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[PMID]:29408271
[Au] Autor:Ben Khelifa S; Martinez R; Dandana A; Khochtali I; Ferchichi S; Castaño L
[Ad] Endereço:Unit of Clinical and Molecular Biology/UR17ES29, Faculty of Pharmacy, Monastir, Tunisia. Electronic address: souhaira34@gmail.com.
[Ti] Título:Maturity Onset Diabetes of the Young (MODY) in Tunisia: Low frequencies of GCK and HNF1A mutations.
[So] Source:Gene;651:44-48, 2018 Apr 20.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance, an early clinical onset and a primary defect in ß-cell function. Mutations in the GCK and HNF1A genes are the most common cause of MODY among Caucasians. The etiology of MODY in Tunisia stills a challenge for researchers. The aim of this study was to screen for mutations in GCK, HNF1A, HNF4A and INS genes in North African Tunisians subjects, in whom the clinical profile was very suggestive of MODY. A total of 23 unrelated patients, with clinical presentation of MODY were tested for mutations in GCK, HNF1A, HNF4A and INS genes, using Denaturing High Performance Liquid Chromatography (DHPLC), Multiplex Ligation-depend Probe Amplification (MLPA) and sequencing analysis. We identified the previously reported mutation c-169C > T in one patient as well as a new mutation c-457C > T in two unrelated patients. No mutations were detected in the HNF1A and INS genes. Despite restrictive clinical criteria used for selecting patients in this study, the most common genes known for MODY do not explain the majority of cases in Tunisians. This suggests that there are others candidate or unidentified genes contributing to the etiology of MODY in Tunisians families.
[Mh] Termos MeSH primário: Diabetes Mellitus Tipo 2/genética
Glucoquinase/genética
Fator 1-alfa Nuclear de Hepatócito/genética
Mutação
[Mh] Termos MeSH secundário: Adulto
Feminino
Frequência do Gene
Fator 4 Nuclear de Hepatócito/genética
Seres Humanos
Masculino
Polimorfismo Genético
Regiões Promotoras Genéticas
Proteínas Serina-Treonina Quinases
Tunísia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HNF1A protein, human); 0 (HNF4A protein, human); 0 (Hepatocyte Nuclear Factor 1-alpha); 0 (Hepatocyte Nuclear Factor 4); EC 2.7.1.2 (Glucokinase); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (germinal center kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180207
[St] Status:MEDLINE


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[PMID]:29268130
[Au] Autor:Lin HY; Han HW; Sun WX; Yang YS; Tang CY; Lu GH; Qi JL; Wang XM; Yang YH
[Ad] Endereço:State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing, 210037, China.
[Ti] Título:Design and characterization of α-lipoic acyl shikonin ester twin drugs as tubulin and PDK1 dual inhibitors.
[So] Source:Eur J Med Chem;144:137-150, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Shikonin exhibits powerful anticancer activities for various cancer cells, but its poor solubility and strong toxicity hinder its development as clinical anticancer agent. We previously confirmed that shikonin and its derivatives can disturb mitosis through targeting tubulin. In this study, α-lipoic acid, the naturally-occurring co-factor of pyruvate dehydrogenase (PDH), was introduced into shikonin to design the twin drugs against both mitosis (tubulin) and glycolysis (PDK). 18 kinds of α-lipoic acid shikonin ester derivatives were achieved through three rounds of screening process performed by computer assistant drug design method, being designated as the outstanding compounds. Among them, 1c displayed the most potent cytotoxicity towards cervical cancer cells (HeLa) with an IC value of 3.14 ± 0.58 µM and inhibited xenotransplanted tumor growth in a dose-dependent manner. Further pharmacologic study demonstrated that 1c can cause cell cycle arrest in G2/M phase as tubulin polymerization inhibitor. Moreover, it also showed good PDK1 inhibitory activity, promoting PDH activity and forced HeLa cells to process more aerobic metabolism to undergo cell apoptosis. We reported here the first dual inhibitors of tubulin and PDK1 based on shikonin. It may form a basis for shikonin optimization through twin drug design framework for the discovery of new and potent shikonin derivatives in the study of targeted cancer therapy.
[Mh] Termos MeSH primário: Antineoplásicos/química
Antineoplásicos/farmacologia
Naftoquinonas/química
Naftoquinonas/farmacologia
Proteínas Serina-Treonina Quinases/antagonistas & inibidores
Moduladores de Tubulina/química
Moduladores de Tubulina/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Desenho de Drogas
Glicólise/efeitos dos fármacos
Células HeLa
Seres Humanos
Mitose/efeitos dos fármacos
Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
Tubulina (Proteína)/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Naphthoquinones); 0 (Tubulin); 0 (Tubulin Modulators); 3IK6592UBW (shikonin); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.2 (pyruvate dehydrogenase (acetyl-transferring) kinase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171222
[St] Status:MEDLINE


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[PMID]:29410090
[Au] Autor:Brewer RA; Collins HE; Berry RD; Brahma MK; Tirado BA; Peliciari-Garcia RA; Stanley HL; Wende AR; Taegtmeyer H; Rajasekaran NS; Darley-Usmar V; Zhang J; Frank SJ; Chatham JC; Young ME
[Ad] Endereço:Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
[Ti] Título:Temporal partitioning of adaptive responses of the murine heart to fasting.
[So] Source:Life Sci;197:30-39, 2018 Mar 15.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Recent studies suggest that the time of day at which food is consumed dramatically influences clinically-relevant cardiometabolic parameters (e.g., adiposity, insulin sensitivity, and cardiac function). Meal feeding benefits may be the result of daily periods of feeding and/or fasting, highlighting the need for improved understanding of the temporal adaptation of cardiometabolic tissues (e.g., heart) to fasting. Such studies may provide mechanistic insight regarding how time-of-day-dependent feeding/fasting cycles influence cardiac function. We hypothesized that fasting during the sleep period elicits beneficial adaptation of the heart at transcriptional, translational, and metabolic levels. To test this hypothesis, temporal adaptation was investigated in wild-type mice fasted for 24-h, or for either the 12-h light/sleep phase or the 12-h dark/awake phase. Fasting maximally induced fatty acid responsive genes (e.g., Pdk4) during the dark/active phase; transcriptional changes were mirrored at translational (e.g., PDK4) and metabolic flux (e.g., glucose/oleate oxidation) levels. Similarly, maximal repression of myocardial p-mTOR and protein synthesis rates occurred during the dark phase; both parameters remained elevated in the heart of fasted mice during the light phase. In contrast, markers of autophagy (e.g., LC3II) exhibited peak responses to fasting during the light phase. Collectively, these data show that responsiveness of the heart to fasting is temporally partitioned. Autophagy peaks during the light/sleep phase, while repression of glucose utilization and protein synthesis is maximized during the dark/active phase. We speculate that sleep phase fasting may benefit cardiac function through augmentation of protein/cellular constituent turnover.
[Mh] Termos MeSH primário: Adaptação Fisiológica
Autofagia
Jejum/metabolismo
Miocárdio/metabolismo
Fases do Sono
[Mh] Termos MeSH secundário: Animais
Masculino
Camundongos
Proteínas Associadas aos Microtúbulos/metabolismo
Biossíntese de Proteínas/fisiologia
Proteínas Serina-Treonina Quinases/biossíntese
Serina-Treonina Quinases TOR/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MAP1LC3 protein, mouse); 0 (Microtubule-Associated Proteins); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (mTOR protein, mouse); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.2 (pyruvate dehydrogenase (acetyl-transferring) kinase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180208
[St] Status:MEDLINE


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[PMID]:29191878
[Au] Autor:Klaeger S; Heinzlmeir S; Wilhelm M; Polzer H; Vick B; Koenig PA; Reinecke M; Ruprecht B; Petzoldt S; Meng C; Zecha J; Reiter K; Qiao H; Helm D; Koch H; Schoof M; Canevari G; Casale E; Depaolini SR; Feuchtinger A; Wu Z; Schmidt T; Rueckert L; Becker W; Huenges J; Garz AK; Gohlke BO; Zolg DP; Kayser G; Vooder T; Preissner R; Hahne H; Tõnisson N; Kramer K; Götze K; Bassermann F; Schlegl J; Ehrlich HC; Aiche S; Walch A; Greif PA; Schneider S; Felder ER; Ruland J; Médard G; Jeremias I; Spiekermann K; Kuster B
[Ad] Endereço:Chair of Proteomics and Bioanalytics, Technical University of Munich (TUM), Freising, Germany.
[Ti] Título:The target landscape of clinical kinase drugs.
[So] Source:Science;358(6367), 2017 12 01.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Descoberta de Drogas/métodos
Terapia de Alvo Molecular
Inibidores de Proteínas Quinases/farmacologia
Proteômica/métodos
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/química
Linhagem Celular Tumoral
Citocinas/metabolismo
Seres Humanos
Leucemia Mieloide Aguda/tratamento farmacológico
Leucemia Mieloide Aguda/enzimologia
Neoplasias Pulmonares/tratamento farmacológico
Neoplasias Pulmonares/enzimologia
Camundongos
Inibidores de Proteínas Quinases/química
Proteínas Serina-Treonina Quinases/antagonistas & inibidores
Ensaios Antitumorais Modelo de Xenoenxerto
Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Cytokines); 0 (Protein Kinase Inhibitors); EC 2.7.1.- (MELK protein, human); EC 2.7.1.- (salt-inducible kinase-2, human); EC 2.7.10.1 (FLT3 protein, human); EC 2.7.10.1 (fms-Like Tyrosine Kinase 3); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171202
[St] Status:MEDLINE


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[PMID]:28455143
[Au] Autor:Li H; Li B; Larose L
[Ad] Endereço:Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada; The Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
[Ti] Título:IRE1α links Nck1 deficiency to attenuated PTP1B expression in HepG2 cells.
[So] Source:Cell Signal;36:79-90, 2017 Aug.
[Is] ISSN:1873-3913
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:PTP1B, a prototype of the non-receptor subfamily of the protein tyrosine phosphatase superfamily, plays a key role in regulating intracellular signaling from various receptor and non-receptor protein tyrosine kinases. Previously, we reported that silencing Nck1 in human hepatocellular carcinoma HepG2 cells enhances basal and growth factor-induced activation of the PI3K-Akt pathway through attenuating PTP1B expression. However, the underlying mechanism by which Nck1 depletion represses PTP1B expression remains unclear. In this study, we found that silencing Nck1 attenuates PTP1B expression in HepG2 cells through down-regulation of IRE1α. Indeed, we show that silencing Nck1 in HepG2 cells leads to decreased IRE1α expression and signaling. Accordingly, IRE1α depletion using siRNA in HepG2 cells enhances PI3K-dependent basal and growth factor-induced Akt activation, reproducing the effects of silencing Nck1 on activation of this pathway. In addition, depletion of IRE1α also leads to reduced PTP1B expression, which was rescued by ectopic expression of IRE1α in Nck1-depleted cells. Mechanistically, we found that silencing either Nck1 or IRE1α in HepG2 cells decreases PTP1B mRNA levels and stability. However, despite miR-122 levels, a miRNA targeting PTP1B 3' UTR and inducing PTP1B mRNA degradation in HepG2 cells, are increased in both Nck1- and IRE1α-depleted HepG2 cells, a miR-122 antagomir did not rescue PTP1B expression in these cells. Overall, this study highlights an important role for Nck1 in fine-tuning IRE1α expression and signaling that regulate PTP1B expression and subsequent activation of the PI3K-Akt pathway in HepG2 cells.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/deficiência
Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Endorribonucleases/metabolismo
Proteínas Oncogênicas/deficiência
Proteínas Oncogênicas/metabolismo
Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/química
Animais
Ativação Enzimática/efeitos dos fármacos
Fibroblastos/efeitos dos fármacos
Fibroblastos/metabolismo
Inativação Gênica/efeitos dos fármacos
Células HeLa
Células Hep G2
Seres Humanos
Camundongos
MicroRNAs/metabolismo
Proteínas Oncogênicas/química
Fosfatidilinositol 3-Quinases/metabolismo
Fosforilação/efeitos dos fármacos
Ligação Proteica/efeitos dos fármacos
Domínios Proteicos
Proteína Tirosina Fosfatase não Receptora Tipo 1/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
Estabilidade de RNA/efeitos dos fármacos
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Transdução de Sinais/efeitos dos fármacos
Tapsigargina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (MIRN122 microRNA, human); 0 (MicroRNAs); 0 (Nck protein); 0 (Oncogene Proteins); 0 (RNA, Messenger); 67526-95-8 (Thapsigargin); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (ERN1 protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.1.- (Endoribonucleases); EC 3.1.3.48 (PTPN1 protein, human); EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 1)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


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[PMID]:29295989
[Au] Autor:Gibori H; Eliyahu S; Krivitsky A; Ben-Shushan D; Epshtein Y; Tiram G; Blau R; Ofek P; Lee JS; Ruppin E; Landsman L; Barshack I; Golan T; Merquiol E; Blum G; Satchi-Fainaro R
[Ad] Endereço:Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
[Ti] Título:Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer.
[So] Source:Nat Commun;9(1):16, 2018 01 02.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies. Here we show a potent combination of microRNA and siRNA delivered by an efficient nanocarrier to PDAC tumors. Using proteomic-microRNA profiles and survival data of PDAC patients from TCGA, we found a novel signature for prolonged survival. Accordingly, we used a microRNA-mimic to increase miR-34a together with siRNA to silence PLK1 oncogene. For in vivo dual-targeting of this combination, we developed a biodegradable amphiphilic polyglutamate amine polymeric nanocarrier (APA). APA-miRNA-siRNA polyplexes systemically administered to orthotopically inoculated PDAC-bearing mice showed no toxicity and accumulated at the tumor, resulting in an enhanced antitumor effect due to inhibition of MYC oncogene, a common target of both miR-34a and PLK1. Taken together, our findings warrant this unique combined polyplex's potential as a novel nanotherapeutic for PDAC.
[Mh] Termos MeSH primário: Carcinoma Ductal Pancreático/genética
Proteínas de Ciclo Celular/genética
Regulação Neoplásica da Expressão Gênica
MicroRNAs/genética
Neoplasias Pancreáticas/genética
Proteínas Serina-Treonina Quinases/genética
Proteínas Proto-Oncogênicas/genética
RNA Interferente Pequeno/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Animais
Carcinoma Ductal Pancreático/metabolismo
Carcinoma Ductal Pancreático/terapia
Proteínas de Ciclo Celular/metabolismo
Linhagem Celular Tumoral
Portadores de Fármacos/química
Feminino
Seres Humanos
Interações Hidrofóbicas e Hidrofílicas
Estimativa de Kaplan-Meier
Masculino
Camundongos Endogâmicos C57BL
Camundongos SCID
Meia-Idade
Nanoestruturas/química
Neoplasias Pancreáticas/metabolismo
Neoplasias Pancreáticas/terapia
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Proto-Oncogênicas/metabolismo
Proteínas Proto-Oncogênicas c-myc/genética
Proteínas Proto-Oncogênicas c-myc/metabolismo
Interferência de RNA
RNA Interferente Pequeno/química
Terapêutica com RNAi/métodos
Ensaios Antitumorais Modelo de Xenoenxerto/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (Drug Carriers); 0 (MIRN34 microRNA, human); 0 (MicroRNAs); 0 (Proto-Oncogene Proteins); 0 (Proto-Oncogene Proteins c-myc); 0 (RNA, Small Interfering); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (polo-like kinase 1)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02283-9


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[PMID]:29295981
[Au] Autor:Kimura K; Hohjoh H; Fukuoka M; Sato W; Oki S; Tomi C; Yamaguchi H; Kondo T; Takahashi R; Yamamura T
[Ad] Endereço:Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan.
[Ti] Título:Circulating exosomes suppress the induction of regulatory T cells via let-7i in multiple sclerosis.
[So] Source:Nat Commun;9(1):17, 2018 01 02.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system. Foxp3 regulatory T (Treg) cells are reduced in frequency and dysfunctional in patients with MS, but the underlying mechanisms of this deficiency are unclear. Here, we show that induction of human IFN-γ IL-17A Foxp3 CD4 T cells is inhibited in the presence of circulating exosomes from patients with MS. The exosomal miRNA profile of patients with MS differs from that of healthy controls, and let-7i, which is markedly increased in patients with MS, suppresses induction of Treg cells by targeting insulin like growth factor 1 receptor (IGF1R) and transforming growth factor beta receptor 1 (TGFBR1). Consistently, the expression of IGF1R and TGFBR1 on circulating naive CD4 T cells is reduced in patients with MS. Thus, our study shows that exosomal let-7i regulates MS pathogenesis by blocking the IGF1R/TGFBR1 pathway.
[Mh] Termos MeSH primário: Exossomos/imunologia
MicroRNAs/imunologia
Esclerose Múltipla/imunologia
Linfócitos T Reguladores/imunologia
[Mh] Termos MeSH secundário: Adulto
Linfócitos T CD4-Positivos/imunologia
Linfócitos T CD4-Positivos/metabolismo
Exossomos/genética
Exossomos/metabolismo
Feminino
Fatores de Transcrição Forkhead/genética
Fatores de Transcrição Forkhead/imunologia
Fatores de Transcrição Forkhead/metabolismo
Seres Humanos
Interleucina-17/genética
Interleucina-17/imunologia
Interleucina-17/metabolismo
Masculino
MicroRNAs/genética
Meia-Idade
Esclerose Múltipla/sangue
Esclerose Múltipla/genética
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/imunologia
Proteínas Serina-Treonina Quinases/metabolismo
Receptores de Somatomedina/genética
Receptores de Somatomedina/imunologia
Receptores de Somatomedina/metabolismo
Receptores de Fatores de Crescimento Transformadores beta/genética
Receptores de Fatores de Crescimento Transformadores beta/imunologia
Receptores de Fatores de Crescimento Transformadores beta/metabolismo
Linfócitos T Reguladores/metabolismo
Transcriptoma/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (FOXP3 protein, human); 0 (Forkhead Transcription Factors); 0 (IGF1R protein, human); 0 (IL17A protein, human); 0 (Interleukin-17); 0 (MicroRNAs); 0 (Receptors, Somatomedin); 0 (Receptors, Transforming Growth Factor beta); 0 (mirnlet7 microRNA, human); EC 2.7.1.11 (TGF-beta type I receptor); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02406-2


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[PMID]:28463114
[Au] Autor:Moura M; Osswald M; Leça N; Barbosa J; Pereira AJ; Maiato H; Sunkel CE; Conde C
[Ad] Endereço:i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
[Ti] Título:Protein Phosphatase 1 inactivates Mps1 to ensure efficient Spindle Assembly Checkpoint silencing.
[So] Source:Elife;6, 2017 05 02.
[Is] ISSN:2050-084X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Faithfull genome partitioning during cell division relies on the Spindle Assembly Checkpoint (SAC), a conserved signaling pathway that delays anaphase onset until all chromosomes are attached to spindle microtubules. Mps1 kinase is an upstream SAC regulator that promotes the assembly of an anaphase inhibitor through a sequential multi-target phosphorylation cascade. Thus, the SAC is highly responsive to Mps1, whose activity peaks in early mitosis as a result of its T-loop autophosphorylation. However, the mechanism controlling Mps1 inactivation once kinetochores attach to microtubules and the SAC is satisfied remains unknown. Here we show and in that Protein Phosphatase 1 (PP1) inactivates Mps1 by dephosphorylating its T-loop. PP1-mediated dephosphorylation of Mps1 occurs at kinetochores and in the cytosol, and inactivation of both pools of Mps1 during metaphase is essential to ensure prompt and efficient SAC silencing. Overall, our findings uncover a mechanism of SAC inactivation required for timely mitotic exit.
[Mh] Termos MeSH primário: Proteínas de Ciclo Celular/metabolismo
Divisão Celular
Segregação de Cromossomos
Proteínas de Drosophila/metabolismo
Drosophila/fisiologia
Pontos de Checagem da Fase M do Ciclo Celular
Proteína Fosfatase 1/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
[Mh] Termos MeSH secundário: Animais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (Drosophila Proteins); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (ald protein, Drosophila); EC 3.1.3.16 (Protein Phosphatase 1)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


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[PMID]:28460466
[Au] Autor:Mesclon F; Lambert-Langlais S; Carraro V; Parry L; Hainault I; Jousse C; Maurin AC; Bruhat A; Fafournoux P; Averous J
[Ad] Endereço:Université Clermont Auvergne, INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, F-63000 Clermont-Ferrand, France.
[Ti] Título:Decreased ATF4 expression as a mechanism of acquired resistance to long-term amino acid limitation in cancer cells.
[So] Source:Oncotarget;8(16):27440-27453, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The uncontrolled growth of tumor can lead to the formation of area deprived in nutrients. Due to their high genetic instability, tumor cells can adapt and develop resistance to this pro-apoptotic environment. Among the resistance mechanisms, those involved in the resistance to long-term amino acid restriction are not elucidated. A long-term amino acid restriction is particularly deleterious since nine of them cannot be synthetized by the cells. In order to determine how cancer cells face a long-term amino acid deprivation, we developed a cell model selected for its capacity to resist a long-term amino acid limitation. We exerted a selection pressure on mouse embryonic fibroblast to isolate clones able to survive with low amino acid concentration. The study of several clones revealed an alteration of the eiF2α/ATF4 pathway. Compared to the parental cells, the clones exhibited a decreased expression of the transcription factor ATF4 and its target genes. Likewise, the knock-down of ATF4 in parental cells renders them resistant to amino acid deprivation. Moreover, this association between a low level of ATF4 protein and the resistance to amino acid deprivation was also observed in the cancer cell line BxPC-3. This resistance was abolished when ATF4 was overexpressed. Therefore, decreasing ATF4 expression may be one important mechanism for cancer cells to survive under prolonged amino acid deprivation.
[Mh] Termos MeSH primário: Fator 4 Ativador da Transcrição/genética
Aminoácidos/metabolismo
Regulação Neoplásica da Expressão Gênica
[Mh] Termos MeSH secundário: Fator 4 Ativador da Transcrição/metabolismo
Animais
Apoptose/genética
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Perfilação da Expressão Gênica
Seres Humanos
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo
Camundongos
Modelos Biológicos
Neoplasias/genética
Neoplasias/metabolismo
Ligação Proteica
Proteínas Serina-Treonina Quinases/metabolismo
Interferência de RNA
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids); 145891-90-3 (Activating Transcription Factor 4); EC 2.7.11.1 (EIF2AK4 protein, human); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15828


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[PMID]:28460446
[Au] Autor:Kapil S; Sharma BK; Patil M; Elattar S; Yuan J; Hou SX; Kolhe R; Satyanarayana A
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Molecular Oncology & Biomarkers Program, Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
[Ti] Título:The cell polarity protein Scrib functions as a tumor suppressor in liver cancer.
[So] Source:Oncotarget;8(16):26515-26531, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Scrib is a membrane protein that is involved in the maintenance of apical-basal cell polarity of the epithelial tissues. However, Scrib has also been shown to be mislocalized to the cytoplasm in breast and prostate cancer. Here, for the first time, we report that Scrib not only translocates to the cytoplasm but also to the nucleus in hepatocellular carcinoma (HCC) cells, and in mouse and human liver tumor samples. We demonstrate that Scrib overexpression suppresses the growth of HCC cells in vitro, and Scrib deficiency enhances liver tumor growth in vivo. At the molecular level, we have identified the existence of a positive feed-back loop between Yap1 and c-Myc in HCC cells, which Scrib disrupts by simultaneously regulating the MAPK/ERK and Hippo signaling pathways. Overall, Scrib inhibits liver cancer cell proliferation by suppressing the expression of three oncogenes, Yap1, c-Myc and cyclin D1, thereby functioning as a tumor suppressor in liver cancer.
[Mh] Termos MeSH primário: Neoplasias Hepáticas/metabolismo
Proteínas de Membrana/metabolismo
Proteínas Supressoras de Tumor/metabolismo
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular
Proteínas Adaptadoras de Transdução de Sinal/genética
Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Animais
Ciclo Celular/genética
Linhagem Celular Tumoral
Proliferação Celular
Transformação Celular Neoplásica/induzido quimicamente
Transformação Celular Neoplásica/genética
Transformação Celular Neoplásica/metabolismo
Ciclina D1/genética
Ciclina D1/metabolismo
Modelos Animais de Doenças
Expressão Gênica
Xenoenxertos
Seres Humanos
Neoplasias Hepáticas/genética
Sistema de Sinalização das MAP Quinases
Proteínas de Membrana/genética
Camundongos
Fosfoproteínas/genética
Fosfoproteínas/metabolismo
Ligação Proteica
Transporte Proteico
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Proto-Oncogênicas c-myc/genética
Proteínas Proto-Oncogênicas c-myc/metabolismo
Transdução de Sinais
Proteínas Supressoras de Tumor/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Membrane Proteins); 0 (Phosphoproteins); 0 (Proto-Oncogene Proteins c-myc); 0 (SCRIB protein, human); 0 (Tumor Suppressor Proteins); 0 (YAP1 (Yes-associated) protein, human); 136601-57-5 (Cyclin D1); EC 2.7.11.1 (Hippo protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15713



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