Global ETD Search

11	The ABC of the cell cycle: roles of the mammalian Cdc25 isoforms / Lundgren, Andreas. January 2006 (has links) Lic.-avh. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 3 uppsatser.
12	From cells to organs the developmental challenge of multicellular organisms / Hebeisen, Michaël. January 1900 (has links) Thesis (Ph.D.). / Written for the Dept. of Biology. Title from title page of PDF (viewed 2009/06/09). Includes bibliographical references.
13	Criblage d'inhibiteurs réversibles et irréversibles des phosphatases CDC25s par spectrométrie de masse : Application à des extraits d'origine végétale / Screening of reversible and irreversible inhibitors of CDC25 phosphatases by mass spectrometry : Application to vegetable extracts Sibille, Estelle 18 October 2013 (has links) Les protéines CDC25 (Cell Cycle Division 25) sont des régulateurs clés de la progression du cycle cellulaire et leur surexpression a été reportée dans de nombreux types de cancers. Leur inhibition apparait donc intéressante dans le cadre de traitements anticancéreux. L'objet de ces recherches a été de développer un test de criblage permettant de détecter les inhibiteurs réversibles et irréversibles des CDC25s, puis d'appliquer ce test à des extraits végétaux. La première partie implique la spectrométrie de masse par désorption/ionisation laser assistée par matrice couplée à un détecteur à temps de vol (MALDI-TOFMS) afin de détecter les molécules se liant aux CDC25s avec une liaison faible (inhibiteurs réversibles). La deuxième partie de ce test beaucoup plus innovante consiste à mettre en évidence les ligands se liant avec une liaison plus forte (inhibiteurs irréversibles) aux CDC25s. Pour cela, une étape de digestion trypsique des protéines est réalisée, puis l'étude de l'empreinte peptidique massique est procédée sur le digest afin de déceler les inhibiteurs irréversibles. En parallèle, nous nous sommes intéressés à l'application de ce test à des extraits végétaux dans le but d'identifier de nouveaux inhibiteurs des CDC25s. L'activité inhibitrice de CDC25s de ces extraits est également évaluée in vitro grâce à des tests biologiques visant à compléter les premiers résultats obtenus lors du criblage par spectrométrie de masse. De ces travaux il résulte qu'une molécule encore non connue pour son activité sur CDC25s a montré un potentiel effet inhibiteur de ces protéines et cytotoxique sur lignées cellulaires humaines / The CDC25s phosphatases are key regulators of the physiological cell cycle progression. Their overexpression has been reported in a significant number of cancers and their inhibition appears to be an interesting strategy for treatments. We propose here a rapid screening test allowing the detection of reversible and irreversible CDC25 inhibitors. The test is based on the incubation of the candidate molecules with the human CDC25 proteins followed by an ultrafiltration step. The retentate is then directly analyzed by MALDI-TOFMS to detect reversible inhibitors or submitted to PMF analysis to reveal irreversible inhibitors. In parallel we applied this test to vegetable extracts in order to identify novel CDC25 inhibitors. The CDC25s inhibitory activity of these extracts is also evaluated in vitro thanks to biological tests. It results from this work that one molecule never known for its activity on the CDC25s shows a potential inhibitory effect and is cytotoxic on human cellular lineage Protéines CDC25 Traitement du cancer Criblage Inhibiteurs Extraits végétaux 616.994 061 572.792
14	Studies on the adaptational strategies to the heat stress in Saccharomyces cerevisiae and the reconstruction of thermotolerance / 酵母Saccharomyces cerevisiaeの熱適応戦略の解明と熱耐性の再構築 Satomura, Atsushi 23 March 2017 (has links) 京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第20439号 / 農博第2224号 / 新制\|\|農\|\|1049(附属図書館) / 学位論文\|\|H29\|\|N5060(農学部図書室) / 京都大学大学院農学研究科応用生命科学専攻 / (主査)教授植田充美, 教授間藤徹, 教授喜多恵子 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM Saccharomyces cerevisiae Thermotolerance CDC25 gene Geneme editing CRISPR Nickase system 610
15	Les phosphates CDC25 constituent-elles des cibles importantes en cancérologie : Des inhibiteurs de l'activité enzymatique vers les inhibiteurs de l'interaction entre CDC25 et leurs substrats CDK-Cycline / Targeting CDC25 phosphatases : from inhibitors of the enzymatic activity towards inhibitors of the protein-protein interaction between CDC25 and CDK/Cyclin Sarkis, Manal 28 November 2012 (has links) Les phosphatases CDC25 sont des éléments-clé de la régulation du cycle cellulaire chez les eucaryotes; elles activent par une double déphosphorylation les complexes CDK/cyclines permettant ainsi la progression dans les différentes phases du cycle. Leur sur-expression, observée dans des cancers très fréquents, est corrélée à une forte agressivité des tumeurs et un mauvais pronostic ce qui en fait des cibles d’intérêt en cancérologie. Deux nouvelles séries d’inhibiteurs ont été développées à partir d’une thiazolopyrimidinone (TZP), capable d’inhiber l’activité des CDC25, et préalablement identifiée par l’équipe. La première série a été obtenue par dimérisation de deux noyaux thiazolones conduisant à des inhibiteurs avec des CI50 de l’ordre du micromolaire sur CDC25B plus actifs que les mono-thiazolones, ces composés étant sélectifs vs PTP1B et VHR. De plus, ces dimères semblent interagir avec le site actif et la poche de liaison des inhibiteurs. Une deuxième série d’analogues de thiazolidin-4-one a été obtenue par simplification de la structure TZP. Une réaction à quatre composants, utilisant l’énergie micro-onde, a été développée pour préparer rapidement des inhibiteurs de CDC25B avec des CI50 de l’ordre du micromolaire. Enfin, une approche originale pour inhiber CDC25 en ciblant l’interaction CDC25/CDK-Cycline a débutée. Un crible in silico/in vitro sera réalisé afin d’identifier de petites molécules inhibitrices de cette interaction. Des études préliminaires pour la mise en place d’outils permettant l’évaluation de l’affinité de ces molécules pour le site de reconnaissance de CDK2 ont été engagées. / CDC25 phosphatases are key regulators of the cell cycle and its checkpoints. Hence, they are required to dephosphorylate and thus activate the Cdk/Cyclin complexes triggering progression through the different phases. Over-expression of CDC25 has been demonstrated in a large number of human tumors and is often associated with aggressiveness and poor clinical prognosis. CDC25 phosphatases may therefore represent attractive targets for anti-cancer therapy. Starting from a thiazolopyrimidinone (TZP) structure, previously reported as CDC25 inhibitor in our laboratory, two series of new compounds have been developed. Dimerisation of the thiazolone scaffold led to bis-thiazolone derivatives with inhibitory activities in the micromolar range greater than that observed for the mono-thiazolones. Moreover, most of these compounds were selective CDC25 inhibitors. A second scaffold was designed by opening of the pyrimidine ring of the TZP, leading to thiazolidine-4-one derivatives that inhibit CDC25B activities with values of IC50 in the micromolar range. A four-component reaction, using micro-wave irradiation, was developed to rapidly prepare these compounds. Finally, an approach aiming at inhibiting the interactions between phosphatase CDC25 and its substrate CDK2 was engaged. Several virtual chemical libraries will be screened in silico, and the small molecules candidates selected will be assessed for their binding affinity using an in vitro assay, that we sought to develop. Cancer Phosphatases CDC25 Inhibiteurs Bis-thiazolone Thiazolidin-4-one Réaction multi-composant Irradiation microonde Cancer Phosphatases CDC25 Inhibitors Bis-thiazolone Thiazolidin-4-one Multi-component reactions Microwave irradiation 612.0150 1
16	The Role of Cell Cycle Machinery in Ischemic Neuronal Death Iyirhiaro, Grace O. 09 October 2013 (has links) Ischemic stroke occurs as a result of a lack or severe reduction of blood supply to the brain. Presently therapeutic interventions are limited and there is a need to develop new and efficacious stroke treatments. To this end, a great deal of research effort has been devoted to studying the potential molecular mechanisms involved in ischemic neuronal death. Correlative evidence demonstrated a paradoxical activation of the cell cycle machinery in ischemic neurons. The levels and activity of key cell cycle regulators including cyclin D1, Cdk2 and Cdk4 are upregulated following ischemic insults. However, the functional relevance of these various signals following ischemic injury was unclear. Accordingly, the research described in this thesis address the functional relevance of the activation of the cell cycle machinery in ischemic neuronal death. The data indicate that the inhibition of Cdk4 protects neurons from ischemia-induced delayed death, whereas abrogation of Cdk5 activity prevents excitotoxicity-induced damage in vitro and in vivo. Examination of upstream activators of mitotic-Cdks showed that Cdc25A is a critical mediator of delayed ischemic neuronal death. Investigation of the potential molecular mechanism by which cell cycle regulators induced neuronal death revealed perturbations in the levels and activity of key downstream targets of Cdk4. The retinoblastoma protein family members, pRb and p130 are increasingly phosphorylated following ischemic stresses. Importantly, p130 and E2F4 proteins are drastically reduced following ischemic insults. Additionally, E2F1 association with promoters of pro-apoptotic genes are induced while that of E2F4 is reduced. These changes appear to be important determinants in ischemic neuronal death. Cumulatively, the data supports the activation of the cell cycle machinery as a pathogenic signal contributing to ischemic neuronal death. The development of neuroprotectant strategies for stroke has been hampered in part by its complex pathophysiology. Previous research indicated that flavopiridol, a general CDK-inhibitor, is unable to provide sustained neuroprotection beyond one week following cerebral ischemia. The potential benefit of combining flavopiridol with another neuroprotectant, minocycline, was explored. The data indicate that while this approach provided histological protection 10 weeks after insult, the protected neurons are not functional due to progressive dendritic degeneration. This evidence indicates that targeting cell cycle pathways in stroke while important must be combined with other therapeutic modalities to fully treat stroke-induced damage. Cell Cycle Cell death Neuronal death Stroke Cerebral Ischemia Cdks Cdc25 E2F4 p130 pRb Neuroprotection Inflammation Flavopiridol Minocycline C-Myb B-Myb Excitotoxicity Cdk4 Cyclin D1 Cdk5
17	The Role of Cell Cycle Machinery in Ischemic Neuronal Death Iyirhiaro, Grace O. January 2013 (has links) Ischemic stroke occurs as a result of a lack or severe reduction of blood supply to the brain. Presently therapeutic interventions are limited and there is a need to develop new and efficacious stroke treatments. To this end, a great deal of research effort has been devoted to studying the potential molecular mechanisms involved in ischemic neuronal death. Correlative evidence demonstrated a paradoxical activation of the cell cycle machinery in ischemic neurons. The levels and activity of key cell cycle regulators including cyclin D1, Cdk2 and Cdk4 are upregulated following ischemic insults. However, the functional relevance of these various signals following ischemic injury was unclear. Accordingly, the research described in this thesis address the functional relevance of the activation of the cell cycle machinery in ischemic neuronal death. The data indicate that the inhibition of Cdk4 protects neurons from ischemia-induced delayed death, whereas abrogation of Cdk5 activity prevents excitotoxicity-induced damage in vitro and in vivo. Examination of upstream activators of mitotic-Cdks showed that Cdc25A is a critical mediator of delayed ischemic neuronal death. Investigation of the potential molecular mechanism by which cell cycle regulators induced neuronal death revealed perturbations in the levels and activity of key downstream targets of Cdk4. The retinoblastoma protein family members, pRb and p130 are increasingly phosphorylated following ischemic stresses. Importantly, p130 and E2F4 proteins are drastically reduced following ischemic insults. Additionally, E2F1 association with promoters of pro-apoptotic genes are induced while that of E2F4 is reduced. These changes appear to be important determinants in ischemic neuronal death. Cumulatively, the data supports the activation of the cell cycle machinery as a pathogenic signal contributing to ischemic neuronal death. The development of neuroprotectant strategies for stroke has been hampered in part by its complex pathophysiology. Previous research indicated that flavopiridol, a general CDK-inhibitor, is unable to provide sustained neuroprotection beyond one week following cerebral ischemia. The potential benefit of combining flavopiridol with another neuroprotectant, minocycline, was explored. The data indicate that while this approach provided histological protection 10 weeks after insult, the protected neurons are not functional due to progressive dendritic degeneration. This evidence indicates that targeting cell cycle pathways in stroke while important must be combined with other therapeutic modalities to fully treat stroke-induced damage. Cell Cycle Cell death Neuronal death Stroke Cerebral Ischemia Cdks Cdc25 E2F4 p130 pRb Neuroprotection Inflammation Flavopiridol Minocycline C-Myb B-Myb Excitotoxicity Cdk4 Cyclin D1 Cdk5
18	Part 1 Design, Synthesis and Bioactivity of a Phosphorylated Prodrug for the Inhibition of Pin1; Part 2 Conformational Specificity of Cdc25c Substrate for Cdc2 Kinase using LC-MS/MS Zhao, Song 18 January 2008 (has links) The phosphorylation-dependent PPIase (peptidyl prolyl isomerase), Pin1 (Protein interacting with NIMA#1), has been found to regulate cell cycle through a simple conformational change, the cis-trans isomerization of phospho-Ser/Thr-Pro amide bonds. A variety of key cell cycle regulatory phosphoproteins, including Cdc25 phosphatase,Cdc27, p53 oncogene, c-Myc oncogene, Wee1 kinase, Myt1 kinase, and NIMA kinas, have been confirmed as substrates of Pin1. Pin1 was also observed to be overexpressed in a variety of cancer cell lines, and the inhibitors of Pin1 showed antiproliferative activities towards these cancer cells. These results implied that Pin1 might serve as a potential anti-cancer drug target. Besides, Pin1 has an important neuroprotective function and represents a potential new therapeutic agent for Alzheimer's disease. In order to understand the interaction between Pin1 and Cdc25c and the role of Pin1 in the mechanism for the regulation of mitosis, two amide isosteres, Ser-Ψ[(Z)CH=C]-Pro-OH and Ser-Ψ[(E)CH=C]-Pro-OH were incorporated into two peptidomimetics derived from human Cdc25c. Phosphorylation of these two peptidomimetics by the incubation with Cdc2 was studied using LC-MS/MS technique. It was found that Cdc2 kinase was conformationally specific to its Cdc25c substrate. Only the trans conformer of Cdc25c at its Ser168-Pro position can be recognized and phosphorylated by Cdc2 kinase, thereby creating the binding site for Pin1. In an effort to improve the cell permeability of the charged inhibitors of Pin1, bisPOM (pivaloyloxymethyl) prodrug moiety was introduced to mask the phosphate group of Fmoc-pSer-Ψ[(Z)CH=C]-Pro-(2)-N-(3)-ethylaminoindole, which is one inhibitor of Pin1. Fmoc-pSer-Ψ[(Z)CH=C]-Pro-(2)-N-(3)-ethylaminoindole and its bisPOM prodrug were synthesized efficiently starting with Boc-Ser-Ψ[(Z)CH=C]-Pro-OH in 24% and 12% yields respectively. The charged inhibitor showed a moderate inhibition towards Pin1 (IC50 = 28.3 μM). Its antiproliferative activity towards A2780 ovarian cancer cells (IC50 = 46.2 μM) was significantly improved by its bisPOM prodrug (IC50 = 26.9 μM), which is comparable to the IC50 of the charged inhibitor towards Pin1 enzymatic activity. These results not only established the bisPOM strategy as an efficient prodrug choice for Pin1 inhibitors, but also added additional evidence for Pin1 as a potential anticancer drug target. / Ph. D. peptidomimetics cell cycle Cdc2 conformation Cdc25 Ser-trans-Pro Ser-cis-Pro Pin1 isosteres LC-MS/MS assay inhibition kinase phosphorylation
19	Study of the regulation and signalling of cdk2-Cyclin o complexes during apoptosis Roset i Huguet, Ramon 04 April 2008 (has links) The aim of this thesis is the characterization of a protein involved in apoptosis. Our group has identified an early step common to different forms of intrinsic apoptosis stimuli. This step requires de novo synthesis of a novel Cyclin, Cyclin O, that upon apoptosis induction in lymphoid cells forms active complexes, primarily with Cdk2. Cyclin O expression precedes glucocorticoid and gamma radiation-induced apoptosis in vivo in mouse thymus and its overexpression induces apoptosis in cultured cells. Knocking down the endogenous expression of Cyclin O by shRNA leads to the inhibition of glucocorticoid and DNA damage-induced apoptosis while leaving CD95 death receptor mediated apoptosis intact. This data demonstrates that apoptosis induction in lymphoid cells is one of the physiological roles of Cyclin O and it does not act by perturbing a normal cellular process such as the cell cycle. In addition we have identified c-Myb a substrate of Cdk2-Cyclin O complexes and we show that c-Myb is downregulated during apoptosis of lymphoid cells. / L'objectiu d'aquesta tesi és la caracterització d'una proteïna involucrada en l'apoptosi. El nostre grup ha identificat un pas primerenc comú en diversos estímuls apoptòtics de la ruta intrínseca. Aquest pas requereix la síntesi de novo d'una nova Ciclina, Ciclina O, que quan s'indueix apoptosi en cèl·lules limfoides forma complexes actius majoritàriament amb Cdk2. L'expressió de la Ciclina O és prèvia a l'apoptosi induïda per glucocorticoids i radiació gamma i la seva sobreexpressió indueix apoptosi en cultius cel·lulars. La baixada dels nivells d'expressió de la Ciclina O endògena amb shRNA provoca una inhibició de l'apoptosi induïda per glucocorticoids o agents que danyen el DNA, mentre que l'apoptosi mediada pel receptor CD95 es manté intacta. Aquests resultats demostren que la inducció d'apoptosi en cèl·lules limfoides és una de les funcions fisiològiques de la Ciclina O i que no es deu a una pertorbació de processos cel·lulars normals com ara el cicle cel·lular. A més a més, hem identificat c-Myb com a substrat dels complexes Cdk2-Ciclina O i demostrem que els nivells de c-Myb baixen durant l'apoptosis de cèl·lules limfoides. Doble híbrid en llevat Dany al DNA Ciclina Apoptosis Yeast two Irbid WEHI7.2 Translation Transcription Thymus Thymocytes siRNA Programmed cell death p53 Mitochondria Mouse Embryonic Fibroblasts Lymphocytes Glucocorticoids Gamma radiation Etoposide DNA-damage Cyclin c-Myb Cdk Cdc25 Caspases Bim Bid BH3-only Bcl-2 Apoptosis Etopòsit Fibroblasts Embrionaris de Ratolí Glucocorticoids Limfòcits Mitocondri Mort cel·lular programada Radiació gamma Timòcits Timus Traducció Transcripció 57 61

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