Academic literature on the topic 'Inhibiteur de CDK'
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Journal articles on the topic "Inhibiteur de CDK"
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Mossalayi, MD, JC Lecron, P. Goube de Laforest, G. Janossy, P. Debre, and J. Tanzer. "Characterization of prothymocytes with cloning capacity in human bone marrow." Blood 71, no. 5 (May 1, 1988): 1281–87. http://dx.doi.org/10.1182/blood.v71.5.1281.1281.
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Abstract The identity of human bone marrow (BM)-derived T cell precursors with colony forming capacity has led to controversy because of contamination with mature clonogenic T cells. We achieved 2 Log elimination of mature T cells from BM using a cocktail of monoclonal antibodies: CD2, CD3, CD4, CD6, and CD8 followed by two successive baby rabbit C' treatment. T cell depleted BM can generate colonies of CD2+, CD3+, Ti+, mostly CD4+, in the presence of PHA, rIL2, and a prothymocyte differentiating activity derived from phytohemagglutinin (PHA) induced mononuclear cells. These precursors could be enriched three- to sixfold by percoll gradient centrifugation and then significantly bypass the number of contaminant mature T cells as shown by limiting dilution analysis. Colony generation by marrow precursors was inhibited by the addition of autologous T cells. This inhibition was mostly caused by the T8+ subset. CFU-TL growth was dramatically inhibited by eliminating CD7+ cells suggesting their positivity for this surface marker. These precursors needed major histocompatibility complex (MHC) II-positive cells for optimal growth but lack DR themselves.
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Mossalayi, MD, JC Lecron, P. Goube de Laforest, G. Janossy, P. Debre, and J. Tanzer. "Characterization of prothymocytes with cloning capacity in human bone marrow." Blood 71, no. 5 (May 1, 1988): 1281–87. http://dx.doi.org/10.1182/blood.v71.5.1281.bloodjournal7151281.
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The identity of human bone marrow (BM)-derived T cell precursors with colony forming capacity has led to controversy because of contamination with mature clonogenic T cells. We achieved 2 Log elimination of mature T cells from BM using a cocktail of monoclonal antibodies: CD2, CD3, CD4, CD6, and CD8 followed by two successive baby rabbit C' treatment. T cell depleted BM can generate colonies of CD2+, CD3+, Ti+, mostly CD4+, in the presence of PHA, rIL2, and a prothymocyte differentiating activity derived from phytohemagglutinin (PHA) induced mononuclear cells. These precursors could be enriched three- to sixfold by percoll gradient centrifugation and then significantly bypass the number of contaminant mature T cells as shown by limiting dilution analysis. Colony generation by marrow precursors was inhibited by the addition of autologous T cells. This inhibition was mostly caused by the T8+ subset. CFU-TL growth was dramatically inhibited by eliminating CD7+ cells suggesting their positivity for this surface marker. These precursors needed major histocompatibility complex (MHC) II-positive cells for optimal growth but lack DR themselves.
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Brown, Julia, Nikolaos Patsoukis, and Vassiliki A. Boussiotis. "PD-1 Signals Inhibit Cell Cycle Progression by Mediating Upregulation of Both KIP and INK Family of Cdk Inhibitors." Blood 116, no. 21 (November 19, 2010): 585. http://dx.doi.org/10.1182/blood.v116.21.585.585.
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Abstract Abstract 585 The PD-1 pathway plays a critical role in the inhibition of T cell activation and the maintenance of T cell tolerance. PD-1 is expressed on activated T cells and limits T cell clonal expansion and effector function upon engagement with its ligands PD-L1 and PD-L2. PD-1 signals are vital for inhibition of autoimmunity whereas PD-1 ligation by PD-L1 and PD-L2 expressed on malignant cells has a detrimental effect on tumor-specific immunity. Furthermore, PD-1 signals result in T cell exhaustion in several chronic viral infections. The mechanism via which PD-1 signals mediate inhibition of T cell expansion is currently poorly understood. Here, we sought to determine the effects of PD-1 signals on mechanistic regulation of cell cycle progression mediated via TCR/CD3 and CD28 in primary human CD4+ T cells using anti-CD3/CD28 with or without agonist anti-PD-1 mAb conjugated to magnetic beads. Cell cycle analysis by ethynyl-deoxyuridine incorporation revealed that PD-1 induced blockade of cell cycle progression at the early G1 phase. To determine the molecular mechanisms underlying the blocked cell cycle progression we examined the expression and activation of cyclins and cdks and the regulation of cdk inhibitors that counterbalance the enzymatic activation of cyclin/cdk holoenzyme complexes. Our studies revealed that PD-1 mediated signals inhibited upregulation of Skp2, the SCF ubiquitin ligase that leads p27kip1 cdk inhibitor to ubiquitin-dependent degradation, and resulted in accumulation of p27kip1. Expression of cyclin E that is induced at the G1/S phase transition, and cyclin A that is synthesized during the S phase of the cell cycle, was dramatically reduced in the presence of PD-1 signaling. Strikingly, although expression of cdk4 and cdk2 was comparable between cells cultured in the presence or in the absence of PD-1, cdk2 enzymatic activation was significantly reduced in the presence of PD-1 signaling. Smad3 is a novel critical cdk substrate. Maximum cdk-mediated Smad3 phosphorylation occurs at the G1/S phase junction and requires activation of cdk2. Phosphorylation by cdk antagonizes TGF-β-induced transcriptional activity and antiproliferative function of Smad3 whereas impaired phosphorylation on the cdk-specific sites renders Smad3 more effective in executing its antiproliferative function. Based on those findings, we examined the effects of PD-1 signaling on Smad3 phosphorylation on cdk-specific and TGF-β-specific sites using site-specific phospho-Smad3 antibodies. Compared to anti-CD3/CD28 alone, culture in the presence of PD-1 induced impaired cdk2 activity, reduced levels of Smad3 phosphorylation on the cdk-specific sites and increased Smad3 phophorylation on the TGF-b-specific site. To determine whether the differential phosphorylation of Smad3 might differentially regulate Smad3 transcriptional activity in CD4+ T cells cultured in the presence versus the absence of PD-1, we examined expression of the INK family cdk4/6 inhibitor p15, a known downstream transcriptional target of Smad3. Expression of p15 was upregulated in CD4+ T cells cultured in the presence of PD-1 but not in cells cultured in the presence of CD3/CD28-coated beads alone. These results indicate that PD-1 signals inhibit cell cycle progression by mediating upregulation of both KIP and INK family of cdk inhibitors and Smad3 is a critical component of this mechanism, regulating blockade at the early G1 phase. Disclosures: No relevant conflicts of interest to declare.
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Harper, J. W., S. J. Elledge, K. Keyomarsi, B. Dynlacht, L. H. Tsai, P. Zhang, S. Dobrowolski, C. Bai, L. Connell-Crowley, and E. Swindell. "Inhibition of cyclin-dependent kinases by p21." Molecular Biology of the Cell 6, no. 4 (April 1995): 387–400. http://dx.doi.org/10.1091/mbc.6.4.387.
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p21Cip1 is a cyclin-dependent kinase (Cdk) inhibitor that is transcriptionally activated by p53 in response to DNA damage. We have explored the interaction of p21 with the currently known Cdks. p21 effectively inhibits Cdk2, Cdk3, Cdk4, and Cdk6 kinases (Ki 0.5-15 nM) but is much less effective toward Cdc2/cyclin B (Ki approximately 400 nM) and Cdk5/p35 (Ki > 2 microM), and does not associate with Cdk7/cyclin H. Overexpression of P21 arrests cells in G1. Thus, p21 is not a universal inhibitor of Cdks but displays selectivity for G1/S Cdk/cyclin complexes. Association of p21 with Cdks is greatly enhanced by cyclin binding. This property is shared by the structurally related inhibitor p27, suggesting a common biochemical mechanism for inhibition. With respect to Cdk2 and Cdk4 complexes, p27 shares the inhibitory potency of p21 but has slightly different kinase specificities. In normal diploid fibroblasts, the vast majority of active Cdk2 is associated with p21, but this active kinase can be fully inhibited by addition of exogenous p21. Reconstruction experiments using purified components indicate that multiple molecules of p21 can associate with Cdk/cyclin complexes and inactive complexes contain more than one molecule of p21. Together, these data suggest a model whereby p21 functions as an inhibitory buffer whose levels determine the threshold kinase activity required for cell cycle progression.
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Swarbrick, Alexander, Christine S. L. Lee, Robert L. Sutherland, and Elizabeth A. Musgrove. "Cooperation of p27Kip1 and p18INK4c in Progestin-Mediated Cell Cycle Arrest in T-47D Breast Cancer Cells." Molecular and Cellular Biology 20, no. 7 (April 1, 2000): 2581–91. http://dx.doi.org/10.1128/mcb.20.7.2581-2591.2000.
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ABSTRACT The steroid hormone progesterone regulates proliferation and differentiation in the mammary gland and uterus by cell cycle phase-specific actions. The long-term effect of progestins on T-47D breast cancer cells is inhibition of cellular proliferation. This is accompanied by decreased G1 cyclin-dependent kinase (CDK) activities, redistribution of the CDK inhibitor p27Kip1among these CDK complexes, and alterations in the elution profile of cyclin E-Cdk2 upon gel filtration chromatography, such that high-molecular-weight complexes predominate. This study aimed to determine the relative contribution of CDK inhibitors to these events. Following progestin treatment, the majority of cyclin E- and D-CDK complexes were bound to p27Kip1 and few were bound to p21Cip1. In vitro, recombinant His6-p27 could quantitatively reproduce the effects on cyclin E-Cdk2 kinase activity and the shift in molecular weight observed following progestin treatment. In contrast, cyclin D-Cdk4 was not inhibited by His6-p27 in vitro or p27Kip1 in vivo. However, an increase in the expression of the Cdk4/6 inhibitor p18INK4c and its extensive association with Cdk4 and Cdk6 were apparent following progestin treatment. Recombinant p18INK4c led to the reassortment of cyclin-CDK-CDK inhibitor complexes in vitro, with consequent decrease in cyclin E-Cdk2 activity. These results suggest a concerted model of progestin action whereby p27Kip1 and p18INK4c cooperate to inhibit cyclin E-Cdk2 and Cdk4. Since similar models have been developed for growth inhibition by transforming growth factor β and during adipogenesis, interaction between the Cip/Kip and INK4 families of inhibitors may be a common theme in physiological growth arrest and differentiation.
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Foster, James S., Donald C. Henley, Antonin Bukovsky, Prem Seth, and Jay Wimalasena. "Multifaceted Regulation of Cell Cycle Progression by Estrogen: Regulation of Cdk Inhibitors and Cdc25A Independent of Cyclin D1-Cdk4 Function." Molecular and Cellular Biology 21, no. 3 (February 1, 2001): 794–810. http://dx.doi.org/10.1128/mcb.21.3.794-810.2001.
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ABSTRACT Estrogens induce proliferation of estrogen receptor (ER)-positive MCF-7 breast cancer cells by stimulating G1/S transition associated with increased cyclin D1 expression, activation of cyclin-dependent kinases (Cdks), and phosphorylation of the retinoblastoma protein (pRb). We have utilized blockade of cyclin D1-Cdk4 complex formation through adenovirus-mediated expression of p16INK4a to demonstrate that estrogen regulates Cdk inhibitor expression and expression of the Cdk-activating phosphatase Cdc25A independent of cyclin D1-Cdk4 function and cell cycle progression. Expression of p16INK4a inhibited G1/S transition induced in MCF-7 cells by 17-β-estradiol (E2) with associated inhibition of both Cdk4- and Cdk2-associated kinase activities. Inhibition of Cdk2 activity was associated with delayed removal of Cdk-inhibitory activity in early G1 and decreased cyclin A expression. Cdk-inhibitory activity and expression of both p21Cip1 and p27Kip1 was decreased, however, in both control and p16INK4a-expressing cells 20 h after estrogen treatment. Expression of Cdc25A mRNA and protein was induced by E2 in control and p16INK4a-expressing MCF-7 cells; however, functional activity of Cdc25A was inhibited in cells expressing p16INK4a. Inhibition of Cdc25A activity in p16INK4a-expressing cells was associated with depressed Cdk2 activity and was reversed in vivo and in vitro by active Cdk2. Transfection of MCF-7 cells with a dominant-negative Cdk2 construct inhibited the E2-dependent activation of ectopic Cdc25A. Supporting a role for Cdc25A in estrogen action, antisenseCDC25A oligonucleotides inhibited estrogen-induced Cdk2 activation and DNA synthesis. In addition, inactive cyclin E-Cdk2 complexes from p16INK4a-expressing, estrogen-treated cells were activated in vitro by treatment with recombinant Cdc25A and in vivo in cells overexpressing Cdc25A. The results demonstrate that functional association of cyclin D1-Cdk4 complexes is required for Cdk2 activation in MCF-7 cells and that Cdk2 activity is, in turn, required for the in vivo activation of Cdc25A. These studies establish Cdc25A as a growth-promoting target of estrogen action and further indicate that estrogens independently regulate multiple components of the cell cycle machinery, including expression of p21Cip1 and p27Kip1.
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Terada, Y., S. Inoshita, O. Nakashima, T. Yamada, M. Kuwahara, S. Sasaki, and F. Marumo. "Lovastatin inhibits mesangial cell proliferation via p27Kip1." Journal of the American Society of Nephrology 9, no. 12 (December 1998): 2235–43. http://dx.doi.org/10.1681/asn.v9122235.
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Mesangial cell proliferation is a key feature of glomerulonephritis. The hydroxymethylglutaryl-coenzyme A reductase inhibitor lovastatin is known to inhibit cell cycle progression. To determine the inhibitory mechanisms of mesangial cell proliferation by lovastatin, the cyclin-dependent kinase (CDK) activity, and expression of CDK inhibitor (p27Kip1, p21Cip1, and p16INK4) mRNA and protein were measured. Lovastatin inhibited phosphorylation of retinoblastoma protein and mesangial cell proliferation dose dependently. Lovastatin increased the p27Kip1 protein level but produced no changes in the abundance of the p27Kip1 mRNA level both in the presence and absence of mitogens. Treatment with lovastatin revealed the increment of both CDK2- and CDK4-bound-p27Kip1. The experiment using antisense oligonucleotide against p27Kip1 showed significant amelioration of lovastatin-induced cell cycle arrest. Lovastatin reduced both platelet-derived growth factor-stimulated CDK2 and CDK4 kinase activities. In conclusion, lovastatin inhibited mesangial proliferation via translational upregulation or impairment of p27Kip1 protein degradation. Lovastatin serves as a potential therapeutic approach to mesangial proliferative disease.
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Musgrove, Elizabeth A., Alexander Swarbrick, Christine S. L. Lee, Ann L. Cornish, and Robert L. Sutherland. "Mechanisms of Cyclin-Dependent Kinase Inactivation by Progestins." Molecular and Cellular Biology 18, no. 4 (April 1, 1998): 1812–25. http://dx.doi.org/10.1128/mcb.18.4.1812.
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ABSTRACT The steroid hormone progesterone regulates proliferation and differentiation in the mammary gland and uterus by cell cycle phase-specific actions. In breast cancer cells the predominant effect of synthetic progestins is long-term growth inhibition and arrest in G1 phase. Progestin-mediated growth arrest of T-47D breast cancer cells was preceded by inhibition of cyclin D1-Cdk4, cyclin D3-Cdk4, and cyclin E-Cdk2 kinase activities in vitro and reduced phosphorylation of pRB and p107. This was accompanied by decreases in the expression of cyclins D1, D3, and E, decreased abundance of cyclin D1- and cyclin D3-Cdk4 complexes, increased association of the cyclin-dependent kinase (CDK) inhibitor p27 with the remaining Cdk4 complexes, and changes in the molecular masses and compositions of cyclin E complexes. In control cells cyclin E eluted from Superdex 200 as two peaks of ∼120 and ∼200 kDa, with the 120-kDa peak displaying greater cyclin E-associated kinase activity. Following progestin treatment, almost all of the cyclin E was in the 200-kDa, low-activity form, which was associated with the CDK inhibitors p21 and p27; this change preceded the inhibition of cell cycle progression. These data suggest preferential formation of this higher-molecular-weight, CDK inhibitor-bound form and a reduced number of cyclin E-Cdk2 complexes as mechanisms for the decreased cyclin E-associated kinase activity following progestin treatment. Ectopic expression of cyclin D1 in progestin-inhibited cells led to the reappearance of the 120-kDa active form of cyclin E-Cdk2 preceding the resumption of cell cycle progression. Thus, decreased cyclin expression and consequent increased CDK inhibitor association are likely to mediate the decreases in CDK activity accompanying progestin-mediated growth inhibition.
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Salman Roghani, Roham, Ali Sanjari moghaddam, Gabrielle Rupprecht, Erdem Altunel, So Young Kim, Shannon McCall, Beatrice Thomas, Katie Ware, Jason Somarelli, and David S. Hsu. "A precision medicine drug discovery pipeline to identify dual CDK2/9 inhibition as a novel treatment for colorectal cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16056-e16056. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16056.
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e16056 Background: Colorectal cancer (CRC) is the 3rdmost common form of cancer in the US, responsible for over 50,000 death each year. Therapeutic options for advanced colorectal cancer are limited, and there remains an unmet clinical need to identify new therapies to treat this deadly disease. To address this need, we have developed a precision medicine pipeline that integrates high throughput chemical screens with matched patient-derived cell lines and patient-derived xenografts (PDXs) to identify new treatments for CRC. Methods: We used high-throughput chemical screens of 2,100 compounds across five low-passage, patient-derived CRC cell lines. These results were validated using dose-response IC50curves for CDK1, CDK2, CDK9 or CDK1/2/9 inhibitors and by siRNA-mediated knockdown of CDK9 with or without CDK2 inhibition. Cell cycle arrest analysis was performed by flow cytometry and anaphase catastrophe was analyzed by immunofluorescence staining. For in vivo studies, matched PDXs were treated with either CDK2, CDK9 or dual CDK2/9 inhibitors. Results: We identified the CDK inhibitor drug class as among the most effective cytotoxic compounds across all five CRC lines. Further analysis of the CDK inhibitor class revealed that combined targeting of CDK1, 2, and 9 was the most effective, with IC50 in the range of 110 nM to 1.2 μM. We further validated the efficacy of combined CDK2/9 inhibition using siRNA-mediated knockdown of CDK9 in the presence of a CDK2 inhibitor(CVT-313), and showed that CDK9 knockdown acted synergistically with CDK2 inhibition. Dual CDK2/9 inhibition led to significant G2/M cell cycle arrest and anaphase catastrophe. Finally, combined CDK2/9 inhibition in vivo synergistically inhibited PDX tumor growth as compared to single-agent CDK inhibitors. Conclusions: Our precision medicine pipeline revealed CDK2/9 dual inhibition as a combinatorial therapy to treat CRC and can also be used to identify new and novel therapies
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Göke, R., P. Barth, A. Schmidt, B. Samans, and B. Lankat-Buttgereit. "Programmed cell death protein 4 suppresses CDK1/cdc2 via induction of p21Waf1/Cip1." American Journal of Physiology-Cell Physiology 287, no. 6 (December 2004): C1541—C1546. http://dx.doi.org/10.1152/ajpcell.00025.2004.
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We show that the recently discovered tumor suppressor pdcd4 represses the transcription of the mitosis-promoting factor cyclin-dependent kinase (CDK)1/cdc2 via upregulation of p21Waf1/Cip1. p21Waf1/Cip1 inhibits CDK4/6 and CDK2. Decrease of CDK4/6 and CDK2 enhances the binding of pRb to E2F/DP, which in turn together bind to and repress the cdc2 promoter. Upregulation of CDK1/cdc2 accompanied by a malignant change was previously reported in colon cancer. We show that expression of pdcd4 as an indirect suppressor of CDK1/cdc2 is lost in progressed carcinomas of lung, breast, colon, and prostate. Furthermore, it seems that localization and expression of pdcd4 directly correlate with tumor progression. Finally, the CDK1/cdc2 inhibitor roscovitine reduces the proliferation of several tumor cell lines, suggesting that inhibition of CDK1/cdc2 may be a useful strategy against malignant transformation. Therefore, pdcd4 might serve as a novel target for antineoplastic therapies.
Dissertations / Theses on the topic "Inhibiteur de CDK"
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Jasinski-Grondard, Sophie. "Caractérisation d'un inhibiteur de kinases cycline-dépendantes de N. Tomentosiformis : analyse de son rôle au cours du développement de la plante." Paris 11, 2002. http://www.theses.fr/2002PA112272.
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Le développement d'une plante nécessite un contrôle précis entre prolifération cellulaire et différenciation. Le cycle cellulaire est contrôlé par des kinases dépendantes des cyclines (CDKs) dont l'activité est régulée à plusieurs niveaux, en particulier par des inhibiteurs (CKIs, cyclin dépendent kinase inhibitors). Le criblage d'une banque double hybride de la suspension cellulaire de tabac BY-2 avec une CDKA comme appât à permis l'isolement de deux ADNc, nommés NtKIS1a et NtKIS1b. Les deux ARNm proviennent d'un même gène de N. Tomentosiformis par épissage alternatif. La séquence protéique déduite de NtKIS1a présente de fortes similarités de séquence avec les CKIs de mammifères de la famille CIP/KIP, alors que ce n'est pas le cas de NtKIS1b. En accord avec cette observation, NtKIS1a mais pas NtKIS1b inhibe in vitro l'activité kinase de complexes CDK/cycline. Pour élucider le rôle de NtKIS1a et NtKIS1b au cours du développement, leur surexpression dans différentes espèces végétales a été réalisée. Les plantes d'Arabidopsis thaliana surexprimant NtKIS1b ont un phénotype sauvage, tandis que celles surexprimant NtKIS1a présentent d'importantes modifications morphologiques. L'ensemble de nos résultats suggèrent que les modifications phénotypiques proviennent d'une inhibition de la division et montrent donc que NtKIS1a est un inhibiteur de la division in planta. Des plantes surexprimant simultanément NtKIS1a et AtCycD3;1 ont été obtenues. Leur analyse montre que la surexpression du CKI NtKIS1a restaure un développement normal des plantes surexprimant AtCycD3;l, fournissant la première évidence d'une coopération CKI-cycline in planta. Dans le but d'appréhender les liens qui existent entre le cycle cellulaire et le développement, l'expression de deux gènes a été modifiée simultanément in planta : KNAT1 (knottedl-like from Arabidopsis thaliana), impliqué dans le développement et la fonction du méristème apical caulinaire, et NtKIS1a, impliqué dans l'inhibition du cycle cellulaire. L'analyse des plantes F1 montre que la co-expression de NtKIS1a et KNAT1 renforce le phénotype des plantes 35S::KNAT1, suggérant que les produits des deux gènes coopèrent au cours du développementPlant development requires stringent controls between cell proliferation and cell differentiation. Proliferation is positively regulated by cyclin dependent kinases (CDKs), whose activity is regulated at several levels including inhibition by CDK inhibitors (CKIs). The screen of a two-hybrid BY-2 cell suspension library with a CDKA as a bait, allows the isolation of two cDNA, named NtKIS1a and NtKIS1b. NtKIS1a and NtKIS1b mRNAs arise from the same N. Tomentosiformis gene by alternative splicing. The deduced polypeptide from NtKIS1a shares strong sequence similarity with mammalian CIP/KIP inhibitors, which is not the case for NtKIS1b. Consistent with this, NtKIS1a but not NtKIS1b inhibits in vitro the kinase activity of CDK/cyclin complexes. To gain insight into the role of NtKIS1a and NtKIS1b during plant development, their overexpression in different species was achieved. Arabidopsis thaliana plants overexpressing NtKIS1b display a wild type phenotype, whereas plants overexpressing NtKIS1a display strong morphological modifications. Our results suggest that the inhibition of cell division is responsible for the phenotypic modifications and thus that NtKIS1a is a cell division inhibitor in planta. Plants overexpressing simultaneously NtKIS1a and AtCycD3;1 were achieved. Their analyze demonstrates that overexpression of the CKI NtKIS1a restores essentially normal development in AtCycD3;1 overexpressing plants, providing for the first time, evidence of Cyclin D-CKI co-operation within the context of a living plant. At the aim of highlighting the links between cell cycle and development, the expression of two genes was modify simultaneously in planta: KNAT1 (knotted1-like from Arabidopsis thaliana) involved in shoot apical meristem development and function, and NtKIS1a involved in cell cycle regulation. The analysis of the F1 plants shows that co-expression of NtKIS1a and KNAT1 enhance the KNAT1 phenotype, suggesting that the two gene products co-operate with each other during plant development
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Delmas, Christelle. "Modes de régulation de l'inhibiteur de CDKs, p27kip1, par les MAPKsp42/p44." Toulouse 3, 2003. http://www.theses.fr/2003TOU30006.
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Borgne, Annie. "Etude de la regulation de cdc2/cycline b a la transition prophase/metaphase de l'ovocyte d'etoile de mer. Caracterisation des effets de la roscovitine, un nouvel inhibiteur chimique de cdk." Paris 6, 1998. http://www.theses.fr/1998PA066422.
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La transition prophase/metaphase du cycle cellulaire est regulee par cdc2/cycline b (ou mpf, m-phase promoting factor). En prophase, la kinase se trouve sous la forme d'un complexe inactif, cdc2 etant phosphorylee sur thr-14 et tyr-15 (forme t p-y p) et la cycline b etant non phosphorylee. L'activation de la kinase se deroule en deux etapes concomitantes : 1) dephosphorylation de cdc2 par la phosphatase cdc25, qui active la kinase (forme t-y), 2) phosphorylation de la cycline b, qui permet la translocation du complexe dans le noyau ou se trouvent ses substrats. En utilisant l'ovocyte d'etoile de mer comme modele cellulaire, nous avons montre que la dephosphorylation de cdc2 in vivo et in vitro se deroule en deux etapes, la dephosphorylation de la thr-14 precedant celle de la tyr-15. La forme transitoire de cdc2 (t-y p) est partiellement active. Ces resultats laissent supposer que la forme t-y p peut etre impliquee dans l'amplification auto-catalytique du complexe. Nous avons egalement etudie la regulation de la phosphorylation de la cycline b. Nous avons mis au point une methode de detection de l'activite cycline b kinase in vitro. Nos resultats montrent que : 1) la phosphorylation de la cycline b n'est pas requise pour l'activite kinase du complexe, 2) cdc2 est responsable de la phosphorylation (shift) de la cycline b en metaphase, 3) la phosphorylation de la cycline b est une reaction intra-mpf. Enfin, nous avons caracterise les effets biochimiques et cellulaires de la roscovitine, un nouvel inhibiteur chimique de cdk. Ce derive de purine inhibe specifiquement cdc2, cdk2 et cdk5 et possede un pouvoir inhibiteur 10 fois superieur a l'olomoucine. La roscovitine empeche la replication de l'adn dans les extraits d'ufs de xenope et provoque l'arret du cycle en g 2/m dans les ovocytes, embryons et lignees de cellules de mammiferes testees. La cible physiologique en prophase de l'inhibiteur est probablement le complexe cdc2/cycline b.
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Millan, Laurine. "Caractérisation d’inhibiteurs de complexes CDK‐cycline chez Arabidopsis thaliana." Thesis, Paris 11, 2011. http://www.theses.fr/2011PA112149.
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Comme pour tous les organismes pluricellulaires, la croissance et le développement des plantes nécessitent une coordination de la production de cellules via la mitose et la différenciation cellulaire. La progression du cycle cellulaire est contrôlée par les complexes CDK-cycline. Les inhibiteurs de ces complexes, les CKIs, représentent d’excellents candidats pour réguler cet équilibre entre les processus de prolifération et différentiation cellulaires qui ont lieu au cours du développement. Afin de mettre en évidence le rôle d’intégrateurs potentiel des CKIs, le développement floral a été utilisé en tant que modèle.Grâce à l’utilisation de la qRT-PCR, nous avons montré que durant le développement floral d’Arabidopsis thaliana, un groupe restreint de CKIs était exprimé. Nous avons choisi de travailler sur les deux CKIs les plus exprimés, KRP6 et KRP7. Une caractérisation fine de leur profil d’expression durant le développement a été réalisée en utilisant des approches complémentaires telles que l’analyse de l’activité de leur promoteur, de la dynamique de leur transcrit, de leur expression protéique et de leur régulation post-traductionnelle.Jusqu’à présent, seules des approches ‘gain de fonction’ ont été utilisées pour étudier le rôle des CKIs chez les plantes. C’est pour cela que nous avons choisi des approches ‘perte de fonction’ pour analyser le rôle de KRP6 et de KRP7 au cours du développement floral. Ainsi, nous avons généré des doubles mutants d’insertion krp6-krp7, krp3-krp6, krp3-krp7, des triples mutants d’insertion krp3-krp6-krp7 et diverses lignées ARN interférence avec des promoteurs spécifiques. Malgré l’étude de ces nombreuses lignées, nous n’avons pas réussi à mettre en évidence des effets phénotypiques associés à l’absence de la fonction CKI au cours du développement floral. Ces résultats mettent en évidence la redondance fonctionnelle qui semble exister entre les KRPs, ainsi un quadruple mutant pourrait être nécessaire pour entrainer des modifications développementales. Afin de mieux comprendre cette fonction d’intégrateurs des KRPs au cours du développement floral, les partenaires de KRP6 et de KRP7 ont été recherchés. Des criblages double-hybride ont été réalisés afin d’identifier des ADNc, spécifiques du développement floral, codant des protéines capables d’interagir avec KRP6 et KRP7. De façon intéressante, mis à part les cyclines de type D, un nouveau type d’interaction a pu être mis en évidence. Un sous-groupe de la famille des rémorines est capable d’interagir avec KRP6 ou KRP7 en système double-hybride. Les rémorines sont des protéines spécifiques du règne végétal, associées à la membrane plasmique mais dont la fonction reste à clarifier. Une approche BiFC en protoplastes BY-2 a permis de confirmer l’existence de ce type d’interaction. De plus, l’influence des rémorines sur la localisation intracellulaire des KRPs a été étudiée. En présence de ces nouveaux partenaires, KRP7 est capable d’adopter une localisation nucléo-cytoplasmique.Enfin, des résultats récents ont montré que l’AMPK était capable de phosphoryler p27KIP1, l’homologue fonctionnel des KRPs chez les mammifères. Ces évènements de phosphorylation entrainent des modifications de sa localisation intracellulaire et de son activité inhibitrice vis-à-vis des complexes CDK-cycline. Après la réalisation d’analyses in silico ayant permis de prédire des sites putatifs de phosphorylation par SnRK1, l’homologue de l’AMPK chez A. thaliana, pour certains KRPs, la protéine KRP6 sous forme recombinante a été utilisée pour réaliser des essais kinase in vitro. Une phosphorylation de KRP6 est détectée en présence de la sous unité catalytique activée de SnRK1. Contrairement aux mammifères, cet évènement de phosphorylation entraine une altération de l’activité inhibitrice de KRP6 sans modification de sa localisation intracellulaire. Cette abolition de l’activité de KRP6 a été confirmée in planta. En effet, les phénotypes associés à la surexpression de KRP6 peuvent être atténués par la surexpression simultanée de la sous-unité catalytique de SnRK1. L’existence de ce lien entre KRP6 et SnRK1 met en évidence une relation directe entre l’homéostasie énergétique et la prolifération cellulaireAs in all multicellular organisms, growth and development in plants require the coordination of cell production by division and cell differentiation. Progression through cell cycle is controlled by the kinase activity of CDK/cyclin complexes. Inhibitors of these complexes, CKIs, represent excellent candidates to regulate the balance between proliferation and differentiation processes during development. To get insight in the potential integrator role of CKIs, floral development was chosen as a developmental model. Using a real time quantitative PCR approach, we bring to light that during floral development of Arabidopsis thaliana, a restricted subset of CKIs was preferentially expressed. It was decided to focus our work on the two major expressed CKIs, KRP6 and KRP7. A better characterization of their expression patterns of during development was undertaken using complementary approaches such as promoter activity analysis, mRNA dynamics, protein expression and post-translational regulation analysis. Because until now ‘gain of function’ approaches have been largely applied to unravel the role of plant CKIs, our challenge was to detect a floral phenotype for KRP6 and KRP7 loss of function mutants, either using knock-out mutants or RNAi lines. We generated krp6-krp7, krp3-krp6, krp3-krp7 double mutants and krp3-krp6-krp7 triple mutant and also several RNAi lines with specifics promoters. Despite the study of these numerous lines, we were not able to highlight phenotypic effects associated with the absence of CKI function during floral development. All these results emphasis functional redundancy which appears to exist between all KRPs, thus quadruple mutant might be needed to provoke some developmental modification.In order to better understand the integrative function of KRPs during floral development, partners of KRP6 and KRP7 were assessed. Two-hybrid screens were performed to identify cDNAs from a “floral-buds-development” library encoding proteins that are able to interact with KRP6 and KRP7. Interestingly, apart from D-type cyclins, we brought to light a new type of interaction. Indeed, a sub-class of the remorin protein family was able to interact with KRP6 or KRP7 in yeast two-hybrid. Remorins are plant specific plasma membrane associated proteins with unknown function. A BiFC approach in BY-2 protoplasts allowed us to confirm remorins/KRP6-7 interactions. Furthermore, the influence of the presence of remorin proteins on KRP6/7 localisation was assessed. KRP7 is able to adopt a nucleo-cytoplasmic localisation in presence of its new partners.Finally, recent results have shown that AMPK is phosphorylating p27KIP1, KRPs functional counterpart in mammals. These phosphorylation events lead to changes in its cellular localisation and its inhibitory activity toward CDK-cyclin complexes. After in silico analysis aiming to predict potential AMPK Arabidopsis homologue SnRK1 phosphorylation sites within some KRPs protein sequences, recombinant KRP6 was used in order to perform in vitro kinase assays. Phosphorylation occurs efficiently on KRP6 when activated SnRK1 catalytic subunit is present. Furthermore, unlike in mammals, this phosphorylation event leads to an alteration of KRP6 inhibitory activity without modification of its cellular localisation. This abolition of KRP6 activity was confirmed by in planta analysis. Indeed, KRP6 overexpression phenotype can be attenuated by simultaneous SnRK1 catalytic subunit overexpression. The existence of this link between KRP6 and SnRK1 underscores a direct relationship between energy homeostasis and cell proliferation
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Zoubir, Mustapha. "Traitement anticancéreux et modulation du système immunitaire." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA11T016.
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Les thérapies anticancéreuses ont apporté un gain largement reconnu en matière de réduction de la charge tumorale, de survie des patients et d’amélioration de leur qualité de vie, dans un certain nombre de cancers. Hélas, ces thérapies exercent un effet immunosuppresseur en détruisant les effecteurs ou en bloquant l’activité de certains facteurs biologiques impliqués dans le recrutement des acteurs du système immunitaire. D’autre part, plusieurs travaux ont permis de démontrer que ces traitements pouvaient avoir un effet contraire en générant ou en favorisant l’induction d’une réponse immunitaire anti-tumorale, soit par effet direct sur le recrutement et l’activation des effecteurs de l’immunité, soit en potentialisant les interactions cellulaires par des mécanismes biologiques. Ces derniers faisant intervenir les cytokines, la stimulation des TLR, l’augmentation des interactions entre cellules du SI; ce qui permet de passer d’une anergie immunologique vers un véritable système d’éradication des cellules cancéreuses.Dans notre laboratoire, nous avons essayé d’évaluer l’implication du système immunitaire dans la réponse thérapeutique induite par des agents cytotoxiques conventionnels. Ici, nous décrivons les effets d’un inhibiteur de cyclines kinases multi-cibles « CDKi PHA-793 887 » testé dans un essai de phase I mené sur deux sites en Europe. C’est le constat inattendu que 6 des 15 patients, traités par ce médicament (PHA-793887) ont développé de graves infections bactériennes et virales et que 6 d’entre eux ont présenté la réactivation du virus de l’herpès qui nous a conduit à étudier ces effets sur le système immunitaire et en particulier sur le dialogue entre cellules dendritiques (CD) et cellules natural killer (NK). Ce travail met en évidence que ce médicament inhibe le signalling des récepteurs toll-like (TLR) réduisant par conséquent l’interaction CD/NK in vitro. Enfin la stimulation des cellules des patients sous traitement démontre une réduction importante de ce signalling ex-vivo. Ainsi, cet effet immunosuppresseur inattendu a permis une réactivation virale chez 40% des patients. La deuxième partie de ce travail, concerne les effets du cyclophosphamide (CTX) utilisé à faible dose. L’injection d'une faible dose chez la souris ou d’un dosage métronomique chez l'homme, promeut la différenciation des cellules lymphocytaires vers Th17 (sécrétant de l’interleukine-17 (IL-17)) et Th1 (sécrétant de l’interféron-γ (IFN)). Ceux-ci ont été retrouvés dans le sang et dans des ascites carcinomateuses de patients. Ainsi, le CTX pourrait participer à la génération de réponses anti-tumorale via la différenciation Th 17 comme cela fut suggéré par de récentes études précliniques montrant l’existence d’une corrélation étroite entre le taux des lymphocytes Th17 infiltrant la tumeur et la destruction tumoraleCancer therapies have made a gain widespread recognition in the reduction of tumor burden, patient survival and improved quality of life in a number of cancers. Unfortunately, these therapies exert an immunosuppressive effect by killing effectors or blocking the activity of certain biological factors involved in recruiting of the immune system. On the other hand, several studies have shown that these treatments could have the opposite effect by generating or promoting the induction of antitumor immune response, either by direct effect on the recruitment and activation of effectors immunity, either by potentiating cellular interactions by biological mechanisms. The latter involving cytokines, TLR stimulation, increased interactions between cells of the IS; which toggles between immunological anergy to a real system to eradicate cancer cells. In our laboratory, we tried to evaluate the involvement of the immune system in the therapeutic response induced by conventional cytotoxic agents. Here, we describe the effects of an inhibitor of cyclin kinases multi-target "CDKIs PHA-793887" tested in a phase I trial conducted at two sites in Europe. This unexpected finding is that 6 of 15 patients treated with this drug (PHA-793887) developed severe bacterial and viral infections and six of them showed reactivation of the herpes virus that has led us to study these effects on the immune system and in particular on the dialogue between dendritic (DCs) and natural killer (NK) cells. This work shows that this drug inhibits the signaling of toll-like receptor (TLR) thereby reducing the interaction DC / NK in vitro. Finally, stimulation of the cells of treated patients demonstrated a significant reduction of this signaling ex vivo. Thus, this immunosuppressive effect has an unexpected viral reactivation in 40% of patients. The second part of this work concerns the effects of metronomic dose of cyclophosphamide (CTX). The injection of a low dose in mice or metronomic dosing in humans, markedly promotes the differentiation of CD4+ T helper 17 (Th17) cells that can be recovered in both blood and tumor beds. However, CTX does not convert regulatory T cells into Th17 cells and promotes cell differentiation into Th17 lymphocytes (secreting interleukin-17 (IL-17)) and Th1 (secreting interferon-γ (IFN)). These were found in blood and in ascites carcinoma patients. Thus, CTX may participate in the generation of antitumor responses through Th 17 differentiation as was suggested by recent preclinical studies showing the existence of a correlation between the rate of Th17 lymphocytes infiltrating the tumor and tumor destruction
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Bacevic, Katarina. "Cdk2 as a model for studying evolutionary selection and therapeutic responses in proliferating cancer cells." Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTT184.
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Les kinases cycline-dépendantes (CDK) sont des protéines régulatrices essentielles du cycle cellulaire. Elles contrôlent la prolifération cellulaire et sont souvent déréglées dans les cancers. De nombreux inhibiteurs de CDKs ont été élaborés et sont actuellement le sujet d'essais cliniques. Bien que Cdk1 soit un régulateur essentiel de cycle cellulaire, Cdk2 n’est pas nécessaire pour la progression du cycle cellulaire, mais favorise la tumorigenèse. Par conséquent, Cdk2 est une cible thérapeutique prometteuse. L’utilisation des inhibiteurs de kinases pour modifier la prolifération cellulaire s’apparente à appliquer une sélection Darwinienne. Cette sélection peut être modélisée mathématiquement. Cette approche a montré que des avantages sélectifs, mêmes marginaux, peuvent être d'une importance majeure dans la compétition inter-cellulaire et la progression du cancer. Selon ce principe, nous avons fait l’hypothèse que le fait que la Cdk2 ait un rôle mineur dans la progression du cycle cellulaire lui confèrerait le statut de cible pertinente pour une thérapie du cancer. Selon cette hypothèse, son inhibition serait bien tolérée, permettant de réduire le niveau d’activité CDK et ainsi agir contre la prolifération déréglée des cellules. Nous avons supposé qu’au lieu d’éliminer entièrement les cellules les plus prolifératives, qui seraient les plus sensibles au traitement, il serait potentiellement intéressant de les exploiter pour concurrencer l’émergence des cellules résistantes, moins prolifératives. L'utilisation d'un traitement continu à faible dose avec les inhibiteurs Cdk2 pourrait permettre de maintenir cet équilibre. L'objectif de la thèse était d'étudier si Cdk2 confère un avantage prolifératif aux cellules cancéreuses, si les cellules peuvent développer une résistance aux inhibiteurs de CDKs, et si oui, déterminer quels étaient les mécanismes de résistance qui permettent de réduire le « fitness » des cellules prolifératives. Pour répondre à ces questions, nous avons généré des lignées cellulaires ayant des degrés variés de résistance à un inhibiteur spécifique de Cdk2 (inhibant également Cdk1 à des concentrations élevées). Nous avons caractérisé leur capacité à proliférer en comparaison avec des cellules parentales et des cellules isogéniques n’exprimant plus Cdk2 en raison d’un « knock-out » du gène. Bien que dans ces premières cellules le gène Cdk2 est retrouvé non muté et que l'expression de la protéine Cdk2 reste inaltérée, l'activité kinase de Cdk2 est diminuée. Les cellules résistantes à l’inhibiteur prolifèrent efficacement in vitro. Cependant, lors des expériences de compétition avec les cellules parentales, sensibles aux inhibiteurs, elles sont perdantes. Ceci montre que le développement d’une résistance à un inhibiteur de kinase entraîne un désavantage sélectif. Malgré une prolifération normale en l’absence de compétiteurs, ce désavantage est mis en évidence dans une population mixte, validant ainsi l’hypothèse de départ. Nous avons constaté que les Cdk2 KO et les cellules résistantes à l’inhibiteur (R50) ont un métabolisme altéré. Ces cellules sont sensibles à l'épuisement des nutriments et du glucose ainsi qu’à l'hypoxie, malgré un taux de consommation d'oxygène normal, ce qui indique une augmentation de la glycolyse aérobique. Les cellules R50 surexpriment la protéine Cdk6, ce qui peut contribuer à la résistance à l'inhibition Cdk2. De plus elles sont sensibles à l’inhibition des Cdk4/6, cibles référencées dans le traitement de certaines classes de cancer du sein. Enfin, les cellules Cdk2 KO présentent un point de contrôle de la phase S perturbé. Ces résultats suggèrent que des inhibiteurs pharmacologiques ciblant Cdk2 pourraient être synergique avec d’autres traitements, par exemple l’inhibition concomitante de la réplication de l'ADN, de la glycolyse, ou de Cdk6. Cela pourrait ainsi diminuer la prolifération des cellules cancéreuses et empêcher l’émergence d'une résistance thérapeutiqueCyclin-dependent kinases (Cdk) are essential regulators of the cell cycle that support cell proliferation and are often deregulated in cancer. While Cdk1 is an essential regulator of the cell cycle, Cdk2 is not required for cell cycle progression but promotes tumorigenesis. Therefore, Cdk2 is a promising drug target. Many Cdk inhibitors have been developed and are currently undergoing clinical trials. Darwinian selection can be modelled mathematically, and such studies have shown that even marginal selective advantages can be of great importance in outcomes of cell-cell competition and cancer progression. We hypothesised that the non-essential role of Cdk2 for cell cycle progression may mean that it is a good target for cancer therapy as continual inhibition should be tolerated and should counteract deregulated cell proliferation in cancer. However, as with all chemotherapeutic agents, the development of clinical resistance is likely. We further hypothesized that applying a low-dose treatment with Cdk2 inhibitors should minimize chances of developing resistance, by maintaining competition between robustly proliferating cells that are sensitive to treatment, and resistant cells.The aim of the thesis was to investigate whether Cdk2 confers a proliferative advantage to cancer cells, whether cells can develop resistance to Cdk inhibitors, and if so, whether the mechanisms allowing resistance reduce cellular proliferative fitness.To answer these questions, we have created cell lines with varying degrees of resistance to a selective Cdk2 inhibitor (that at high doses, also inhibits Cdk1) and have characterised their proliferation capacity in comparison with parental cells and isogenic Cdk2 knockout cells. Although in these cells the Cdk2 gene is not mutated and the expression of Cdk2 protein remained unaltered, the kinase activity of Cdk2 is decreased. Similarly, Cdk2 gene knockout (Cdk2 KO) cells have reduced sensitivity to Cdk2 inhibition. Inhibitor-resistant cells proliferate efficiently but are outcompeted by parental, inhibitor-sensitive cells in competition experiments, confirming that inhibitor resistance entails a selective disadvantage. We found that the proliferation of both Cdk2 knockout and inhibitor-resistant (R50) cells is sensitive to nutrient and glucose depletion as well as hypoxia, despite a normal oxygen consumption rate, indicating increased aerobic glycolysis. R50 cells have highly upregulated Cdk6, which may contribute to resistance to Cdk2 inhibition. Moreover, they are sensitised to Cdk4/6 inhibition, which is currently authorised as a treatment for some classes of breast cancer. Finally, Cdk2 knockout cells have an impaired S-phase checkpoint. These results suggest that pharmacological inhibitors targeting Cdk2 might be synthetically lethal with other treatments, eg inhibition of DNA replication, of glycolysis, or of Cdk6. This might diminish cancer cell proliferation and prevent emergence of therapeutic resistance
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Cot, Emilie. "Inhibition chimique des Cdk : mécanisme biochimiques et conséquences cellulaires." Thesis, Montpellier 2, 2010. http://www.theses.fr/2010MON20054.
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Les kinases dépendantes des Cyclines (Cdk) contrôlent le déroulement du cycle cellulaire, mais leur étude est difficile car des mécanismes de compensation se développent lorsqu'une Cdk est absente. Cdk2 est principalement impliquée dans la phase de réplication de l'ADN, cependant l'ablation génétique de Cdk2 chez la souris n'a pas d'effet sur leur développement: les fonctions de Cdk2 sont compensées par d'autres Cdk. L'inhibition chimique permet de bloquer une Cdk et de limiter les compensations. Pour étudier les rôles de Cdk2, nous l'avons inhibé avec NU6102 qui sélectif pour Cdk2 dans le modèle xénope. Nous avons aussi développé des mutants de Cdk2 résistants à NU6102 pour vérifier sa sélectivité et avons cherché à mieux comprendre les paramètres qui déterminent l'affinité entre Cdk2 et un ligand. D'autre part, nous déterminons in vitro que NU6102 serait plus sélectif pour Cdk2 que pour les autres Cdk chez l'humain, et avons décrit les phénotypes induits par cet inhibiteur dans les cellules humaines en cultures. Ces résultats ne permettent pas de confirmer la sélectivité de NU6102 mais montrent que NU6102 a des caractéristiques intéressantes pour être utilisé dans le traitement contre le cancer. L'activité des Cdk est essentielle à l'initiation de la réplication de l'ADN, mais aucun substrat essentiel n'a été identifié chez les métazoaires. Nous avons réalisé un crible des protéines chargées sur la chromatine en présence et en absence d'activité Cdk dans le modèle xénope, afin d'identifier des substrats qui pourraient être impliqués dans la réplication. Ces résultats suggèrent que l'activité Cdk, qui initie la réplication au niveau des origines de réplication de l'ADN, pourrait être impliquée dans d'autres fonctions cellulairesCycline Dependant Kinases (Cdk) control cell cycle progression. The study of their roles is often difficult because of functional redundancy; when a given Cdk is absent, others may compensate. The main role of Cdk2 in the cell cycle is in the initiation of DNA replication, but absence of Cdk2 is compensated for by Cdk1. For example, mice with a genetic knockout of Cdk2 are viable. The chemical inhibition of Cdks may limit compensation by other Cdks. Therefore, to study Cdk2 roles, we have studied chemical inhibition by NU6102, which seems to be selective for Cdk2 in the Xenopus model. To verify the selectivity and study parameters that determine selectivity, we have designed and produced mutants of Cdk2 which are resistant to NU6102, allowing restoration of function in the presence of inhibitor. Moreover, we demonstrate in vitro that NU6102 is selective for Cdk2 compared to other human Cdks, and we describe phenotypes induced by NU6102 in cultured cells, which are interesting in the light of potential applications of NU6102 in cancer chemotherapy. Cdk activity is essential for initiation of DNA replication, but in metazoans no essential substrates are known. To identify potential Cdk substrates during DNA replication, we have performed a proteomics screen of the proteins loaded onto chromatin in the presence or absence of Cdk activity, in the Xenopus model. The results suggest that Cdk activity is not only required for assembling DNA replication complexes onto origins of replication, but may also be implicated in other cellular functions
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Furnish, Robin. "Evaluating Immune Modulatory Therapeutic Strategies for Diffuse Intrinsic Pontine Glioma." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595849080346532.
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Peyressatre, Marion. "Développement de biosenseurs fluorescents et d’inhibiteurs pour suivre et cibler CDK5/p25 dans le glioblastome." Thesis, Montpellier, 2016. http://www.theses.fr/2016MONT3513/document.
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CDK5 est une protéine kinase exprimée de façon ubiquitaire et activée principalement dans le système nerveux central, ou elle joue un rôle important dans la transmission synaptique, la guidance axonale et la migration cellulaire, la plasticité synaptique et le développement neuronal. CDK5 est associée à la protéine p35 au niveau de la membrane cellulaire, et activée par clivage calpaine-dépendant de cette dernière en p25, ce qui conduit à la relocalisation de CDK5/p25 dans le cytoplasme cellulaire. CDK5/p25 phosphoryle de nombreux substrats dont la protéine Tau, contribuant ainsi à l’apparition de plaques neurofibrillaires responsable des pathologies neurodégénératives comme Alzheimer et Parkinson, lorsqu’elle est hyperactivée. Plus récemment, l’expression et l’hyperactivation de CDK5 a été décrite comme impliquée dans le développement de cancers et en particulier de tumeurs cérébrales. Toutefois aucune approche ne permet actuellement de détecter et de mesurer l’activité de CDK5/p25 directement dans des cellules vivantes, au sein des tissus et des tumeurs concernées, dû à un manque d’outils fiables et sensibles pour quantifier les changements dynamiques de son activité kinase. Par ailleurs, peu d’inhibiteurs sont actuellement disponibles pour inhiber CDK5/p25, de manière spécifique, la plupart ciblant la poche de fixation de l’ATP.Le premier objectif de ma thèse a consisté à développer un biosenseur d’activité fluorescent de nature peptidique appelé CDKACT5 qui rapporte l’activité kinase de CDK5/p25 recombinante et dans des extraits cellulaires de manière dynamique et réversible suivant stimulation ou inhibition de cette kinase. Une fois caractérisé et validé in vitro, le biosenseur a été appliqué à la détection d’altérations de CDK5/p25 dans différentes lignées cellulaires de glioblastome dans des essais fluorescents d’activité kinase. Enfin CDKACT5 a été introduit dans des cellules neuronales vivantes afin de suivre les changements dynamiques d’activité de CDK5/p25 par microscopie de fluorescence et vidéo microscopie.Le deuxième objectif de ma thèse a consisté à développer un biosenseur fluorescent conformationnel dans le but d’identifier des inhibiteurs non compétitifs de l’ATP ciblant la boucle d’activation de CDK5. Le biosenseur CDKCONF5 a été exploité pour réaliser un criblage haut débit de trois chimiothèques de petites molécules. Les touches identifiées ont été validées et caractérisées in vitro, pour déterminer leur potentiel inhibiteur dans des tests d’activité kinase et de prolifération cellulaire, ainsi que leur mécanisme d’action. Ces molécules constituent des candidats prometteurs pour une chimiothérapie sélective du glioblastomeCDK5 is a protein kinase ubiquitously expressed but mainly activated in the central nervous system, where it plays an important role in neuronal functions such as synaptic transmission, axonal guidance and migration, synaptic plasticity and neuronal development. CDK5 is associated with p35 protein at the cell membrane, then activated by calpain-mediated cleavage of p35 into p25, which promotes relocalization of CDK5/p25 into the cytoplasm. CDK5/p25 phosphorylates a wide variety of substrates including Tau, thereby contributing to appearance of neurofibrillary plaques responsable for neurodegenerative pathologies such as comme Alzheimer’s et Parkinson’s, when hyperactivated. More recent studies suggest that CDK5 expression and hyperactivation are involved in glioblastoma during cell invasion and CDK5 expression has been reported to be correlated with the pathological grade of gliomas. However there are currently no tools available to monitor CDK5/p25 activity in its native cellular environment, in tissues or in tumours, due to an overall lack of reliable tools to quantify dynamic changes in its kinase activity in a sensitive and continuous fashion. Furthermore, few inhibitors are currently available to target CDK5/p25 in a specific fashion and most of them are ATP competitive inhibitors.The first goal of my thesis was to develop a fluorescent peptide biosensor named CDKACT5, that specifically reports on recombinant CDK5/p25 and on endogenous CDK5 activity in cell extracts in a dynamic and reversible fashion following stimulation or inhibition of this kinase. Once validated in vitro, this biosensor was applied to detect alterations in CDK5/p25 activity in different glioblastoma cell lines in fluorescent kinase activity assays. Finally CDKACT5 was introduced into cultured neuronal cells to monitor dynamic changes in CDK5/p25 activity by fluorescence imaging and time-lapse microscopy.The second goal of my thesis project consisted in developing a conformational fluorescent biosensor to identify non-ATP competitive inhibitors targeting the activation loop of CDK5. CDKCONF5 was implemented to perform a high throughput screen of three small molecule libraries. The hits identified were validated and characterized to determine their inhibitory potential in kinase activity and proliferation assays, as well as their mechanism of action. These compounds constitute promising for selective chemotherapy in glioblastoma
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Vandromme, Lucie. "Synthèse de purines trisubstituées en tant qu'inhibiteurs potentiels d'enzymes : application à l'inhibition des protéines kinases dépendantes des cyclines (CDK)." Paris 11, 2005. http://www.theses.fr/2005PA112160.
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Les CDK sont les enzymes régulatrices du cycle cellulaire et leur dérégulation est impliquée dans l'apparition du cancer. Elles représentent de ce fait des cibles de choix dans la thérapie anti-cancéreuse. Au laboratoire, les recherches sont donc focalisées sur la synthèse d'inhibiteurs de CDK à la fois puissants et spécifiques. Des inhibiteurs synthétiques efficaces ont pu être découverts malgré la grande similitude structurale existant entre chaque CDK, et les purines constituent une des familles comportant les inhibiteurs les plus spécifiques. Au sein du laboratoire, la synthèse de purines 2,6,9-trisubstituées en tant qu'inhibiteurs potentiels de CDK est effectuée par synthèse parallèle. Cette stratégie a été appliquée tout d'abord en solution, et devra être optimisée sur résine pour ensuite aboutir à des bibliothèques de produits par synthèse supportée. L'objectif de ce travail de thèse est la synthèse de bibliothèques de purines originales à l'aide de la chimie du palladium, ainsi que leur évaluation biologique. Ainsi, après optimisation des conditions opératoires, de nouvelles purines ont pu être obtenues en solution en utilisant les réactions de Suzuki, de Sonogashira, d'amidation ou de carbonylation, puis leur activité inhibitrice de CDK a été déterminée. Une première approche sur support solide a consisté à étudier l'influence de la longueur du bras espaceur sur certaines réactions de couplage au palladiumCDK are key regulatory of cell cycle enzymes and their deregulation is involved in cancer. Therefore, they are targets of choice for cancer therapy. In the laboratory, researches are focused on the synthesis of powerful and specific CDK inhibitors. Effective synthetic inhibitors have been discovered despite the great structural similarity between each CDK, and purines are one of several families which include the most specific inhibitors. The synthesis of 2,6,9-trisubstituted purines as potential CDK inhibitors is carried out by parallel synthesis. This strategy was applied in solution at first, and should be optimized on resin to lead then to supported syntheses of libraries. This thesis deals with synthesis of new original purine libraries obtained by palladium coupling reactions, and their biological evaluation. Thus, after rection conditions optimization, new purines have been obtained using Suzuki, Sonogashira, amidation or carbonylation reactions. Then their CDK inhibitory activity has been tested. As a first approach on solid support, the influence of the spacer arm length in some palladium coupling reactions has been studied
Books on the topic "Inhibiteur de CDK"
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Vogt, P. K. Cyclin Dependent Kinase (cdk) Inhibitors (Current Topics in Microbiology & Immunology). Edited by P. K. Vogt. SPRINGER-VERLAG, 1998.
Find full textBook chapters on the topic "Inhibiteur de CDK"
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Grigoroudis, Asterios I., and George Kontopidis. "Preparation of CDK/Cyclin Inhibitor Complexes for Structural Determination." In Methods in Molecular Biology, 29–45. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4939-2926-9_4.
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Gortat, Anna. "Analysis of CDK Inhibitor Action on Mitochondria-Mediated Apoptosis." In Methods in Molecular Biology, 95–109. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4939-2926-9_9.
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Wang, Hong, Yongming Zhou, Susan Gilmer, Ann Cleary, Pete John, Steve Whitwell, and Larry Fowke. "The CDK Inhibitor ICK1 Affects Cell Division, Plant Growth and Morphogenesis." In Plant Biotechnology 2002 and Beyond, 259–60. Dordrecht: Springer Netherlands, 2003. http://dx.doi.org/10.1007/978-94-017-2679-5_51.
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Dutto, Ilaria, Micol Tillhon, and Ennio Prosperi. "Assessing Cell Cycle Independent Function of the CDK Inhibitor p21CDKN1A in DNA Repair." In Methods in Molecular Biology, 123–39. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4939-2926-9_11.
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Hudnall, S. David, and Mihaela Kurbe. "Role of CD8+ and CD8- Cytolytic Effectors in IL2 Reversal of Cyclosporin-Inhibited EBV-B-Cell Cytotoxicity." In Epstein-Barr Virus and Human Disease, 513–15. Totowa, NJ: Humana Press, 1987. http://dx.doi.org/10.1007/978-1-4612-4590-2_110.
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Toogood, Peter L., and Nathan D. Ide. "Palbociclib (Ibrance): The First-in-Class CDK4/6 Inhibitor for Breast Cancer." In Innovative Drug Synthesis, 167–96. Hoboken, NJ, USA: John Wiley & Sons, Inc, 2015. http://dx.doi.org/10.1002/9781118819951.ch9.
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Reding, Mark T., Huiyun Wut, Mark Krampft, David K. Okita, Brenda M. Diethelm-Okita, Nigel S. Key, and Bianca M. Conti-Fine. "CD4+ T Cells Specific for Factor VIII as a Target for Specific Suppression of Inhibitor Production." In Advances in Experimental Medicine and Biology, 119–34. Boston, MA: Springer US, 2001. http://dx.doi.org/10.1007/978-1-4615-1277-6_11.
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Togashi, Ken-Ichi, Takao Kataoka, and Kazuo Nagai. "Concanamycin A, a Vacuolar Type H+-Atpase Inhibitor, Selectively Induces Cell Death in Activated CD8+ CTL." In Animal Cell Technology: Basic & Applied Aspects, 177–82. Dordrecht: Springer Netherlands, 1998. http://dx.doi.org/10.1007/978-94-011-5161-0_31.
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Bach, Stéphane, Marc Blondel, and Laurent Meijer. "Evaluation of CDK Inhibitor Selectivity." In Enzyme Inhibitors Series, 103–19. CRC Press, 2006. http://dx.doi.org/10.1201/9781420005400.ch5.
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H. Ravindranath, Mepur, and Fatiha E.L. Hilali. "Monospecific and Polyreactive Monoclonal Antibodies against Human Leukocyte Antigen-E: Diagnostic and Therapeutic Relevance." In Monoclonal Antibodies. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.95235.
Full textAbstract:
A monoclonal antibody (mAb) binds to an antigen recognizing an epitope (a sequence of amino acids). A protein antigen may carry amino acid sequence unique to that antigen as well as sequences found in other proteins. Human leukocyte antigens (HLA), a family of proteins expressed by the Major Histocompatibility Complex gene family represent a special case, in that it displays a high degree of polymorphism. Every HLA molecule possesses both specific (private) epitopes and epitopes shared (public) with other HLA class Ia and class Ib molecules. HLA-E is overexpressed in cancer cells more than any other HLA Class I molecules. Therefore specific localization of HLA-E with mAbs is pivotal for developing targeted therapy against cancer. However, the commercially available mAbs for immunodiagnosis are polyreactive. We have developed anti-HLA-E mAbs and distinguished monospecific from polyreactive mAbs using Luminex multiplex single antigen bead (SAB) assay. HLA-E-binding of monospecific-mAbs was also inhibited by E-restricted epitopes. The amino acid sequences in the region of the epitopes bind to CD94/NKG2A receptors on CD8+ T cells and NK cells and block their antitumor functions. Monospecific-HLA-E mAbs recognizing the epitopes sequences can interfere with the binding to restore the anti-tumor efficacy of NK cells. Also, monospecific-mAbs augment the proliferation of CD4-/CD+ cytotoxic T-lymphocytes. Therefore, anti-HLA-E monospecific-mAb can serve as a double-edged sword for eliminating tumor cells.
Conference papers on the topic "Inhibiteur de CDK"
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Nguyen, Tri K., and Steven Grant. "Abstract 2686: The CDK inhibitor dinaciclib (SCH727965) inhibits the unfolded protein response (UPR) through a CDK1- and CDK5-dependent mechanism." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-2686.
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Torres-Guzmán, Raquel, Carmen Baquero, Maria Patricia Ganado, Carlos Marugán, Huimin Bian, Yi Zeng, Ramón Rama, Jian Du, and Maria José Lallena. "Abstract 4850: Targeting prostate cancer with the CDK4 and CDK6 inhibitor abemaciclib." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-4850.
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Delach, Scott, and Giordano Caponigro. "Abstract PS19-10: Preclinical head-to-head comparison of CDK4/6 inhibitor activity toward CDK4 vs CDK6." In Abstracts: 2020 San Antonio Breast Cancer Virtual Symposium; December 8-11, 2020; San Antonio, Texas. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.sabcs20-ps19-10.
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Xueqian, Gong, Li-Chun Chio, Yue Webster, Maria Jose Lallena, Karsten Boehnke, Raquel Torres, Phil Iversen, et al. "Abstract A07: The identification of combinations for the CDK4 and CDK6 inhibitor, abemaciclib." In Abstracts: AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; February 28 - March 2, 2016; Orlando, FL. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1557-3125.cellcycle16-a07.
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Kunadharaju, R., A. Saradna, M. Ahmad, and G. Fuhrer. "Palbociclib (Cyclin-Dependent Kinases CDK4 and CDK6 Selective Inhibitor) Induced Grade 3 Interstitial Pneumonitis." In American Thoracic Society 2021 International Conference, May 14-19, 2021 - San Diego, CA. American Thoracic Society, 2021. http://dx.doi.org/10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a2118.
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Yu, Donghoon, Yeejin Jeon, Dongsik Park, Mooyoung Seo, Wongyun Ahn, Jaeseung Kim, and Kiyean Nam. "Abstract 1953: Q901, a selective CDK7 inhibitor, a potential new strategy for primary and CDK4/6 inhibitor resistant ER-positive breast cancer." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-1953.
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Tadesse, Solomon, Laychiluh Bantie, Khamis Tomusange, Saiful Islam, Muhammed H. Rahaman, Benjamin Noll, Frankie Lam, Mingfeng Yu, and Shudong Wang. "Abstract 2353: CDKI-15, a novel and highly selective CDK4/6 inhibitor: discovery,in vitroandin vivoanticancer efficacy." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-2353.
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Hatch, Harold, Robert Booher, Samanthi Perera, Thi Nguyen, Brian Dolinski, Samer Al-Assaad, Lauren Harmonay, et al. "Abstract 698: MCL1 dependent cells are sensitive to the CDK inhibitor Dinaciclib." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-698.
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Yau, Helen Loo. "Abstract B053: Characterizing the effects of the DNA methylation inhibitor 5-AZA-CdR during CD8 T cell expansion." In Abstracts: Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; September 25-28, 2016; New York, NY. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/2326-6066.imm2016-b053.
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McNulty, Ann M., Teresa Burke, Jack A. Dempsey, Christophe C. Marchal, Andrew E. Schade, Hadrian P. Szpurka, Michele S. Dowless, et al. "Abstract A12: The CDK4/CDK6 inhibitor abemaciclib inhibits transcriptional targets which facilitate growth in ER+ breast cancer cells." In Abstracts: AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; February 28 - March 2, 2016; Orlando, FL. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1557-3125.cellcycle16-a12.
Full textReports on the topic "Inhibiteur de CDK"
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Schneider, Brandt. Role of the Cdk Inhibitor Sic 1 in Start. Fort Belvoir, VA: Defense Technical Information Center, August 1998. http://dx.doi.org/10.21236/ada359281.
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Schneider, Brandt. Role of the Cdk Inhibitor Sic 1 in Start. Fort Belvoir, VA: Defense Technical Information Center, September 2000. http://dx.doi.org/10.21236/ada392485.
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Schneider, Brandt. Role of the Cdk Inhibitor Sic 1 in Start. Fort Belvoir, VA: Defense Technical Information Center, August 1999. http://dx.doi.org/10.21236/ada378108.
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Ringer, Lymor. Role of p53 in cdk Inhibitor VMY-1-103-Induced Apoptosis in Prostate Cancer. Fort Belvoir, VA: Defense Technical Information Center, September 2012. http://dx.doi.org/10.21236/ada567635.
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Ringer, Lymor. Role of p53 in cdk Inhibitor VMY-1-103-induced Apoptosis in Prostate Cancer. Fort Belvoir, VA: Defense Technical Information Center, November 2013. http://dx.doi.org/10.21236/ada592440.
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McCarville, Joseph, and Yue Xiong. Regulation of Ubiquitin Mediated Proteolysis of G1 Cyclins and the CDK Inhibitor p27 by the Cullin Gene Family in Normal Tumorigenic Human Breast Cells. Fort Belvoir, VA: Defense Technical Information Center, July 2001. http://dx.doi.org/10.21236/ada398199.
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Michel, Jennifer J. Regulation of Ubiquitin Mediated Proteolysis of G1 Cyclins and the CDK Inhibitor p27 by the Cullin Gene Family in Normal and Tumorigenic Human Breast Cells. Fort Belvoir, VA: Defense Technical Information Center, July 1999. http://dx.doi.org/10.21236/ada384004.
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Michel, Jennifer. Regulation of Ubiquitin Mediated Proteolysis of G1 Cyclins and the CDK Inhibitor p27 by the Cullin Gene Family in Normal and Tumorigenic Human Breast Cells. Fort Belvoir, VA: Defense Technical Information Center, July 2000. http://dx.doi.org/10.21236/ada393108.
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