Base de dados : MEDLINE
Pesquisa : D12.644.360.262.100 [Categoria DeCS]
Referências encontradas : 1828 [refinar]
Mostrando: 1 .. 10   no formato [Detalhado]

página 1 de 183 ir para página                         

  1 / 1828 MEDLINE  
              next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28873083
[Au] Autor:Barzegar M; Ma S; Zhang C; Chen X; Gu Y; Shang C; Jiang X; Yang J; Nathan CA; Yang S; Huang S
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA.
[Ti] Título:SKLB188 inhibits the growth of head and neck squamous cell carcinoma by suppressing EGFR signalling.
[So] Source:Br J Cancer;117(8):1154-1163, 2017 Oct 10.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Overexpression of epidermal growth factor receptor (EGFR) occurs in approximately 90% of head and neck squamous cell carcinoma (HNSCC), and is correlated with poor prognosis. Thus, targeting EGFR is a promising strategy for treatment of HNSCC. Several small molecule EGFR inhibitors have been tested in clinical trials for treatment of HNSCC, but none of them are more effective than the current chemotherapeutic drugs. Thus, it is urgently needed to develop novel EGFR inhibitors for HNSCC treatment. METHODS: By screening an in-house focused library containing approximately 650 000 known kinase inhibitors and kinase inhibitor-like compounds containing common kinase inhibitor core scaffolds, we identified SKLB188 as a lead compound for inhibition of EGFR. The anticancer effects of SKLB188 on HNSCC cells were investigated by in vitro cell growth, cell cycle and apoptosis assays, as well as in vivo FaDu xenograft mouse model. Molecular docking, in vitro kinase profiling and western blotting were performed to characterise EGFR as the molecular target. RESULTS: SKLB188 inhibited HNSCC cell proliferation by inducing G cell cycle arrest, which was associated with downregulating the expression of Cdc25A, cyclins D1/A and cyclin-dependent kinases (CDK2/4), and upregulating the expression of cyclin-dependent kinase (CDK) inhibitors (p21 and p27 ), leading to decreased phosphorylation of Rb. SKLB188 also induced caspase-dependent apoptosis of HNSCC cells by downregulating the expression of Mcl-1 and survivin. Molecular docking revealed that SKLB188 could bind to the kinase domain of EGFR through hydrogen bonds and hydrophobic interactions. In vitro kinase assay showed that SKLB188 inhibited the activity of a recombinant human EGFR very potently (IC =5 nM). Western blot analysis demonstrated that SKLB188 inhibited the phosphorylation of EGFR and its downstream targets, extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and Akt in the cells. In addition, SKLB188 dose-dependently inhibited FaDu xenograft growth in nude mice, and concurrently inhibited the phosphorylation of Erk1/2 and Akt in the tumours. CONCLUSIONS: SKLB188 potently inhibits the growth of HNSCC cells in vitro and in vivo by targeting EGFR signalling. The results provide a basis for further clinical investigation of SKLB188 as a targeted therapy for HNSCC. Our findings may open a new avenue for development of novel EGFR inhibitors for treatment of HNSCC and other cancers.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Carcinoma de Células Escamosas/metabolismo
Proliferação Celular/efeitos dos fármacos
Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos
Neoplasias de Cabeça e Pescoço/metabolismo
Purinas/farmacologia
Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Western Blotting
Ciclina A/efeitos dos fármacos
Ciclina A/metabolismo
Ciclina D1/efeitos dos fármacos
Ciclina D1/metabolismo
Quinase 2 Dependente de Ciclina/efeitos dos fármacos
Quinase 2 Dependente de Ciclina/metabolismo
Quinase 4 Dependente de Ciclina/efeitos dos fármacos
Quinase 4 Dependente de Ciclina/metabolismo
Inibidor de Quinase Dependente de Ciclina p21/efeitos dos fármacos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo
Inibidor de Quinase Dependente de Ciclina p27/efeitos dos fármacos
Inibidor de Quinase Dependente de Ciclina p27/metabolismo
Regulação para Baixo
Seres Humanos
Imuno-Histoquímica
Marcação In Situ das Extremidades Cortadas
Técnicas In Vitro
Camundongos
Camundongos Nus
Simulação de Acoplamento Molecular
Receptor do Fator de Crescimento Epidérmico/metabolismo
Transdução de Sinais
Regulação para Cima
Ensaios Antitumorais Modelo de Xenoenxerto
Fosfatases cdc25/efeitos dos fármacos
Fosfatases cdc25/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCND1 protein, human); 0 (Cyclin A); 0 (Cyclin-Dependent Kinase Inhibitor p21); 0 (Purines); 0 (SKLB188); 136601-57-5 (Cyclin D1); 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.11.22 (CDK2 protein, human); EC 2.7.11.22 (CDK4 protein, human); EC 2.7.11.22 (Cyclin-Dependent Kinase 2); EC 2.7.11.22 (Cyclin-Dependent Kinase 4); EC 3.1.3.48 (CDC25A protein, human); EC 3.1.3.48 (cdc25 Phosphatases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.298


  2 / 1828 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28506552
[Au] Autor:Preya UH; Lee KT; Kim NJ; Lee JY; Jang DS; Choi JH
[Ad] Endereço:Department of Life and Nanopharamceutical Sciences, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02447, South Korea.
[Ti] Título:The natural terthiophene α-terthienylmethanol induces S phase cell cycle arrest of human ovarian cancer cells via the generation of ROS stress.
[So] Source:Chem Biol Interact;272:72-79, 2017 Jun 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Ovarian cancer is the most lethal gynecological malignancy worldwide. Thiophenes such as terthiophene have been shown to have anti-tumor effects on several cancer cell lines, including ovarian cancer cells. However, the underlying mechanisms behind the anti-proliferative effect of thiophenes are poorly understood. In this study, we investigated the molecular mechanisms underlying the anti-proliferative effect of α-terthienylmethanol, a terthiophene isolated from Eclipta prostrata (False Daisy), on human ovarian cancer cells. We found that α-terthienylmethanol is a more potent inhibitor of cell growth than is cisplatin in human ovarian cancer cells. α-Terthienylmethanol induces cell cycle arrest in ovarian cancer cells, as shown by the accumulation of cells in S phase. In addition, α-terthienylmethanol induced a change in S phase-related proteins cyclin A, cyclin-dependent kinase 2, and cyclin D2. Knockdown of cyclin A using specific siRNAs significantly compromised α-terthienylmethanol-induced S phase arrest. We further demonstrated that α-terthienylmethanol induced an increase in intracellular ROS, and the antioxidant N-acetyl-l-cysteine significantly reversed the S phase arrest induced by α-terthienylmethanol. Moreover, α-terthienylmethanol significantly increased the levels of p-H2AX, a DNA damage marker. These results suggest that α-terthienylmethanol inhibits the growth of human ovarian cancer cells by S phase cell cycle arrest via induction of ROS stress and DNA damage.
[Mh] Termos MeSH primário: Espécies Reativas de Oxigênio/metabolismo
Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos
Tiofenos/toxicidade
[Mh] Termos MeSH secundário: Acetilcisteína/farmacologia
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Ciclina A/antagonistas & inibidores
Ciclina A/genética
Ciclina A/metabolismo
Quinase 2 Dependente de Ciclina/metabolismo
Dano ao DNA/efeitos dos fármacos
Eclipta/química
Eclipta/metabolismo
Feminino
Histonas/metabolismo
Seres Humanos
Neoplasias Ovarianas/metabolismo
Neoplasias Ovarianas/patologia
Fosforilação/efeitos dos fármacos
Interferência de RNA
RNA Interferente Pequeno/metabolismo
Tiofenos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclin A); 0 (Histones); 0 (RNA, Small Interfering); 0 (Reactive Oxygen Species); 0 (Thiophenes); 0 (alpha-terthienylmethanol); 0P77RAU2RR (alpha-terthienyl); EC 2.7.11.22 (Cyclin-Dependent Kinase 2); WYQ7N0BPYC (Acetylcysteine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170620
[Lr] Data última revisão:
170620
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170517
[St] Status:MEDLINE


  3 / 1828 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28485218
[Au] Autor:Ueno M; Nishiguchi T; Takeshita S; Yamaguchi K; Oda T
[Ad] Endereço:a Graduate School of Fisheries Science and Environmental Studies , Nagasaki University , Nagasaki , Japan.
[Ti] Título:Effects of alginate oligomer on the expression of cell cycle- and stress-related genes in Chlamydomonas reinhardtii.
[So] Source:Biosci Biotechnol Biochem;81(6):1254-1260, 2017 Jun.
[Is] ISSN:1347-6947
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Enzymatically prepared alginate oligomer (AO) promoted the growth of Chlamydomonas reinhardtii in a concentration-dependent manner. AO at 2.5 mg/mL induced increase in expression levels of cyclin A, cyclin B, and cyclin D in C. reinhardtii. CuSO at 100 µM suppressed the growth of C. reinhardtiin, and AO at 2.5 mg/mL significantly alleviated the toxicity of CuSO . Increased intracellular reactive oxygen species level in C. reinhardtii induced by CuSO was reduced by AO. After cultivation with CuSO at 100 µM, expression levels of ascorbate peroxidase and superoxide dismutase in C. reinhardtii were increased, and AO reduced the increased levels of these enzymes. These results suggest that AO exhibits beneficial effects on C. reinhardtii through influencing the expression of various genes not only at normal growth condition but also under CuSO stress.
[Mh] Termos MeSH primário: Proteínas de Algas/genética
Alginatos/farmacologia
Antioxidantes/farmacologia
Ciclo Celular/efeitos dos fármacos
Chlamydomonas reinhardtii/efeitos dos fármacos
Regulação da Expressão Gênica/efeitos dos fármacos
[Mh] Termos MeSH secundário: Proteínas de Algas/metabolismo
Ascorbato Peroxidases/genética
Ascorbato Peroxidases/metabolismo
Ciclo Celular/genética
Chlamydomonas reinhardtii/genética
Chlamydomonas reinhardtii/crescimento & desenvolvimento
Chlamydomonas reinhardtii/metabolismo
Sulfato de Cobre/antagonistas & inibidores
Sulfato de Cobre/toxicidade
Ciclina A/genética
Ciclina A/metabolismo
Ciclina B/genética
Ciclina B/metabolismo
Ciclina D/genética
Ciclina D/metabolismo
Citotoxinas/antagonistas & inibidores
Citotoxinas/toxicidade
Ácido Glucurônico/farmacologia
Ácidos Hexurônicos/farmacologia
Polimerização
Espécies Reativas de Oxigênio/antagonistas & inibidores
Espécies Reativas de Oxigênio/metabolismo
Superóxido Dismutase/genética
Superóxido Dismutase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Algal Proteins); 0 (Alginates); 0 (Antioxidants); 0 (Cyclin A); 0 (Cyclin B); 0 (Cyclin D); 0 (Cytotoxins); 0 (Hexuronic Acids); 0 (Reactive Oxygen Species); 8A5D83Q4RW (Glucuronic Acid); 8C3Z4148WZ (alginic acid); EC 1.11.1.11 (Ascorbate Peroxidases); EC 1.15.1.1 (Superoxide Dismutase); LRX7AJ16DT (Copper Sulfate)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170703
[Lr] Data última revisão:
170703
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170510
[St] Status:MEDLINE
[do] DOI:10.1080/09168451.2017.1292836


  4 / 1828 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28394262
[Au] Autor:Singh S; Vaughan CA; Frum RA; Grossman SR; Deb S; Palit Deb S
[Ti] Título:Mutant p53 establishes targetable tumor dependency by promoting unscheduled replication.
[So] Source:J Clin Invest;127(5):1839-1855, 2017 May 01.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gain-of-function (GOF) p53 mutations are observed frequently in most intractable human cancers and establish dependency for tumor maintenance and progression. While some of the genes induced by GOF p53 have been implicated in more rapid cell proliferation compared with p53-null cancer cells, the mechanism for dependency of tumor growth on mutant p53 is unknown. This report reveals a therapeutically targetable mechanism for GOF p53 dependency. We have shown that GOF p53 increases DNA replication origin firing, stabilizes replication forks, and promotes micronuclei formation, thus facilitating the proliferation of cells with genomic abnormalities. In contrast, absence or depletion of GOF p53 leads to decreased origin firing and a higher frequency of fork collapse in isogenic cells, explaining their poorer proliferation rate. Following genome-wide analyses utilizing ChIP-Seq and RNA-Seq, GOF p53-induced origin firing, micronuclei formation, and fork protection were traced to the ability of GOF p53 to transactivate cyclin A and CHK1. Highlighting the therapeutic potential of CHK1's role in GOF p53 dependency, experiments in cell culture and mouse xenografts demonstrated that inhibition of CHK1 selectively blocked proliferation of cells and tumors expressing GOF p53. Our data suggest the possibility that checkpoint inhibitors could efficiently and selectively target cancers expressing GOF p53 alleles.
[Mh] Termos MeSH primário: Pontos de Checagem do Ciclo Celular
Replicação do DNA
DNA de Neoplasias/biossíntese
Mutação
Neoplasias Experimentais/metabolismo
Proteína Supressora de Tumor p53/metabolismo
[Mh] Termos MeSH secundário: Animais
Quinase do Ponto de Checagem 1/genética
Quinase do Ponto de Checagem 1/metabolismo
Ciclina A/genética
Ciclina A/metabolismo
DNA de Neoplasias/genética
Estudo de Associação Genômica Ampla
Seres Humanos
Camundongos
Camundongos Mutantes
Neoplasias Experimentais/genética
Neoplasias Experimentais/patologia
Neoplasias Experimentais/terapia
Proteína Supressora de Tumor p53/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclin A); 0 (DNA, Neoplasm); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); EC 2.7.11.1 (CHEK1 protein, human); EC 2.7.11.1 (Checkpoint Kinase 1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170411
[St] Status:MEDLINE


  5 / 1828 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28188175
[Au] Autor:Liu T; Wang Q; Li W; Mao F; Yue S; Liu S; Liu X; Xiao S; Xia L
[Ad] Endereço:State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; and.
[Ti] Título:Gcn5 determines the fate of germline stem cells through degradation of Cyclin A.
[So] Source:FASEB J;31(5):2185-2194, 2017 May.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The fluctuating CDK-CYCLIN complex plays a general role in cell-cycle control. Many types of stem cells use unique features of the cell cycle to facilitate asymmetric division. However, the manner in which these features are established remains poorly understood. The cell cycle of female germline stem cells (GSCs) is characterized by short G and very long G phases, making it an excellent model for the study of cell cycle control in stem cell fate determination. Using a female GSC model, we found Gcn5, the first discovered histone acetyltransferase, to maintain germline stem cells in ovaries. Results showed that Gcn5 is dispensable for the transcriptional silencing of , but interacts with Cyclin A to facilitate proper turnover in GSCs. Results also showed that Gcn5 promotes Cyclin A ubiquitination, which is dependent on its acetylating activity. Finally, results showed that knockdown of Cyclin A rescued the GSC-loss phenotype caused by lack of Gcn5. Collectively, these findings support the conclusion that Gcn5 acts through acetylation to facilitate Cyclin A ubiquitination and proper turnover, thereby determining the fate of GSCs.-Liu, T., Wang, Q., Li, W., Mao, F., Yue, S., Liu, S., Liu, X., Xiao, S., Xia, L. Gcn5 determines the fate of germline stem cells through degradation of Cyclin A.
[Mh] Termos MeSH primário: Ciclo Celular/fisiologia
Diferenciação Celular/genética
Ciclina A/metabolismo
Proteínas de Drosophila/metabolismo
Células Germinativas/metabolismo
Histona Acetiltransferases/metabolismo
Células-Tronco/metabolismo
[Mh] Termos MeSH secundário: Animais
Divisão Celular/fisiologia
Drosophila melanogaster
Feminino
Ovário/metabolismo
Fenótipo
Transdução de Sinais
Células-Tronco/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclin A); 0 (Drosophila Proteins); EC 2.3.1.48 (Histone Acetyltransferases); EC 2.3.1.48 (Pcaf protein, Drosophila)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170212
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201601217R


  6 / 1828 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28129404
[Au] Autor:Weisbach H; Schablowsky C; Vetter B; Gruska I; Hagemeier C; Wiebusch L
[Ad] Endereço:Charité Universitätsmedizin Berlin, Labor für Pädiatrische Molekularbiologie, Berlin, Germany.
[Ti] Título:Synthetic lethal mutations in the cyclin A interface of human cytomegalovirus.
[So] Source:PLoS Pathog;13(1):e1006193, 2017 Jan.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Generally, the antagonism between host restriction factors and viral countermeasures decides on cellular permissiveness or resistance to virus infection. Human cytomegalovirus (HCMV) has evolved an additional level of self-imposed restriction by the viral tegument protein pp150. Depending on a cyclin A-binding motif, pp150 prevents the onset of viral gene expression in the S/G2 cell cycle phase of otherwise fully permissive cells. Here we address the physiological relevance of this restriction during productive HCMV infection by employing a cyclin A-binding deficient pp150 mutant virus. One consequence of unrestricted viral gene expression in S/G2 was the induction of a G2/M arrest. G2-arrested but not mitotic cells supported viral replication. Cyclin A destabilization by the viral gene product pUL21a was required to maintain the virus-permissive G2-arrest. An HCMV double-point mutant where both pp150 and pUL21a are disabled in cyclin A interaction forced mitotic entry of the majority of infected cells, with a severe negative impact on cell viability and virus growth. Thus, pp150 and pUL21a functionally cooperate, together building a cell cycle synchronization strategy of cyclin A targeting and avoidance that is essential for productive HCMV infection.
[Mh] Termos MeSH primário: Ciclina A/genética
Infecções por Citomegalovirus/virologia
Citomegalovirus/patogenicidade
Fosfoproteínas/metabolismo
Mutações Sintéticas Letais/genética
Proteínas da Matriz Viral/metabolismo
Replicação Viral/fisiologia
[Mh] Termos MeSH secundário: Células Cultivadas
Citomegalovirus/metabolismo
Infecções por Citomegalovirus/metabolismo
Citometria de Fluxo
Interações Hospedeiro-Patógeno/genética
Seres Humanos
Immunoblotting
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclin A); 0 (Phosphoproteins); 0 (Viral Matrix Proteins); 0 (pp150 protein, Cytomegalovirus)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170128
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006193


  7 / 1828 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28112398
[Au] Autor:Lin Y; Liu H; Waraky A; Haglund F; Agarwal P; Jernberg-Wiklund H; Warsito D; Larsson O
[Ad] Endereço:Department of Oncology and Pathology, CCK R8: 04, Karolinska Institutet, Stockholm, Sweden.
[Ti] Título:SUMO-modified insulin-like growth factor 1 receptor (IGF-1R) increases cell cycle progression and cell proliferation.
[So] Source:J Cell Physiol;232(10):2722-2730, 2017 Oct.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Increasing number of studies have shown nuclear localization of the insulin-like growth factor 1 receptor (nIGF-1R) in tumor cells and its links to adverse clinical outcome in various cancers. Any obvious cell physiological roles of nIGF-1R have, however, still not been disclosed. Previously, we reported that IGF-1R translocates to cell nucleus and modulates gene expression by binding to enhancers, provided that the receptor is SUMOylated. In this study, we constructed stable transfectants of wild type IGF1R (WT) and triple-SUMO-site-mutated IGF1R (TSM) using igf1r knockout mouse fibroblasts (R-). Cell clones (R-WT and R-TSM) expressing equal amounts of IGF-1R were selected for experiments. Phosphorylation of IGF-1R, Akt, and Erk upon IGF-1 stimulation was equal in R-WT and R-TSM. WT was confirmed to enter nuclei. TSM did also undergo nuclear translocation, although to a lesser extent. This may be explained by that TSM heterodimerizes with insulin receptor, which is known to translocate to cell nuclei. R-WT proliferated substantially faster than R-TSM, which did not differ significantly from the empty vector control. Upon IGF-1 stimulation G1-S-phase progression of R-WT increased from 12 to 38%, compared to 13 to 20% of R-TSM. The G1-S progression of R-WT correlated with increased expression of cyclin D1, A, and CDK2, as well as downregulation of p27. This suggests that SUMO-IGF-1R affects upstream mechanisms that control and coordinate expression of cell cycle regulators. Further studies to identify such SUMO-IGF-1R dependent mechanisms seem important.
[Mh] Termos MeSH primário: Proliferação Celular
Fibroblastos/metabolismo
Fase G1
Receptor IGF Tipo 1/metabolismo
Receptores de Somatomedina/metabolismo
Fase S
Sumoilação
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Ciclina A/metabolismo
Ciclina D1/metabolismo
Quinase 2 Dependente de Ciclina/metabolismo
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Genótipo
Camundongos Knockout
Fenótipo
Fosforilação
Proteínas Proto-Oncogênicas c-akt/metabolismo
Receptor IGF Tipo 1/deficiência
Receptor IGF Tipo 1/genética
Receptores de Somatomedina/deficiência
Receptores de Somatomedina/genética
Transdução de Sinais
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ccnd1 protein, mouse); 0 (Cyclin A); 0 (Receptors, Somatomedin); 136601-57-5 (Cyclin D1); EC 2.7.10.1 (Receptor, IGF Type 1); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.22 (Cdk2 protein, mouse); EC 2.7.11.22 (Cyclin-Dependent Kinase 2); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170124
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.25818


  8 / 1828 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28056778
[Au] Autor:Li J; Vervoorts J; Carloni P; Rossetti G; Lüscher B
[Ad] Endereço:College of Chemistry, Fuzhou University, Fuzhou, 350002, China.
[Ti] Título:Structural prediction of the interaction of the tumor suppressor p27 with cyclin A/CDK2 identifies a novel catalytically relevant determinant.
[So] Source:BMC Bioinformatics;18(1):15, 2017 Jan 05.
[Is] ISSN:1471-2105
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The cyclin-dependent kinase 2 (CDK2) together with its cyclin E and A partners is a central regulator of cell growth and division. Deregulation of CDK2 activity is associated with diseases such as cancer. The analysis of substrates identified S/T-P-X-R/K/H as the CDK2 consensus sequence. The crystal structure of cyclin A/CDK2 with a short model peptide supports this sequence and identifies key interactions. However, CDKs use additional determinants to recognize substrates, including the RXL motif that is read by the cyclin subunits. We were interested to determine whether additional amino acids beyond the minimal consensus sequence of the well-studied substrate and tumor suppressor p27 were relevant for catalysis. RESULTS: To address whether additional amino acids, close to the minimal consensus sequence, play a role in binding, we investigate the interaction of cyclin A/CDK2 with an in vivo cellular partner and CDK inhibitor p27 . This protein is an intrinsically unfolded protein and, in particular, the C-terminal half of the protein has not been accessible to structural analysis. This part harbors the CDK2 phosphorylation site. We used bioinformatics tools, including MODELLER, iTASSER and HADDOCK, along with partial structural information to build a model of the C-terminal region of p27 with cyclin A/CDK2. This revealed novel interactions beyond the consensus sequence with a proline and a basic amino acid at the P + 1 and the P + 3 sites, respectively. We suggest that the lysine at P + 2 might regulate the reversible association of the second counter ion in the active site of CDK2. The arginine at P + 7 interacts with both cyclin A and CDK2 and is important for the catalytic turnover rate. CONCLUSION: Our modeling identifies additional amino acids in p27 beyond the consensus sequence that contribute to the efficiency of substrate phosphorylation.
[Mh] Termos MeSH primário: Quinase 2 Dependente de Ciclina/química
Inibidor de Quinase Dependente de Ciclina p27/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Biologia Computacional
Ciclina A/química
Ciclina E/química
Seres Humanos
Fosforilação
Conformação Proteica
Spodoptera
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclin A); 0 (Cyclin E); 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27); EC 2.7.11.22 (CDK2 protein, human); EC 2.7.11.22 (Cyclin-Dependent Kinase 2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170107
[St] Status:MEDLINE
[do] DOI:10.1186/s12859-016-1411-0


  9 / 1828 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28039837
[Au] Autor:Hylsová M; Carbain B; Fanfrlík J; Musilová L; Haldar S; Köprülüoglu C; Ajani H; Brahmkshatriya PS; Jorda R; Krystof V; Hobza P; Echalier A; Paruch K; Lepsík M
[Ad] Endereço:Department of Chemistry, CZ Openscreen, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.
[Ti] Título:Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines.
[So] Source:Eur J Med Chem;126:1118-1128, 2017 Jan 27.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:We present comprehensive testing of solvent representation in quantum mechanics (QM)-based scoring of protein-ligand affinities. To this aim, we prepared 21 new inhibitors of cyclin-dependent kinase 2 (CDK2) with the pyrazolo[1,5-a]pyrimidine core, whose activities spanned three orders of magnitude. The crystal structure of a potent inhibitor bound to the active CDK2/cyclin A complex revealed that the biphenyl substituent at position 5 of the pyrazolo[1,5-a]pyrimidine scaffold was located in a previously unexplored pocket and that six water molecules resided in the active site. Using molecular dynamics, protein-ligand interactions and active-site water H-bond networks as well as thermodynamics were probed. Thereafter, all the inhibitors were scored by the QM approach utilizing the COSMO implicit solvent model. Such a standard treatment failed to produce a correlation with the experiment (R = 0.49). However, the addition of the active-site waters resulted in significant improvement (R = 0.68). The activities of the compounds could thus be interpreted by taking into account their specific noncovalent interactions with CDK2 and the active-site waters. In summary, using a combination of several experimental and theoretical approaches we demonstrate that the inclusion of explicit solvent effects enhance QM/COSMO scoring to produce a reliable structure-activity relationship with physical insights. More generally, this approach is envisioned to contribute to increased accuracy of the computational design of novel inhibitors.
[Mh] Termos MeSH primário: Domínio Catalítico
Quinase 2 Dependente de Ciclina/antagonistas & inibidores
Pirimidinas/química
Pirimidinas/farmacologia
Teoria Quântica
Solventes/química
Água/química
[Mh] Termos MeSH secundário: Ciclina A/metabolismo
Quinase 2 Dependente de Ciclina/química
Quinase 2 Dependente de Ciclina/metabolismo
Desenho de Drogas
Seres Humanos
Simulação de Dinâmica Molecular
Inibidores de Proteínas Quinases/química
Inibidores de Proteínas Quinases/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Pirimidinas/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclin A); 0 (Protein Kinase Inhibitors); 0 (Pyrimidines); 0 (Solvents); 059QF0KO0R (Water); EC 2.7.11.22 (Cyclin-Dependent Kinase 2)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170222
[Lr] Data última revisão:
170222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170101
[St] Status:MEDLINE


  10 / 1828 MEDLINE  
              first record previous record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28017591
[Au] Autor:Stankovic A; Guo LY; Mata JF; Bodor DL; Cao XJ; Bailey AO; Shabanowitz J; Hunt DF; Garcia BA; Black BE; Jansen LE
[Ad] Endereço:Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
[Ti] Título:A Dual Inhibitory Mechanism Sufficient to Maintain Cell-Cycle-Restricted CENP-A Assembly.
[So] Source:Mol Cell;65(2):231-246, 2017 Jan 19.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chromatin featuring the H3 variant CENP-A at the centromere is critical for its mitotic function and epigenetic maintenance. Assembly of centromeric chromatin is restricted to G1 phase through inhibitory action of Cdk1/2 kinases in other phases of the cell cycle. Here, we identify the two key targets sufficient to maintain cell-cycle control of CENP-A assembly. We uncovered a single phosphorylation site in the licensing factor M18BP1 and a cyclin A binding site in the CENP-A chaperone, HJURP, that mediated specific inhibitory phosphorylation. Simultaneous expression of mutant proteins lacking these residues results in complete uncoupling from the cell cycle. Consequently, CENP-A assembly is fully recapitulated under high Cdk activities, indistinguishable from G1 assembly. We find that Cdk-mediated inhibition is exerted by sequestering active factors away from the centromere. Finally, we show that displacement of M18BP1 from the centromere is critical for the assembly mechanism of CENP-A.
[Mh] Termos MeSH primário: Autoantígenos/metabolismo
Centrômero/metabolismo
Montagem e Desmontagem da Cromatina
Cromatina/metabolismo
Proteínas Cromossômicas não Histona/metabolismo
Pontos de Checagem da Fase G1 do Ciclo Celular
[Mh] Termos MeSH secundário: Autoantígenos/genética
Proteína Quinase CDC2
Centrômero/genética
Proteína Centromérica A
Cromatina/genética
Proteínas Cromossômicas não Histona/genética
Ciclina A/genética
Ciclina A/metabolismo
Quinase 2 Dependente de Ciclina/genética
Quinase 2 Dependente de Ciclina/metabolismo
Quinases Ciclina-Dependentes/genética
Quinases Ciclina-Dependentes/metabolismo
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Células HEK293
Células HeLa
Seres Humanos
Mutação
Fosforilação
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Transdução de Sinais
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantigens); 0 (CENPA protein, human); 0 (Centromere Protein A); 0 (Chromatin); 0 (Chromosomal Proteins, Non-Histone); 0 (Cyclin A); 0 (DNA-Binding Proteins); 0 (Holliday junction recognizing protein, human); 0 (MIS18BP1 protein, human); EC 2.7.11.22 (CDC2 Protein Kinase); EC 2.7.11.22 (CDK1 protein, human); EC 2.7.11.22 (CDK2 protein, human); EC 2.7.11.22 (Cyclin-Dependent Kinase 2); EC 2.7.11.22 (Cyclin-Dependent Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161227
[St] Status:MEDLINE



página 1 de 183 ir para página                         
   


Refinar a pesquisa
  Base de dados : MEDLINE Formulário avançado   

    Pesquisar no campo  
1  
2
3
 
           



Search engine: iAH v2.6 powered by WWWISIS

BIREME/OPAS/OMS - Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde