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Studies on the Underlying Mechanisms of GTN-induced Cell Cycle Arrests in Hepatocellular Carcinoma Derived CellsLiu, Hui-wen 09 February 2010 (has links)
Our previous study identified both high p27kip1 and low CKS1B protein levels were independent prognosis markers in hepatocelular carcinomas (HCC), however, CKS1B overexpression implicated clinical aggressiveness of HCC but not p27Kip1 protein turnover. In this study, we demonstrated a cytotoxic compound, goniothalamin (GTN), that stabilized p27kip1 protein and downregulated CKS1B mRNA as well as protein levels in HCC-derived cell lines. The IC50 of TP53-negative Hep-3B and TP53-positive SK-Hep1 after treatment with GTN for 48 h were detected as 25 and 10 £gM, respectively. The GTN induced DNA damages, formation of £^H2AFX foci, and upregulation of £^H2AFX protein levels in dose-dependent manners in both cell lines. In addition, GTN arrested Hep-3B and SK-Hep1 cells in G2/M and G1 phases, respectively. Protein levels of several cell cycle regulators, including p27Kip1 in Hep-3B and, p21Cip1 and CKS1B in SK-Hep1 cells have been noticeable upregulated after treatment with GTN. In Hep-3B cells, GTN induced the configuration of p27Kip1/CCND1, p27Kip1/CDK2; p27Kip1/CCNB1 and p27Kip1/CDK1, however, repressed the p27Kip1/STMN1 complexes. On the other hand, GTN evidently induced the configuration of p21Cip1/CDK2 and p21Cip1/CCNE1, but repressed the p21Cip1/SKP2 and p21Cip1/CKS1B complexes, in SK-Hep1 cells. The CKS1B protein abundance that was induced by GTN was stemmed from the CKS1B transactivity. However, GTN-induced p27Kip protein profusion in Hep-3B cell line was, instead, due to the stabilization of p27Kip1 protein, mainly in the cytosol. Both GTN and the proteasome inhibitor, MG132, induced p27Kip1 ubiquitination and p27Kip1 protein profusion with an additive effect, regardless of CKS1B protein level, suggesting that the p27Kip1 protein might be regulated by GTN through an alternative ubiquitin-complex in Hep-3B cells. In addition to the quantitative reverse transcription -polymerase chain reaction, GTN-induced p21Cip1 protein level in SK-Hep1 cells could be traced back to mRNA level, by evidence of quantitative immunoprecipitation/chromatin immunoprecipitation assay with primer sets specific to two regions of the p21Cip1 proximal promoter. Taken together, GTN is able to induce the cell cycle arrest via stabilization of p27Kip1 protein and downregulation of CSK1B mRNA and subsequent protein levels in TP53-negative Hep-3B and TP53-positive SK-Hep1 cells, respectively. The GTN-repressed CKS1B transcription and thereafter, cell cycle arrest, was irrelevant to the p27Kip1 protein stability in Hep-3B cells.
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The Tumour Suppressor p27kip1 Interacts with NF-kB Activator IKK and Plays a Role in InflammationAntony, Charlene 15 December 2009 (has links)
The tumour suppressor p27kip1 (p27) is a potent inhibitor of cell growth and proliferation. We identified NF-κB activator, IKKα, as a novel interacting partner of p27 in a protein microarray screen. Both the IKKα and IKKβ components of the IKK complex were mapped to the C-terminal
domain of p27. To investigate the physiological function of the p27-IKK interaction, we employed a well-established model of LPS-induced sepsis which is known to activate the IKK/NF-κB pathway. Lentivirally-mediated overexpression of p27 blocked LPS activation of NF-κB. Furthermore, in LPS-injected animals transduced with TAT-p27, a significant improvement in the left ventricular function of the heart was observed. TAT-p27 treatment was also shown to attenuate the endotoxin effect and significantly improve survival compared to both saline and TAT-LacZ controls. Our results indicate that p27 attenuates inflammation, possibly through inhibiting the IKK-dependent activation of NF-κB, thus supporting a novel link between both cell cycle regulation and inflammation.
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The Tumour Suppressor p27kip1 Interacts with NF-kB Activator IKK and Plays a Role in InflammationAntony, Charlene 15 December 2009 (has links)
The tumour suppressor p27kip1 (p27) is a potent inhibitor of cell growth and proliferation. We identified NF-κB activator, IKKα, as a novel interacting partner of p27 in a protein microarray screen. Both the IKKα and IKKβ components of the IKK complex were mapped to the C-terminal
domain of p27. To investigate the physiological function of the p27-IKK interaction, we employed a well-established model of LPS-induced sepsis which is known to activate the IKK/NF-κB pathway. Lentivirally-mediated overexpression of p27 blocked LPS activation of NF-κB. Furthermore, in LPS-injected animals transduced with TAT-p27, a significant improvement in the left ventricular function of the heart was observed. TAT-p27 treatment was also shown to attenuate the endotoxin effect and significantly improve survival compared to both saline and TAT-LacZ controls. Our results indicate that p27 attenuates inflammation, possibly through inhibiting the IKK-dependent activation of NF-κB, thus supporting a novel link between both cell cycle regulation and inflammation.
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A Study of p27Kip1 Gene Overexpression on Pathogenicity of Nasopharyngeal Carcinoma Cells by an Inducible VectorHsu, Fu-Fei 07 July 2002 (has links)
Nasopharyngeal carcinoma is a commonly occuring tumor in Southern China. However, the genetic basis underlying its tumorigenicity is still unclear. In eukaryotic cells, progression of the cell cycle is regulated by interactions of cyclins, cyclin dependent kinase (CDKs) and CDK inhibitors (CDKIs). These cell cycle-regulator proteins play important roles in growth of both normal and tumor cells. Many human tumors exhibit deregulation of one or more genes which involved in regulation of cell cycle progression.
p27Kip1, a member of the Cip/Kip family, inhibits both cyclin D-CDK4, and cyclin E-CDK2 complexes and regulates progression of the cell cycle from G1 to S phase. Although p27Kip1 gene mutations are rare in human tumors, low expression of p27Kip1 are observed in several cancers, such as colon, breast and esophagus.
In our previous study, p27Kip1 shown lower expression in two NPC cell lines compared with NNE and 293 (HEK). A doxycycline inducible construct, pBIG2r/p27Kip1, included a full length of human p27Kip1 cDNA was transfected into two NPC cell lines. Expression of several cell cycle-related genes were analyzed.
By increasing p27Kip1 in NPC cell lines, we found that the G1 phase and the doubling time were lengthened. Protein expression of cyclin E and CDK2 were up-regulated. These data suggest that the overexpression of p27Kip1 might be cause NPC cells to arrest at G1 phase and might lead to apoptosis.
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Coordination of cell cycle and cell differentiation by receptor activator of NF-KAPA-B ligand during osteoclast differentiationSankar, Uma January 2003 (has links)
No description available.
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Study of the coupling between interkinetic nuclear migration and cell-cycle progression in the mouse developing cortex / Étude du couplage entre la migration nucléaire intercinétique et la progression dans le cycle cellulaire dans le cortex en développement de la sourisFousse, Julie 11 December 2017 (has links)
Résumé confidentiel / Résumé confidentiel
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Coordination of neuronal proliferation and migration during corticogenesis : role of p27kip1 / Coordination de la prolifération et de la migration neuronale par p27kip1 au cours de la corticogénèseGautier, Élodie 09 December 2011 (has links)
La cytoarchitecture du néocortex repose sur la coordination spatiotemporelle des taux de production des neurones ‐via la régulation du cycle cellulaire de leurs progéniteurs‐ et de leur migration radiale vers la surface corticale. Chez le primate, les couches supragranulaires de l'aire 17 sont plus développées que celles de l'aire 18, conséquence d'une prolifération et d'une production neuronale accrues dans l'aire 17 à E77‐80. Des observations en vidéomicroscopie bi‐photonique, sur tranches organotypiques de cortex, révèlent que la migration radiale est plus rapide dans l'aire 17. Les variations aire‐spécifiques des taux de prolifération et de migration neuronale sont donc congruentes. L'étude des mécanismes moléculaires qui sous‐tendent la régulation coordonnée de la prolifération et de la migration est centrée sur le régulateur du cycle cellulaire p27kip1, qui via son domaine C‐terminal promeut la migration en inhibant la GTPase RhoA. Ce rôle pléiotrope de p27 a été exploré dans la migration nucléaire intercinétique (INM) qu'effectuent les précurseurs de la zone ventriculaire corticale, en synchronie avec les phases du cycle cellulaire. Des formes mutantes de p27 ou des shRNA ont été électroporés spécifiquement dans les neuroblastes d'embryons murins à E14‐15. Des observations en vidéomicroscopie bi‐photonique sur tranches organotypiques révèlent que le domaine C-terminal de p27 affecte l'INM, promeut les décisions différenciatives et la migration radiale. P27 se place donc au sein d'un réseau moléculaire contrôlant conjointement, et de façon aire-spécifique, les divisions successives des précurseurs corticaux, ainsi que la migration des neurones qui en sont issus / Cortical cytoarchitecture relies on the spatiotemporal coordination of neuronal production rate, precursors cell-cycle control and neuronal radial migration towards the cortical plate. In the primate, area 17 supragranular layers are more developed than in area 18, due to higher proliferation and neuronal production rates in area 17 between E77-80. Two-photon videomicroscopy observations on cortical organotypic slices revealed that radial migration is faster in area 17 than 18. This indicates that area-specific variations of proliferation and migration rates are congruent during corticogenesis. The study of molecular mechanisms underlying the coordinated regulation of proliferation and migration focused on the cell-cycle regulator p27kip1, which promotes migration, via inhibition of the Rhoa GTPase by its C-terminal domain. This p27 dual function could play a major role during the Interkinetic Nuclear Migration (INM) performed by cortical precursor cells from the ventricular zone, in synchrony with the cell-cycle phases. Mutant forms of p27 or shRNA were electroporated into neuroblasts of E14-15 mice embryos. Two-photon videomicroscopy observations on organotypic slices revealed that p27 affects INM, promotes differentiative divisions and neuronal radial migration, though its C-terminal domain. P27 is thus part of a molecular network which finely tunes, in an area-specific manner, the successive rounds of divisions of precursor, as well as the migratory behavior of the newborn neurons
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Identificação de moduladores genéticos em uma grande família com neoplasia endócrina múltipla (NEM1) / Identification of modifying genetic fatctors in a large family with multiple endocrine neoplasia type 1Longuini, Viviane Cristina 18 March 2011 (has links)
A Neoplasia endócrina múltipla tipo 1 (NEM1; OMIM 131100) é uma síndrome endócrina hereditária, que envolve tumores nas glândulas paratireóides, pâncreas endócrino/duodeno e hipófise. Mutações germinativas no gene supressor de tumor MEN1 são identificadas em aproximadamente 80% dos casos familiais. Os casos restantes podem apresentar grandes deleções no gene MEN1 (raras), não identificáveis ao seqüenciamento direto, ou mutações em outros genes, ainda pouco conhecidos. Recentemente, mutações germinativas em genes que codificam quinases dependentes de ciclinas, como o gene supressor de tumor p27Kip1, foram identificadas em cerca de 1-2% dos pacientes NEM1 sem mutação no gene MEN1. Esses pacientes apresentam uma clínica similar à NEM1, sendo chamada de NEM-like ou NEM4. Estudos in vitro mostraram que a proteína codificada pelo gene MEN1, MENIN, controla a expressão gênica de p27Kip1, indicando que ambos os genes fazem parte da mesma via celular supressora de tumor. Devido à correlação genótipo-fenótipo ser muito fraca nessa síndrome e à grande variabilidade fenotípica encontrada em pacientes com NEM1 (mesmo entre indivíduos/familiares que possuem mesma mutação no gene MEN1), no presente estudo investigamos a hipótese do envolvimento do gene p27Kip1, e de outro gene supressor de tumor recentemente associado com um fenótipo tumores hipofisários famílias, o gene AIP, como possíveis moduladores de fenótipo entre os pacientes com NEM1 de uma extensa família brasileira com a mutação germinativa MEN1 c.308delC e ampla variabilidade fenotípica. Dentre uma série de variáveis clínicas investigadas, observamos um possível papel modulador de fenótipo do gene p27Kip1 nesta família com NEM1. Foi encontrada associação significante entre o genótipo do polimorfismo p.V109G do gene p27Kip1, localizado em um domínio de ligação com a proteína p38 (que é um regulador negativo de p27 por levar à degradação dessa proteína), com os seguintes aspectos clínicos: maior agressividade do tumor hipofisário (macro vs. microadenomas), precocidade no desenvolvimento do tumor pancreático, e presença de carcinóides e metástases nos pacientes analisados (p< 0,05). Não foi observada nenhuma associação do gene AIP e o fenótipo dos pacientes com NEM1. O presente estudo investigou, pela primeira vez, o status germinativo do gene p27Kip1 em pacientes com mutação MEN1 e identificou uma associação significante em relação à susceptibilidade e agressividade dos tumores na coorte estudada / Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumoral syndrome that involves tumors in the parathyroids, anterior pituitary and in the pancreatic islet(s) cells. Germline mutations in the tumor suppressor gene MEN1 are detectable through direct sequencing in the majority (80%) of the patients with familial MEN1. The remaining patients may present large MEN1 gene deletions, not detectable through direct sequencing, or mutations in other genes, so far largely unknown. Recently, rare mutations in genes that encode cyclin-dependent kinases, as p27Kip1, have been reported in approximately 1-2% of the patients without a MEN1 mutation. These patients were reported as presenting a MEN1-like (or the MEN4) syndrome phenotype. In vitro studies have demonstrated that the protein encoded by the MEN1 gene, MENIN, controls the expression of the p27Kip1 gene and, therefore, these two genes seem to act in the same intracellular tumor suppressor pathway. Due to the lack of genotype-phenotype correlation in MEN1 and the large clinical variability usually observed within unrelated patients carrying the same MEN1 mutation, we hypothesized that p27Kip1 (as well as AIP gene, recently associated with familial predisposition to pituitary tumors) may act as phenotypic modifying gene(s) in the MEN1 syndrome. Herein, we analyzed possible correlations between p27Kip1 genotype and a number of clinical features. We identified significant statistic associations between the p.V109G p27Kip1 polymorphism and phenotype manifestations, indicating a potential role of p27Kip1 in modifying MEN1 phenotype, as follows: pituitary tumor size; early development of pancreatic tumors, and presence of carcinoids and metastasis (p< 0,05). In addition, a possible association with the AIP gene was excluded. The present study analyzed, for the first time, the germline status of p27Kip1 gene in MEN1-mutated patients and identified a potential interaction between the genotype of this tumor suppressor gene in regulating susceptibility and the tumor aggressiveness in MEN1 patients
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Identificação de moduladores genéticos em uma grande família com neoplasia endócrina múltipla (NEM1) / Identification of modifying genetic fatctors in a large family with multiple endocrine neoplasia type 1Viviane Cristina Longuini 18 March 2011 (has links)
A Neoplasia endócrina múltipla tipo 1 (NEM1; OMIM 131100) é uma síndrome endócrina hereditária, que envolve tumores nas glândulas paratireóides, pâncreas endócrino/duodeno e hipófise. Mutações germinativas no gene supressor de tumor MEN1 são identificadas em aproximadamente 80% dos casos familiais. Os casos restantes podem apresentar grandes deleções no gene MEN1 (raras), não identificáveis ao seqüenciamento direto, ou mutações em outros genes, ainda pouco conhecidos. Recentemente, mutações germinativas em genes que codificam quinases dependentes de ciclinas, como o gene supressor de tumor p27Kip1, foram identificadas em cerca de 1-2% dos pacientes NEM1 sem mutação no gene MEN1. Esses pacientes apresentam uma clínica similar à NEM1, sendo chamada de NEM-like ou NEM4. Estudos in vitro mostraram que a proteína codificada pelo gene MEN1, MENIN, controla a expressão gênica de p27Kip1, indicando que ambos os genes fazem parte da mesma via celular supressora de tumor. Devido à correlação genótipo-fenótipo ser muito fraca nessa síndrome e à grande variabilidade fenotípica encontrada em pacientes com NEM1 (mesmo entre indivíduos/familiares que possuem mesma mutação no gene MEN1), no presente estudo investigamos a hipótese do envolvimento do gene p27Kip1, e de outro gene supressor de tumor recentemente associado com um fenótipo tumores hipofisários famílias, o gene AIP, como possíveis moduladores de fenótipo entre os pacientes com NEM1 de uma extensa família brasileira com a mutação germinativa MEN1 c.308delC e ampla variabilidade fenotípica. Dentre uma série de variáveis clínicas investigadas, observamos um possível papel modulador de fenótipo do gene p27Kip1 nesta família com NEM1. Foi encontrada associação significante entre o genótipo do polimorfismo p.V109G do gene p27Kip1, localizado em um domínio de ligação com a proteína p38 (que é um regulador negativo de p27 por levar à degradação dessa proteína), com os seguintes aspectos clínicos: maior agressividade do tumor hipofisário (macro vs. microadenomas), precocidade no desenvolvimento do tumor pancreático, e presença de carcinóides e metástases nos pacientes analisados (p< 0,05). Não foi observada nenhuma associação do gene AIP e o fenótipo dos pacientes com NEM1. O presente estudo investigou, pela primeira vez, o status germinativo do gene p27Kip1 em pacientes com mutação MEN1 e identificou uma associação significante em relação à susceptibilidade e agressividade dos tumores na coorte estudada / Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumoral syndrome that involves tumors in the parathyroids, anterior pituitary and in the pancreatic islet(s) cells. Germline mutations in the tumor suppressor gene MEN1 are detectable through direct sequencing in the majority (80%) of the patients with familial MEN1. The remaining patients may present large MEN1 gene deletions, not detectable through direct sequencing, or mutations in other genes, so far largely unknown. Recently, rare mutations in genes that encode cyclin-dependent kinases, as p27Kip1, have been reported in approximately 1-2% of the patients without a MEN1 mutation. These patients were reported as presenting a MEN1-like (or the MEN4) syndrome phenotype. In vitro studies have demonstrated that the protein encoded by the MEN1 gene, MENIN, controls the expression of the p27Kip1 gene and, therefore, these two genes seem to act in the same intracellular tumor suppressor pathway. Due to the lack of genotype-phenotype correlation in MEN1 and the large clinical variability usually observed within unrelated patients carrying the same MEN1 mutation, we hypothesized that p27Kip1 (as well as AIP gene, recently associated with familial predisposition to pituitary tumors) may act as phenotypic modifying gene(s) in the MEN1 syndrome. Herein, we analyzed possible correlations between p27Kip1 genotype and a number of clinical features. We identified significant statistic associations between the p.V109G p27Kip1 polymorphism and phenotype manifestations, indicating a potential role of p27Kip1 in modifying MEN1 phenotype, as follows: pituitary tumor size; early development of pancreatic tumors, and presence of carcinoids and metastasis (p< 0,05). In addition, a possible association with the AIP gene was excluded. The present study analyzed, for the first time, the germline status of p27Kip1 gene in MEN1-mutated patients and identified a potential interaction between the genotype of this tumor suppressor gene in regulating susceptibility and the tumor aggressiveness in MEN1 patients
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Untersuchungen zur Expression der zellzyklusassoziierten Proteine p27Kip1 und Ki-67 und der Matrixmetalloproteinaseinhibitoren TIMP-1, TIMP-2 und TIMP-3 in häufigen humanen Karzinomen / Cell-cycle associated proteins p27Kip1 and Ki-67 and metalloproteinases TIMP-1, TIMP-2 and TIMP-3 in human carcinomaHuber, Julia 01 March 2011 (has links)
No description available.
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