´ependantes de cyclines (CDKs) qui agissent par inhibition competitive via le site d'union de l'ATP. Son profil inhibiteur est tr-es prometteur dans le traitement du cancer. Présentent une grande spécificité "in vitro"face aux CDK1, 2, 5, 7, 9 e aux ERKs. Dans ce travail, nous avons d´emontré que la lignée neuroblastique SH-SY5Y et la promyélocitique HL-60, mouraient apoptotiquement en réponse àces drogues. Une plus large caractérisation de l'apoptose dans les SH-SY5Y a mis enévidence que la surexpression de Bcl-2 ou de Bcl-XL ne se traduisait par une augmentation de la résistance au traitement. Cependant, le traitement avec un inhibiteur général des caspases (z-VAD-fmk) présentaient des effets protecteurs partiels. Au vu de ces résultats, notre hypothèse reposait sur límplication d'une voie extrinsèque d'apoptose qui d´ependait de l'activation de la caspase 8 (CASP8) ou de la caspase 10 (CASP10). Néanmoins, la m´ethylation des gènes des CASP8 et 10 dans les SH-SY5Y empèche l'expression de ces protéines et, plus encore, l'olomoucine et la roscovitine nínduiraient pas la réexpression de ces caspases. En conclusion, l'apoptose par une voie extrinsèque classique pouvait ètreécartée dans notre paradigme expérimental. D'un autre coté, les inhibiteurs de la synthèse des protéines protégeaient les SH-SY5Y de l'apoptose. De manière surprenante, on avait observé l'existence de synergie dans la protection avec z-VAD-fmk et, par exemple, le cycloheximide.Ce fait suggérait la présence de différents sous-poupulations cellulaires dans les SH-SY5Y qui engageaient des voies apoptotiques distinctes. Le manque d'effets toxiques du PD98059 or UO126, deux inhibiteurs de la voie d'Erk1/2, avait écarté l'inhibition de Erk1/Erk2 comme la responsable de l'apoptose.Plus encore, l'olomoucine et la roscovitine induisaient la phosphorylation et subséquente activation d'Erk1/Erk2. De manière surprenante, l'iso-olomoucine, un isomère inactif de l'olomoucine, induisait aussi la phosphorylation et l'activation dans notre modèle cellulaire. Sur base de ces résultats, nous avons conclu que la phosphorylation d'Erk1/Erk2 et son activation, n'avait pas un corr´elat avec l'apoptose, la prolifération et la différentiation cellulaire. Finalement, nous avons mis en évidence que les SH-SY5Y différentiées devenaient résistantes à l'olomoucine ou à la roscovitine. Ce fait suggérait que l'inhibition des CDKs avait un role dans le d´eclenchement de l'apoptose. Alternativement, l'olomoucine et la roscovitine sont de plus en plus étudiées dans le contexte de la th´erapie combinatoire face au cancer.J'ai utilisé la R-roscovitine dans nos expériences, l'un des deux stéréoisomères de la roscovitine. La combinaison avec le docétaxel (DTX) n'avait pas des effets l´etaux synergiques, en revanche la R-roscovitine sensibilisait les SH-SY5Y à lápoptose par la nutline-3, un nouvel agent inducteur de la voie p53.
Serres, Murielle. "Étude des fonctions indépendantes des cyclines/CDKs de p27Kip1 au cours de l'oncogénèse et de la progression mitotique." Toulouse 3, 2012. http://thesesups.ups-tlse.fr/1605/.
Повний текст джерелаThe cell cycle inhibitor p27Kip1 (p27) also has cyclin-CDK independent functions. Genetic evidence for these functions was provided by p27CK- knock-in mice in which p27 cannot bind or inhibit cyclin-CDK complexes. P27CK- mice have an increased incidence of tumor development in multiple organs compared to wild-type and p27-/- mice, revealing an oncogenic role for p27. In the first part of my PhD thesis, I studied the roles played by p27 during tumorigenesis. The susceptibility to urethane-induced tumorigenesis of mice either entirely lacking p27 or expressing the p27CK- allele was compared. Our results indicate a cooperation between p27CK- and activated Ras. We propose that the p27CK- protein needs to be localized in the cytoplasm in order to function as an oncogene, otherwise it just behaves similarly to a null allele. In the second part of my PhD thesis, a phenotype of multinucleation and polyploidy was identified in p27CK- mice that is not present in p27-/- animals, suggesting a role for p27 in G2/M independent of cyclin-CDK regulation. We identified the Rho effector Citron-Kinase as a p27-interacting protein in vitro and in vivo. Our data suggests that p27 may play a role during cytokinesis via the regulation of Citron-Kinase activity
Lubini, Greice. "Caracterização do Gene NtCDKG;2 Expresso no Pistilo de Nicotiana tabacum L." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/17/17135/tde-22042013-141248/.
Повний текст джерелаThe biology of plant sexual reproduction is a research field of great importance, since most of the food consumed by humans is composed of plant reproductive parts (fruits and seeds), originated by the development of fertilized pistil parts. In Nicotiana tabacum, it was identified a stigma/style-specific gene, SCI1 (Stigma/style Cell-cycle Inhibitor 1), which acts in the inhibition of cell proliferation (DePaoli et al., 2011). Through pull down assays, the interaction of the SCI1 protein with a cyclin-dependent protein kinase (CDK) was verified (Strini, unpublished). This work aimed the characterization of this new CDK, orthologous to the Arabidopsis CDKG;2. The N. tabacum corresponding sequence (NtCDKG;2) was PCR amplified, from stigmas/styles cDNAs, cloned and sequenced, which allowed the confirmation of its identity. The NtCDKG;2 expression was analyzed in the different vegetative and reproductive organs, by qRT-PCR, evidentiating an ubiquitous expression pattern. Studying the expression pattern of this gene in stigmas/styles of the twelve stages of N. tabacum flower development, it was observed that NtCDKG;2 is more expressed at the later developmental stages towards anthesis, indicating an important function of its protein in the end of pistil development. NtCDKG;2 expression analyses in stigmas/styles of N. tabacum plants with an enhanced auxin production in the pistil suggest that NtCDKG;2 is transcriptionally regulated by this hormone. The transient expression of the fusion protein NtCDKG;2-GFP, in N. tabacum leaves, evidentiated the nuclear localization of the studied protein. Stable transgenic plants overexpressing and silencing NtCDKG;2 by RNAi were also generated. Despite the high transcript levels in the plants overexpressing NtCDKG;2 and the low transcript levels in the silencing plants, macroscopic phenotypic alterations were not observed on these plants. Additionally, the expression of the NtCDKG;2 protein, with a histidine tag fused in its N-terminal, was obtained in Escherichia coli BL21(DE3)CodonPlusRP cells. Through studies performed on this work and literature analyses, it is possible to propose that NtCDKG;2 encodes a protein that is involved in the control of cell cycle at the N. tabacum stigmas/styles.
Pellegatti, Laurent. "Méthodologie en chimie hétérocyclique et application à la synthèse d'inhibiteurs de kinases." Thesis, Orléans, 2010. http://www.theses.fr/2010ORLE2046.
Повний текст джерелаCancer, one of the leading causes of death, represents today a major public health problem. Over the last few years, marine alkaloids represent a source of inspiration for chemists in order to obtain new anticancer drugs. For this purpose, as a part of our laboratory researches, analogues of marine alkaloids were synthesized possessing a tris-aromatic structure. We developed originals analogs of these alacaloïds formed by a central heterocycle core (1,2,4-triazine et imidazo[1,2-b][1,2,4,5]tetrazine) on wich is graft two arylic moiety variously substituted. Obtaining these compounds was also an opportunity to develop news synthetic methodologies. So a new Buchwald-Hartwig reaction type based on methylsulfanyl-1,2,4-triazines has been perfect, as palladocatalyzed CH arylation pathway on imidazo[1,2-b][1,2,4,5]tetrazine. A part is devoted to Groebke-Blackburn multicomponant reaction. Various pharmacological analyses were carried out in particular with inhibition of various kinases and cytotoxicity evaluation on various human cancer cell lines
Lengronne, Armelle. "Dynamique de la réplication et instabilité du génome chez la levure S. Cerevisiae en l'abscence de l'inhibiteur de CDKs, Sic1p." Paris 11, 2002. http://www.theses.fr/2002PA112087.
Повний текст джерелаSic1p belongs to the CKI family (Cyclin-Dependent-Kinase Inhibitor), like p21 or p27 in mammalian cells, and is expressed from the end of mitosis to the end of G1 phase of the cell cycle in the budding yeast S. Cerevisiae. One of the main goals of my thesis was to gain a better understanding of the molecular basis of the genomic instability observed in cells lacking the SIC1 gene. These strains show a decrease in viability, an increase of chromosome loss and are delayed in mitosis. Previous work in the laboratory had suggested, based on genetic evidences, that sic1 mutants suffer from a reduction in the number of competent replication origins. In the first part of my thesis, to better characterize potential replication defects of sic1 strains, I have developed a set of molecular, electrophoretic and microscopic techniques that allow precise monitoring of S phase progression in yeast cells using BrdU incorporation. In the second part of my thesis, using these techniques, I showed that cells lacking Sic1 initiate DNA replication from fewer origins, have an extended S phase and inefficiently separate sister chromatids during anaphase. To our surprise, sic1d cells were not retarted at metaphase as expected if the S/M checkpoint were triggered to allow completion of replication before mitosis. Sic1d mutants show a 600-fold increase in the frequency of gross chromosomal rearrangements, probably as a consequence of inappropriate entry into anaphase. We propose that precocious CDK activation causes genomic instability by altering the dynamics of S phase which then hinders normal chromosome segregation
Babar, Sandly. "Cross-talk between cell-cycle control and the environment." Phd thesis, Université de Strasbourg, 2013. http://tel.archives-ouvertes.fr/tel-00998938.
Повний текст джерелаSilva, Alessandra Renata Lente da. "Estudo estrutural de quinases dependentes de ciclinas por métodos de modelagem molecular comparativa /." São José do Rio Preto : [s.n.], 2006. http://hdl.handle.net/11449/87509.
Повний текст джерелаBanca: Andreia Machado Leopoldino
Banca: José Ramon Beltran Abrego
Resumo: As CDKs têm sido extensivamente estudadas, porque exercem papéis essenciais na regulação da proliferação celular, nos processos neuronais e transcricionais. A progressão do ciclo celular é firmemente controlada pela atividade das CDKs. Este projeto de Mestrado tem como objetivo estudar a interação das proteínas CDK8 e CDK10 com vários inibidores, e estabelecer as bases estruturais para inibição das mesmas. Foram realizadas modelagens moleculares dos complexos binários CDKs:Inibidores, utilizando como molde a estrutura da CDK2 complexada com os mesmos ligantes: ATP, flavopiridol, olomoucina e roscovitina. Para realização dessas modelagens foi utilizado o programa Parmodel, que é uma implementação paralela do programa MODELLER. Espera-se que os modelos computacionais produzam avanços no entendimento de suas estruturas, destacando-se seus sítios de ligações, para um possível estudo sobre inibidores específicos para estas CDKs.
Abstract: The CDKs have been extensively studied because of their essential role in the regulation of cell proliferation, in the neuronal process and transcription. Cell cycle progression is tightly controlled by the activity of CDKs. This master project aimed to study the interaction of the CDK8 and CDK10 with several inhibitors in order to establish the structural bases for its inhibition. Were carried out the molecular modeling of the binary complexes CDKs:Inhibitors, using as template the CDK2 structure with the following ligands and inhibitors: ATP, Flavopiridol, Olomoucine and Roscovitine. For the achievement of those modeling was utilized the Parmodel program which is a parallel implementation of the MODELLER program. One expects that the computational models produce advances in the agreement structures, showing their binding sites, for a possible study about specific inhibitors against CDKs.
Mestre
Reichl, Joachim. "Expressionsanalyse der Zellzyklusregulatorproteine der Zyklin-, CDK-, CDKI- und Rb-Familie in humanen Chondrocyten in-vitro in Abhängigkeit von Proliferation und Differenzierung." [S.l. : s.n.], 2000. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB8884750.
Повний текст джерелаGarrofé, Ochoa Xènia. "Anàlisi dels mecanismes moleculars implicats en els processos de mort cel·lular causats per Roscovitina i 7-Bromoindirubina-3'-Oxima(7BIO)." Doctoral thesis, Universitat de Lleida, 2010. http://hdl.handle.net/10803/8108.
Повний текст джерелаCASAGRANDE, FABRICE. "Mode d'action des flavonoides dans les cellules de melanome humain : regulation des kinases cdks impliquees en phase g1 ou g2 du cycle cellulaire." Toulouse 3, 2000. http://www.theses.fr/2000TOU30058.
Повний текст джерелаReichl, Joachim [Verfasser]. "Expressionsanalyse der Zellzyklusregulatorproteine der Zyklin-, CDK-, CDKI- und Rb-Familie in humanen Chondrocyten in-vitro in Abhängigkeit von Proliferation und Differenzierung / vorgelegt von Joachim Reichl." Tübingen, Käsenbachstr. 18/1 : J. Reichl, 2000. http://d-nb.info/963185918/34.
Повний текст джерелаSilva, Alessandra Renata Lente da [UNESP]. "Estudo estrutural de quinases dependentes de ciclinas por métodos de modelagem molecular comparativa." Universidade Estadual Paulista (UNESP), 2006. http://hdl.handle.net/11449/87509.
Повний текст джерелаCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
As CDKs têm sido extensivamente estudadas, porque exercem papéis essenciais na regulação da proliferação celular, nos processos neuronais e transcricionais. A progressão do ciclo celular é firmemente controlada pela atividade das CDKs. Este projeto de Mestrado tem como objetivo estudar a interação das proteínas CDK8 e CDK10 com vários inibidores, e estabelecer as bases estruturais para inibição das mesmas. Foram realizadas modelagens moleculares dos complexos binários CDKs:Inibidores, utilizando como molde a estrutura da CDK2 complexada com os mesmos ligantes: ATP, flavopiridol, olomoucina e roscovitina. Para realização dessas modelagens foi utilizado o programa Parmodel, que é uma implementação paralela do programa MODELLER. Espera-se que os modelos computacionais produzam avanços no entendimento de suas estruturas, destacando-se seus sítios de ligações, para um possível estudo sobre inibidores específicos para estas CDKs.
The CDKs have been extensively studied because of their essential role in the regulation of cell proliferation, in the neuronal process and transcription. Cell cycle progression is tightly controlled by the activity of CDKs. This master project aimed to study the interaction of the CDK8 and CDK10 with several inhibitors in order to establish the structural bases for its inhibition. Were carried out the molecular modeling of the binary complexes CDKs:Inhibitors, using as template the CDK2 structure with the following ligands and inhibitors: ATP, Flavopiridol, Olomoucine and Roscovitine. For the achievement of those modeling was utilized the Parmodel program which is a parallel implementation of the MODELLER program. One expects that the computational models produce advances in the agreement structures, showing their binding sites, for a possible study about specific inhibitors against CDKs.
Bisteau, Xavier. "Activation de la CDK4, clef de l'engagement du cycle cellulaire et carrefour des voies oncogéniques: évaluation de l'implication de la kinase activatrice des CDKs (CAK) et des phosphorylations de p21." Doctoral thesis, Universite Libre de Bruxelles, 2013. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209523.
Повний текст джерелаFigueiredo, Daniella de 1986. "Expressão de quinases dependentes de ciclinas (Cdks 1, 2, 4 e 6) em ilhotas pancreáticas de camundongos NOD (non-obese diabetic) tratados com extrato aquoso das folhas de Passiflora alata." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311760.
Повний текст джерелаDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-24T11:47:48Z (GMT). No. of bitstreams: 1 Figueiredo_Daniellade_M.pdf: 3504963 bytes, checksum: 2a5ced4957aa0233b6b6f5417ad31dc3 (MD5) Previous issue date: 2014
Resumo: A procura por novos fármacos a partir de plantas medicinais tem motivado a busca alternativa de substâncias com potencial antiinflamatório que possam auxiliar no tratamento das doenças inflamatórias, como no caso do diabetes mellitus tipo1. Como ferramenta para estudar essas substâncias que modulam a inflamação, é comum o uso de animais com propensão a desenvolver a doença, como os camundongos NOD (diabéticos não obesos). Dentre os constituintes das folhas de Passiflora alata Curtis, conhecido popularmente por maracujá doce, os flavonóides são compostos que podem atuar como antioxidantes e antiproliferativos, podendo modular a expressão de substâncias reguladoras do ciclo celular promovendo, desta forma, a sua interrupção em células em proliferação. Como resultados, nós obtivemos no grupo tratado com extrato aquoso das folhas de P. alata, redução na incidência do diabetes, aumento da expressão de insulina e diminuição do infiltrado inflamatório, estresse oxidativo e células CDK6+ em ilhotas pancreáticas. Como neste modelo animal a expressão de CDK6 está presente no infiltrado inflamatório, a sua diminuição no grupo tratado sugere que componentes nas folhas de P. alata possam atuar na inibição do ciclo celular de células inflamatórias ativadas promovendo efeito antiinflamatório e, consequentemente, diminuição na incidência do diabetes tipo 1. Visto os efeitos antiinflamatórios e consequente preservação de células beta, o estudo visa investir no desenvolvimento de novas drogas com potencial de interferir na evolução da doença, atuando desta forma como suporte no tratamento do diabetes autoimune
Abstract: The search for new medicinal drugs from plants has motivated the search for alternative potential anti-inflammatory substances that may assist in the treatment of inflammatory diseases, such as type 1 diabetes mellitus. As a tool to study these substances that modulate inflammation, is common to use animals with a propensity to develop the disease, such as NOD mice (non-obese diabetic). Among the constituents of Passiflora alata Curtis leaves, known popularly as sweet passion fruit, flavonoids are compounds that can act as antioxidants and anti-proliferative, which can modulate the expression of cell cycle regulatory substances promoting in this way, the cell cycle arrest in proliferating cells. As a result, we have obtained in the treated group with P. alata leaves aqueous extract, reduction in the incidence of diabetes, increased expression of insulin and decreased inflammatory infiltrate, oxidative stress and CDK6+ cells in pancreatic islets. As in this animal model the marking of CDK6 is present in the inflammatory infiltrate, the decreased expression of this protein in the treated group suggests that components in the leaves of P. alata may act on cell cycle inhibition of activated inflammatory cells promoting anti-inflammatory effect and reduction in the incidence of type 1 diabetes. Since the anti-inflammatory effects and consequent preservation of beta cells, the study intend to investing in the development of new drugs with the potential to interfere with the course of the disease, acting as a support in the treatment of autoimmune diabetes
Mestrado
Clinica Medica
Mestra em Clínica Médica
Virgós, Soler Ariadna. "Efecte represor de Snail en la proliferació cel·lular." Doctoral thesis, Universitat Pompeu Fabra, 2008. http://hdl.handle.net/10803/7212.
Повний текст джерелаSnail és un factor clau en la regulació dels processos EMT, tant en el desenvolupament com en la progressió tumoral gràcies a la seva capacitat de reprimir directament la transcripció de gens epitelials i promoure l'expressió de gens mesenquimals.
Uns clons estables de dues línies cel·lulars epitelials, generats en el nostre grup proliferaven més lentament a l'expressar Snail de manera que ens vam proposar descriure el mecanisme utilitzat per Snail per fer disminuir la taxa de proliferació cel.lular al ser expressat ectòpicament en cèl.lules en cultiu que havien patit una EMT.
Els resultats d'aquesta tesi indiquen que Snail bloqueja el cicle cel·lular al ser expressat en cèl·lules epitelials fent que disminueixin els nivells de proteïna CDC25A, fosfatasa que pot activar els complexes CDK-ciclina implicats en la progressió per diverses etapes del cicle. Els nostre estudi suggereix que Snail reté el mRNA de CDC25A al nucli, impedint que sigui exportat i traduit.
YERLY, MOTTA VERONIQUE. "Proliferation et cinetique tumorale : etude des marqueurs pcna, ki-67, tpot, cyclines et cdks et de leur correlation au cours de pathologies neoplasiques (doctorat : sciences de la vie et de la sante)." Besançon, 1999. http://www.theses.fr/1999BESA3702.
Повний текст джерелаLin, Ho-Pi. "Celecoxib its non-COX-2 targets and its anti-cancer effects /." Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1124114562.
Повний текст джерелаTitle from first page of PDF file. Document formatted into pages; contains xix, 94 p.; also includes graphics (some col.). Includes bibliographical references (p. 87-94). Available online via OhioLINK's ETD Center
Ali, Mohammad Mojiballah. "Centralised demand information sharing in supply chains." Thesis, Bucks New University, 2008. http://bucks.collections.crest.ac.uk/10106/.
Повний текст джерелаDixon-Clarke, Sarah. "Structure and inhibition of novel cyclin-dependent kinases." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:3c6955c9-469a-4f4b-9577-309ccb57b742.
Повний текст джерелаIyirhiaro, Grace O. "The Role of Cell Cycle Machinery in Ischemic Neuronal Death." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/26230.
Повний текст джерелаLossaint, Gérald. "Mécanismes orchestrant la sortie du cycle cellulaire opérant en G2." Thesis, Montpellier 2, 2010. http://www.theses.fr/2010MON20040/document.
Повний текст джерелаCancer is a multi-step process resulting from abrogation of several barriers to uncontrolled proliferation. They include inhibitory pathways with appropriate checkpoints that lead to reversible (quiescence) or irreversible (senescence, apoptosis) block of cell proliferation. We are especially interested in pathways orchestrating cell cycle exit that operate in the G2 phase. The first objective of this thesis was to decipher mechanisms that prevent mitosis in response to DNA damage. We found that Cdk inhibitor p21Waf1 plays a crucial role in blocking mitotic onset in normal cells; acting in tandem with checkpoint kinase Chk1, p21 inactivates mitotic Cdks and inhibits pRb phosphorylation, thereby irreversibly blocking mitotic entry. In contrast, in p53-proficient transformed cells, the induction of p21 in G2 is impaired, most likely because of deficient ATM activation. While, in some cases, Chk1 hyper-activation prevents mitosis, the absence of p21 compromises the senescence program from G2. Finally, we showed that Chk2 is dispensable for G2 arrest in both non-transformed and transformed cells (Lossaint et al., submitted). Our second objective was to elucidate the pathways that induce quiescence (G0). This reversible cell cycle exit occurs in G1, requires pRb family members and p27Kip1-dependent Cdk inactivation. Based on observations obtained in our team and the data in the literature, we hypothesized that reversible cell cycle exit program might be launched before mitosis. By using an in vitro wounding model, we showed that confluence-driven quiescence is preceded by pre-mitotic CDK inhibition by p27, cyclin D1 downregulation and reduced pre-mitotic pRb phosphorylation (Chassot et al., 2008). Moreover, our results obtained in synchronized fibroblasts that were serum-starved after release from G1/S block suggest that cyclin D1 might stimulate proliferation by keeping pocket proteins phosphorylated during G2/M progression (Lossaint et al., in preparation)
Bendjeddou, Lyamin. "Synthèse et évaluation biologique de nouveaux inhibiteurs de kinases : identification d‘inhibiteurs de kinases parasitaires." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05P615.
Повний текст джерелаPhosphorylation by protein kinases is one of the most important post-translational modification in cellular processes such as division, differentiation, proliferation and apoptosis. Kinase deregulation is associated with numerous diseases such as cancer or neurodegenerative diseases. Imidazo[1,2-b]pyridazine and imidazo[4,5-b]pyridine were prepared to inhibit protein kinases involved in diseases targeted in the laboratory. The imidazo[1,2-b]pyridazines were synthesized to identify inhibitors of CLK1 and DYRK1A, potential targets in Alzheimer's disease. Among the imidazo[1,2-b]pyridazines synthesized, several molecules were found selective of DYRKs and CLKs, with IC50 < 100 nM. A structure-activity relationship based on the synthesis of 70 molecules, led to the identification of the structural bases of the selectivity. Products were also evaluated against parasite kinases. It was possible to identify some highly potent inhibitors on PfCLK1. The aim of second part of this thesis was to optimize the synthetic process to obtain imidazo[4,5-b]pyridines, which are close analogues of roscovitine. Derivatives had proved capable of inhibiting the formation of cysts in a cellular model of polycystic kidney disease. A seven-step synthesis has led to several grams of 3,5,7-trisubstituted imidazo[4,5-b]pyridine which is now available for evaluation in vivo
Bourderioux, Aurélie. "Synthèse d'hybrides d'indolocarbazoles et de la caulersine, composés à visée antitumorale." Phd thesis, Université d'Orléans, 2007. http://tel.archives-ouvertes.fr/tel-00147916.
Повний текст джерелаDans le cadre de la recherche de nouveaux agents cytotoxiques et d'inhibiteurs de kinases toujours plus sélectifs, la structure principale des phénylcarbazoles, appartenant à la famille des indolocarbazoles, a été modifiée par introduction d'une tropone centrale, cycle à 7 chaînons porteur d'une fonction carbonyle. Les différentes voies de synthèse permettant d'accéder à cette nouvelle famille de composés appelés oxophénylarcyriaflavines ont été étudiées. La méthode de choix retenue pour l'étape finale de la synthèse est la cyclisation électrophile en position 2 de l'indole. Cette synthèse a ensuite été généralisée aux composés substitués par des groupements hydroxyles en position 5 de l'indole d'une part et en position 4' et 5' du noyau phényle d'autre part. Les 17 molécules finales ainsi synthétisées ont subi divers tests biologiques permettant d'établir les RSA de cette nouvelle famille de composés. Finalement, la méthodologie mise au point pour les oxophénylarcyriaflavines a été étendue à la synthèse de la toute première famille de composés bisindoliques possédant également une tropone centrale.
Γιαννίκου, Άννα. "Σύνθεση πυρρολικών παραγώγων ως δομικών ενδιάμεσων για τη σύνθεση νέων αναστολέων πρωτεϊνικών κινασών". Thesis, 2010. http://nemertes.lis.upatras.gr/jspui/handle/10889/4628.
Повний текст джерелаThe rapid progress made in recent years to decode the signaling pathways and important clarification cellular components involved in the genesis, development, spread of cancer, has turned an important part of scientific community towards the discovery of chemical inhibitors of cell cycle. Prominent role in this process played by cyclin-dependent kinases (cyclin dependent kinases, CDKs). The CDKs are a family of protein serine / threonine kinases that are activated in specific parts of the cell cycle. Deregulation contributes to the onset illnesses such as cancer and neurodegenerative diseases This work was aimed at the creation of small molecules that will be precursor stages to synthesize compounds which will be studied in their ability to inhibit the action of various protein kinases including the cyclin-dependent kinases (CDKs). It was possible to synthesize the compound 11 which has functional groups which, if modified properly, can give us precursor molecules for the synthesis of final compounds.
Macias, Everardo. "The role of CDKs in normal and neoplastic proliferation." 2007. http://www.lib.ncsu.edu/theses/available/etd-08082007-215157/unrestricted/etd.pdf.
Повний текст джерела林緯. "Transduced CDKI p21 induces growth arrest and inhibits apoptosis elicited by oxidative stress." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/01179191779980579820.
Повний текст джерела國立海洋大學
水產生物技術研究所
90
Abstract Microglials are resident monocyte-lineaged cells in the brain. Their characteristic feature is that they react to injury and diseases of the brain and become functionally activated and generates (ROS) reactive oxygen species. Reactive oxygen species play an important role in apoptosis under microglial cells activated. Progression through the cell cycle is regulated by cyclins and cyclin-dependent kinases (CDK). The cyclin inhibitor p21 can induce G1 arrest and block entry into S phase by inactivating CDKs. We conciude that transduction of TAT-p21 into cells resulted in the loss of CDK kinase activity, elicited an G1 cell cycle arrest, and inhibited apoptosis elicited by oxidative stress.
Κουστένης, Αθανάσιος. "Στατιστική ανάλυση σχέσης δομής δράσης πουρινικών και οξινδολικών παραγώγων". Thesis, 2012. http://hdl.handle.net/10889/6482.
Повний текст джерела-
Saini, Priyanka. "Combining gemcitabine with checkpoint kinase inhibitors to sensitize pancreatic tumors." Doctoral thesis, 2014. http://hdl.handle.net/11858/00-1735-0000-0022-5FB7-B.
Повний текст джерелаSmyers, Serena Ashley. "An assessment of the GPS L5 signal based on multiple vendor receivers." Thesis, 2011. http://hdl.handle.net/2152/ETD-UT-2011-12-4921.
Повний текст джерелаtext
Calvo, Gonzalez Llilians. "Dissection moléculaire de la sénescence cellulaire induite par le stress et la thérapie dans le cancer de l’ovaire et son impact sur la réponse des patientes." Thèse, 2015. http://hdl.handle.net/1866/13853.
Повний текст джерелаHuman ovarian cancer (OvCa) is the deadliest gynecologic malignancy and existing surgical/chemotherapeutic treatment options have been relatively static for decades. We propose that understanding OvCa cell fate decisions taken in response to chemotherapy could guide new therapeutic opportunities. Damage-induced cellular senescence is often associated with TP53 activity, which is heavily mutated in high grade serous (HGS) OvCa (>90%), the most common form of this disease. Here, using patient derived tissues, we show that primary HGS-OvCa cultures predominantly trigger CDKN2A- associated (p16INK4A isoform) senescence following exposure to stress or chemotherapy. Key senescence hallmarks including altered morphology, senescence-associated-Betagalactosidase, DNA damage, cell cycle arrest and the senescence-associated secretory phenotype were evaluated and detected in damaged cells. Using tissue microarrays built from pre- and post-treatment human HGS-OvC tissue samples with accompanying clinical data, we quantified post-treatment hallmarks of senescence including reduced cell proliferation weeks after chemotherapy. Importantly, p16INK4A expression in pretreatment HGS-OvC samples correlated with increased patients survival, suggesting for the first time that senescence-competence in human cancer cells may have a beneficial impact on treatment outcomes for patients. In order to guide the potential improvement of existing human therapies via pharmacological senescence manipulation, our results suggests that it is important to determine for many types of human cancer whether treatment-induced senescence positively or negatively impacts disease progression and patient survival.