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Pesquisa : D12.644.360.325.150.500.460 [Categoria DeCS]
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[PMID]:29179212
[Au] Autor:Sun XX; Zhang SS; Dai CY; Peng J; Pan Q; Xu LF; Ma XL
[Ad] Endereço:Department of Laboratory Medicine, Anhui Provincial Hospital, Anhui Medical University, Hefei, China.
[Ti] Título:LukS-PV-Regulated MicroRNA-125a-3p Promotes THP-1 Macrophages Differentiation and Apoptosis by Down-Regulating NF1 and Bcl-2.
[So] Source:Cell Physiol Biochem;44(3):1093-1105, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: LukS-PV is a component of Panton-Valentine leukocidin (PVL). We have previously demonstrated that LukS-PV potently promoted differentiation and induced apoptosis in THP-1 cells. However, the precise mechanisms of these actions remain unknown. MicroRNAs (miRs) play important roles in cellular differentiation and apoptosis. This study aimed to investigate the role of miR-125a-3p in LukS-PV-regulated differentiation and apoptosis and its underlying mechanism in THP-1 cells. METHODS: MicroRNA profiling analyses were conducted to determine differential miRNA expression levels in THP-1 cells treated with LukS-PV. Cell differentiation and apoptosis were measured in THP-1 cells by gain-of-function and loss-of-function experiments. Bioinformatics analysis and luciferase reporter assays were used to confirm the targets of miR-125a-3p. The effects of the miR-125a-3p targets on cellular differentiation were determined by knocking them down. RESULTS: MiR-125a-3p was up-regulated after treating the human monocytic leukaemia cell line THP-1 with LukS-PV. In addition, miR-125a-3p positively regulated apoptosis and differentiation in THP-1 cells treated with LukS-PV. Concordantly, luciferase reporter assays confirmed that neurofibromatosis type 1 (NF1) and B-cell lymphoma 2 (Bcl-2) were direct target genes of miR-125a-3p. Moreover, NF1 knockdown in THP-1 cells significantly promoted differentiation in vitro. Finally, the extracellular signal-regulated kinase (ERK) pathway, a downstream target of NF1, was activated after NF1 knockdown. CONCLUSIONS: These findings confirm that miR-125a-3p is involved in LukS-PV-mediated cell differentiation and apoptosis in THP-1 cells.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Toxinas Bacterianas/farmacologia
Diferenciação Celular/efeitos dos fármacos
Exotoxinas/farmacologia
Leucocidinas/farmacologia
MicroRNAs/metabolismo
Neurofibromina 1/metabolismo
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas
Antagomirs/metabolismo
Toxinas Bacterianas/genética
Toxinas Bacterianas/metabolismo
Sequência de Bases
Caspase 3/metabolismo
Linhagem Celular
Regulação para Baixo/efeitos dos fármacos
Exotoxinas/genética
Exotoxinas/metabolismo
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos
Seres Humanos
Leucocidinas/genética
Leucocidinas/metabolismo
Macrófagos/citologia
Macrófagos/efeitos dos fármacos
Macrófagos/metabolismo
MicroRNAs/antagonistas & inibidores
MicroRNAs/genética
Neurofibromina 1/antagonistas & inibidores
Neurofibromina 1/genética
Fosforilação/efeitos dos fármacos
Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-bcl-2/genética
Proteínas Recombinantes/biossíntese
Proteínas Recombinantes/isolamento & purificação
Proteínas Recombinantes/farmacologia
Alinhamento de Sequência
Transdução de Sinais/efeitos dos fármacos
Transcriptoma/efeitos dos fármacos
Proteína X Associada a bcl-2/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (Antagomirs); 0 (Bacterial Toxins); 0 (Exotoxins); 0 (Leukocidins); 0 (MIRN125 microRNA, human); 0 (MicroRNAs); 0 (Neurofibromin 1); 0 (Panton-Valentine leukocidin); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Recombinant Proteins); 0 (bcl-2-Associated X Protein); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.4.22.- (Caspase 3)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1159/000485415


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[PMID]:27773571
[Au] Autor:Xie K; Colgan LA; Dao MT; Muntean BS; Sutton LP; Orlandi C; Boye SL; Boye SE; Shih CC; Li Y; Xu B; Smith RG; Yasuda R; Martemyanov KA
[Ad] Endereço:Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
[Ti] Título:NF1 Is a Direct G Protein Effector Essential for Opioid Signaling to Ras in the Striatum.
[So] Source:Curr Biol;26(22):2992-3003, 2016 Nov 21.
[Is] ISSN:1879-0445
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:It is well recognized that G-protein-coupled receptors (GPCRs) can activate Ras-regulated kinase pathways to produce lasting changes in neuronal function. Mechanisms by which GPCRs transduce these signals and their relevance to brain disorders are not well understood. Here, we identify a major Ras regulator, neurofibromin 1 (NF1), as a direct effector of GPCR signaling via Gßγ subunits in the striatum. We find that binding of Gßγ to NF1 inhibits its ability to inactivate Ras. Deletion of NF1 in striatal neurons prevents the opioid-receptor-induced activation of Ras and eliminates its coupling to Akt-mTOR-signaling pathway. By acting in the striatal medium spiny neurons of the direct pathway, NF1 regulates opioid-induced changes in Ras activity, thereby sensitizing mice to psychomotor and rewarding effects of morphine. These results delineate a novel mechanism of GPCR signaling to Ras pathways and establish a critical role of NF1 in opioid addiction.
[Mh] Termos MeSH primário: Analgésicos Opioides/metabolismo
Neurofibromina 1/genética
Receptores Acoplados a Proteínas-G/metabolismo
Transdução de Sinais
Proteínas ras/metabolismo
[Mh] Termos MeSH secundário: Animais
Feminino
Masculino
Camundongos
Neostriado/metabolismo
Neurofibromina 1/metabolismo
Neurônios/metabolismo
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics, Opioid); 0 (Neurofibromin 1); 0 (Receptors, G-Protein-Coupled); EC 3.6.5.2 (ras Proteins)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180112
[Lr] Data última revisão:
180112
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


  3 / 1091 MEDLINE  
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[PMID]:28637693
[Au] Autor:Fell SM; Li S; Wallis K; Kock A; Surova O; Rraklli V; Höfig CS; Li W; Mittag J; Henriksson MA; Kenchappa RS; Holmberg J; Kogner P; Schlisio S
[Ad] Endereço:Ludwig Institute for Cancer Research Ltd., SE-17177 Stockholm, Sweden.
[Ti] Título:Neuroblast differentiation during development and in neuroblastoma requires KIF1Bß-mediated transport of TRKA.
[So] Source:Genes Dev;31(10):1036-1053, 2017 May 15.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We recently identified pathogenic ß mutations in sympathetic nervous system malignancies that are defective in developmental apoptosis. Here we deleted ß in the mouse sympathetic nervous system and observed impaired sympathetic nervous function and misexpression of genes required for sympathoadrenal lineage differentiation. We discovered that KIF1Bß is required for nerve growth factor (NGF)-dependent neuronal differentiation through anterograde transport of the NGF receptor TRKA. Moreover, pathogenic ß mutations identified in neuroblastoma impair TRKA transport. Expression of neuronal differentiation markers is ablated in both ß-deficient mouse neuroblasts and human neuroblastomas that lack KIF1Bß. Transcriptomic analyses show that unfavorable neuroblastomas resemble mouse sympathetic neuroblasts lacking KIF1Bß independent of amplification and the loss of genes neighboring on chromosome 1p36. Thus, defective precursor cell differentiation, a common trait of aggressive childhood malignancies, is a pathogenic effect of KIF1Bß loss in neuroblastomas. Furthermore, neuropathy-associated mutations impede cargo transport, providing a direct link between neuroblastomas and neurodegeneration.
[Mh] Termos MeSH primário: Diferenciação Celular/genética
Cinesina/genética
Cinesina/metabolismo
Neuroblastoma/genética
Neurônios/citologia
Receptor trkA/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose/genética
Linhagem Celular Tumoral
Regulação da Expressão Gênica no Desenvolvimento
Inativação Gênica
Mutação
Neuroblastoma/fisiopatologia
Doenças Neurodegenerativas/genética
Doenças Neurodegenerativas/fisiopatologia
Neurofibromina 1/genética
Neurofibromina 1/metabolismo
Células PC12
Ratos
Transdução de Sinais/genética
Sistema Nervoso Simpático/citologia
Proteínas ras/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Kif1b protein, mouse); 0 (Neurofibromin 1); EC 2.7.10.1 (Receptor, trkA); EC 3.6.4.4 (Kinesin); EC 3.6.5.2 (ras Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1101/gad.297077.117


  4 / 1091 MEDLINE  
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[PMID]:28543693
[Au] Autor:Reddy BY; Miller DM; Tsao H
[Ad] Endereço:Department of Dermatology, Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
[Ti] Título:Somatic driver mutations in melanoma.
[So] Source:Cancer;123(S11):2104-2117, 2017 Jun 01.
[Is] ISSN:1097-0142
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Melanoma has one of the highest somatic mutational burdens among solid malignancies. Although the rapid progress in genomic research has contributed immensely to our understanding of the pathogenesis of melanoma, the clinical significance of the vast array of genomic alterations discovered by next-generation sequencing is far from being fully characterized. Most mutations prevalent in melanoma are simply neutral "passengers," which accompany functionally significant "drivers" under transforming conditions. The delineation of driver mutations from passenger mutations is critical to the development of targeted therapies. Novel advances in genomic data analysis have aided in distinguishing true driver mutations involved in tumor progression. Here, the authors review the current literature on important somatic driver mutations in melanoma, along with the implications for treatment. Cancer 2017;123:2104-17. © 2017 American Cancer Society.
[Mh] Termos MeSH primário: Melanoma/genética
Mutação
Neoplasias Cutâneas/genética
Neoplasias Uveais/genética
[Mh] Termos MeSH secundário: Ciclina D1/genética
GTP Fosfo-Hidrolases/genética
Subunidades alfa de Proteínas de Ligação ao GTP/genética
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética
Fatores de Troca do Nucleotídeo Guanina/genética
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Proteínas de Membrana/genética
Metaloproteínas/genética
Fator de Transcrição Associado à Microftalmia/genética
Neurofibromina 1/genética
Proteínas Nucleares/genética
PTEN Fosfo-Hidrolase/genética
Proteínas Proto-Oncogênicas B-raf/genética
Proteínas Proto-Oncogênicas c-kit/genética
Proteínas de Ligação a RNA/genética
Proteínas Ribossômicas/genética
Análise de Sequência de DNA
Telomerase/genética
Proteína Supressora de Tumor p53/genética
Proteínas rac1 de Ligação ao GTP/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (GNA11 protein, human); 0 (GNAQ protein, human); 0 (GTP-Binding Protein alpha Subunits); 0 (Guanine Nucleotide Exchange Factors); 0 (Membrane Proteins); 0 (Metalloproteins); 0 (Microphthalmia-Associated Transcription Factor); 0 (Neurofibromin 1); 0 (Nuclear Proteins); 0 (PREX2 protein, human); 0 (RAC1 protein, human); 0 (RNA-Binding Proteins); 0 (RPS27 protein, human); 0 (Ribosomal Proteins); 0 (Tumor Suppressor Protein p53); 136601-57-5 (Cyclin D1); EC 2.7.10.1 (Proto-Oncogene Proteins c-kit); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); EC 2.7.7.49 (TERT protein, human); EC 2.7.7.49 (Telomerase); EC 3.1.3.67 (PTEN Phosphohydrolase); EC 3.6.1.- (GTP Phosphohydrolases); EC 3.6.1.- (NRAS protein, human); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gq-G11); EC 3.6.5.2 (rac1 GTP-Binding Protein)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1002/cncr.30593


  5 / 1091 MEDLINE  
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[PMID]:28445745
[Au] Autor:Walter C; Crawford L; Lai M; Toonen JA; Pan Y; Sakiyama-Elbert S; Gutmann DH; Pathak A
[Ad] Endereço:Department of Biomedical Engineering, Washington University, St. Louis, Missouri.
[Ti] Título:Increased Tissue Stiffness in Tumors from Mice with Neurofibromatosis-1 Optic Glioma.
[So] Source:Biophys J;112(8):1535-1538, 2017 Apr 25.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Children with neurofibromatosis type 1 (NF1) cancer predisposition syndrome are prone to the development of low-grade brain tumors (gliomas) within the optic pathway (optic gliomas). One of the key obstacles to developing successful therapeutic strategies for these tumors is the striking lack of information about the mechanical properties that characterize these tumors relative to non-neoplastic optic nerve tissue. To study the physical changes that may occur when an optic nerve glioma is present, we employed atomic force microscopy to measure the stiffness of healthy versus tumor-bearing optic nerve tissue. We found that the average elastic moduli of non-neoplastic and tumor-bearing optic nerves were ∼3 and ∼6 kPa, respectively. Based on previous studies implicating changes in extracellular matrix remodeling in other, related optic nerve pathological states, we found decreased expression of one major metalloproteinase protein (MMP-2) and unchanged expression of lysyl oxidase and a second metalloproteinase, MMP-9, in murine optic gliomas relative to normal non-neoplastic optic nerve. Collectively, these observations suggest a productive interplay between physical properties of mouse optic nerve gliomas and the extracellular matrix.
[Mh] Termos MeSH primário: Neurofibromatose 1/fisiopatologia
Glioma do Nervo Óptico/fisiopatologia
Nervo Óptico/fisiopatologia
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Módulo de Elasticidade
Matriz Extracelular/fisiologia
Metaloproteinase 2 da Matriz/metabolismo
Metaloproteinase 9 da Matriz/metabolismo
Camundongos Transgênicos
Microscopia de Força Atômica
Neurofibromina 1
Proteína-Lisina 6-Oxidase/metabolismo
RNA Mensageiro/metabolismo
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0 (Neurofibromin 1); 0 (RNA, Messenger); EC 1.4.3.13 (Protein-Lysine 6-Oxidase); EC 3.4.24.24 (Matrix Metalloproteinase 2); EC 3.4.24.24 (Mmp2 protein, mouse); EC 3.4.24.35 (Matrix Metalloproteinase 9); EC 3.4.24.35 (Mmp9 protein, mouse)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170813
[Lr] Data última revisão:
170813
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170427
[St] Status:MEDLINE


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[PMID]:28423318
[Au] Autor:López-Juárez A; Titus HE; Silbak SH; Pressler JW; Rizvi TA; Bogard M; Bennett MR; Ciraolo G; Williams MT; Vorhees CV; Ratner N
[Ad] Endereço:Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
[Ti] Título:Oligodendrocyte Nf1 Controls Aberrant Notch Activation and Regulates Myelin Structure and Behavior.
[So] Source:Cell Rep;19(3):545-557, 2017 Apr 18.
[Is] ISSN:2211-1247
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The RASopathy neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic disorders. In NF1 patients, neurological issues may result from damaged myelin, and mice with a neurofibromin gene (Nf1) mutation show white matter (WM) defects including myelin decompaction. Using mouse genetics, we find that altered Nf1 gene-dose in mature oligodendrocytes results in progressive myelin defects and behavioral abnormalities mediated by aberrant Notch activation. Blocking Notch, upstream mitogen-activated protein kinase (MAPK), or nitric oxide signaling rescues myelin defects in hemizygous Nf1 mutants, and pharmacological gamma secretase inhibition rescues aberrant behavior with no effects in wild-type (WT) mice. Concomitant pathway inhibition rescues myelin abnormalities in homozygous mutants. Notch activation is also observed in Nf1 mouse brains, and cells containing active Notch are increased in NF1 patient WM. We thus identify Notch as an Nf1 effector regulating myelin structure and behavior in a RASopathy and suggest that inhibition of Notch signaling may be a therapeutic strategy for NF1.
[Mh] Termos MeSH primário: Bainha de Mielina/metabolismo
Neurofibromina 1/metabolismo
Receptores Notch/metabolismo
[Mh] Termos MeSH secundário: Secretases da Proteína Precursora do Amiloide/metabolismo
Animais
Comportamento Animal
Contagem de Células
Claudinas/metabolismo
Dosagem de Genes
Seres Humanos
Sistema de Sinalização das MAP Quinases
Camundongos Endogâmicos C57BL
Modelos Biológicos
Mutação/genética
Neuroglia/metabolismo
Óxido Nítrico/metabolismo
Oligodendroglia/citologia
Oligodendroglia/metabolismo
Transdução de Sinais
Proteínas ras/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Claudins); 0 (Neurofibromin 1); 0 (Receptors, Notch); 31C4KY9ESH (Nitric Oxide); EC 3.4.- (Amyloid Precursor Protein Secretases); EC 3.6.5.2 (ras Proteins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170509
[Lr] Data última revisão:
170509
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170420
[St] Status:MEDLINE


  7 / 1091 MEDLINE  
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[PMID]:28418444
[Au] Autor:Couch FJ; Shimelis H; Hu C; Hart SN; Polley EC; Na J; Hallberg E; Moore R; Thomas A; Lilyquist J; Feng B; McFarland R; Pesaran T; Huether R; LaDuca H; Chao EC; Goldgar DE; Dolinsky JS
[Ad] Endereço:Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
[Ti] Título:Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer.
[So] Source:JAMA Oncol;3(9):1190-1196, 2017 Sep 01.
[Is] ISSN:2374-2445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Importance: Germline pathogenic variants in BRCA1 and BRCA2 predispose to an increased lifetime risk of breast cancer. However, the relevance of germline variants in other genes from multigene hereditary cancer testing panels is not well defined. Objective: To determine the risks of breast cancer associated with germline variants in cancer predisposition genes. Design, Setting, and Participants: A study population of 65 057 patients with breast cancer receiving germline genetic testing of cancer predisposition genes with hereditary cancer multigene panels. Associations between pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes and breast cancer risk were estimated in a case-control analysis of patients with breast cancer and Exome Aggregation Consortium reference controls. The women underwent testing between March 15, 2012, and June 30, 2016. Main Outcomes and Measures: Breast cancer risk conferred by pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes. Results: The mean (SD) age at diagnosis for the 65 057 women included in the analysis was 48.5 (11.1) years. The frequency of pathogenic variants in 21 panel genes identified in 41 611 consecutively tested white women with breast cancer was estimated at 10.2%. After exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, and TP53), observed pathogenic variants in 5 of 16 genes were associated with high or moderately increased risks of breast cancer: ATM (OR, 2.78; 95% CI, 2.22-3.62), BARD1 (OR, 2.16; 95% CI, 1.31-3.63), CHEK2 (OR, 1.48; 95% CI, 1.31-1.67), PALB2 (OR, 7.46; 95% CI, 5.12-11.19), and RAD51D (OR, 3.07; 95% CI, 1.21-7.88). Conversely, variants in the BRIP1 and RAD51C ovarian cancer risk genes; the MRE11A, RAD50, and NBN MRN complex genes; the MLH1 and PMS2 mismatch repair genes; and NF1 were not associated with increased risks of breast cancer. Conclusions and Relevance: This study establishes several panel genes as high- and moderate-risk breast cancer genes and provides estimates of breast cancer risk associated with pathogenic variants in these genes among individuals qualifying for clinical genetic testing.
[Mh] Termos MeSH primário: Proteínas Mutadas de Ataxia Telangiectasia/genética
Neoplasias da Mama/genética
Quinase do Ponto de Checagem 2/genética
Proteínas de Ligação a DNA/genética
Predisposição Genética para Doença
Proteínas Nucleares/genética
Neoplasias Ovarianas/genética
Proteínas Supressoras de Tumor/genética
Ubiquitina-Proteína Ligases/genética
[Mh] Termos MeSH secundário: Adulto
Estudos de Casos e Controles
Proteínas de Ciclo Celular/genética
Inibidor de Quinase Dependente de Ciclina p18/genética
Enzimas Reparadoras do DNA/genética
Grupo com Ancestrais do Continente Europeu/genética
Proteína do Grupo de Complementação N da Anemia de Fanconi
Proteínas de Grupos de Complementação da Anemia de Fanconi
Feminino
Testes Genéticos
Mutação em Linhagem Germinativa
Seres Humanos
Proteína Homóloga a MRE11
Meia-Idade
Endonuclease PMS2 de Reparo de Erro de Pareamento/genética
Proteína 1 Homóloga a MutL/genética
Proteína 2 Homóloga a MutS/genética
Neurofibromina 1/genética
Fenótipo
RNA Helicases/genética
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CDKN2A protein, human); 0 (Cell Cycle Proteins); 0 (Cyclin-Dependent Kinase Inhibitor p18); 0 (DNA-Binding Proteins); 0 (Fanconi Anemia Complementation Group N Protein); 0 (Fanconi Anemia Complementation Group Proteins); 0 (G-T mismatch-binding protein); 0 (MLH1 protein, human); 0 (MRE11A protein, human); 0 (NBN protein, human); 0 (Neurofibromin 1); 0 (Nuclear Proteins); 0 (PALB2 protein, human); 0 (RAD51C protein, human); 0 (RAD51D protein, human); 0 (Rad50 protein, human); 0 (Tumor Suppressor Proteins); EC 2.3.2.27 (BARD1 protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 2.7.1.11 (Checkpoint Kinase 2); EC 2.7.11.1 (ATM protein, human); EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins); EC 2.7.11.1 (CHEK2 protein, human); EC 3.1.- (MRE11 Homologue Protein); EC 3.6.1.- (PMS2 protein, human); EC 3.6.1.3 (MSH2 protein, human); EC 3.6.1.3 (Mismatch Repair Endonuclease PMS2); EC 3.6.1.3 (MutL Protein Homolog 1); EC 3.6.1.3 (MutS Homolog 2 Protein); EC 3.6.4.13 (BRIP1 protein, human); EC 3.6.4.13 (RNA Helicases); EC 6.5.1.- (DNA Repair Enzymes)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.1001/jamaoncol.2017.0424


  8 / 1091 MEDLINE  
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[PMID]:28267273
[Au] Autor:Cirenajwis H; Lauss M; Ekedahl H; Törngren T; Kvist A; Saal LH; Olsson H; Staaf J; Carneiro A; Ingvar C; Harbst K; Hayward NK; Jönsson G
[Ad] Endereço:Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Sweden.
[Ti] Título:NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics.
[So] Source:Mol Oncol;11(4):438-451, 2017 Apr.
[Is] ISSN:1878-0261
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In general, melanoma can be considered as a UV-driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen-activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF, RAS, NF1 mutation or triple-wild-type status and correlated with tumor and patient characteristics. We found that the NF1-mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co-occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain-containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1-mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease-specific survival, DSS; HR, 1.9; 95% CI, 1.21-3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28-2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.
[Mh] Termos MeSH primário: Melanoma/genética
Melanoma/patologia
Mutação/genética
Neurofibromina 1/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Estudos de Coortes
Feminino
Genoma Humano
Seres Humanos
Sistema de Sinalização das MAP Quinases/genética
Masculino
Melanoma/enzimologia
Meia-Idade
Análise de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neurofibromin 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170308
[St] Status:MEDLINE
[do] DOI:10.1002/1878-0261.12050


  9 / 1091 MEDLINE  
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[PMID]:28254468
[Au] Autor:Baht GS; Nadesan P; Silkstone D; Alman BA
[Ad] Endereço:Department of Orthopaedic Surgery, Duke University, Durham, USA; Duke Molecular Physiology Institute, Duke University, Durham, USA.
[Ti] Título:Pharmacologically targeting beta-catenin for NF1 associated deficiencies in fracture repair.
[So] Source:Bone;98:31-36, 2017 May.
[Is] ISSN:1873-2763
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Patients with Neurofibromatosis type 1 display delayed fracture healing and the increased deposition of fibrous tissue at the fracture site. Severe cases can lead to non-union and even congenital pseudarthrosis. Neurofibromatosis type 1 is caused by a mutation in the NF1 gene and mice lacking the Nf1 gene show a fracture repair phenotype similar to that seen in patients. Tissue from the fracture site of patients with Neurofibromatosis type 1 and from mice deficient in the Nf1 gene both show elevated levels of ß-catenin protein and activation of ß-catenin mediated signaling. Constitutively elevated ß-catenin leads to a delayed and fibrous fracture repair process, and (RS)-5-methyl-1-phenyl-1,3,4,6-tetrahydro-2,5-benzoxazocine (Nefopam, a centrally-acting, non-narcotic analgesic agent) inhibits ß-catenin mediated signaling during skin wound repair. Here we investigate Nefopam's potential as a modulator of bone repair in mice deficient in Nf1. Mice were treated with Nefopam and investigated for bone fracture repair. Bone marrow stromal cells flushed from the long bones of unfractured mice were treated with Nefopam and investigated for osteogenic potential. Treatment with Nefopam was able to lower the ß-catenin level and the Axin2 transcript level in the fracture calluses of Nf1 deficient mice. Cultures from the bone marrow of Nf1 mice had significantly lower osteoblastic colonies and mineralized nodules, which was increased when cells were cultured in the presence of Nefopam. Fracture calluses were harvested and analyzed 14days and 21days after injury. Nf1 calluses had less bone, less cartilage, and higher fibrous tissue content than control calluses. Treatment with Nefopam increased the bone and cartilage content and decreased the fibrous tissue content in Nf1 calluses. These findings present a potential treatment for patients with Neurofibromatosis 1 in the context of bone repair. Since Nefopam is already in use in patient care, it could be rapidly translated to the clinical setting.
[Mh] Termos MeSH primário: Analgésicos não Entorpecentes/farmacologia
Consolidação da Fratura/efeitos dos fármacos
beta Catenina/metabolismo
[Mh] Termos MeSH secundário: Animais
Western Blotting
Diferenciação Celular/efeitos dos fármacos
Modelos Animais de Doenças
Consolidação da Fratura/fisiologia
Fraturas Ósseas/metabolismo
Genes da Neurofibromatose 1
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Neurofibromina 1/deficiência
Osteoblastos/citologia
Osteoblastos/efeitos dos fármacos
Reação em Cadeia da Polimerase em Tempo Real
Transdução de Sinais/efeitos dos fármacos
Transdução de Sinais/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics, Non-Narcotic); 0 (Neurofibromin 1); 0 (beta Catenin)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170427
[Lr] Data última revisão:
170427
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170304
[St] Status:MEDLINE


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[PMID]:28174230
[Au] Autor:Li X; Gao M; Choi JM; Kim BJ; Zhou MT; Chen Z; Jain AN; Jung SY; Yuan J; Wang W; Wang Y; Chen J
[Ad] Endereço:From the ‡Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
[Ti] Título:Clustered, Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9-coupled Affinity Purification/Mass Spectrometry Analysis Revealed a Novel Role of Neurofibromin in mTOR Signaling.
[So] Source:Mol Cell Proteomics;16(4):594-607, 2017 Apr.
[Is] ISSN:1535-9484
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neurofibromin (NF1) is a well known tumor suppressor that is commonly mutated in cancer patients. It physically interacts with RAS and negatively regulates RAS GTPase activity. Despite the importance of NF1 in cancer, a high quality endogenous NF1 interactome has yet to be established. In this study, we combined lustered, egularly nterspaced hort alindromic epeats (CRISPR)/Cas9-mediated gene knock-out technology with affinity purification using antibodies against endogenous proteins, followed by mass spectrometry analysis, to sensitively and accurately detect NF1 protein-protein interactions in unaltered settings. Using this system, we analyzed endogenous NF1-associated protein complexes and identified 49 high-confidence candidate interaction proteins, including RAS and other functionally relevant proteins. Through functional validation, we found that NF1 negatively regulates mechanistic target of rapamycin signaling (mTOR) in a LAMTOR1-dependent manner. In addition, the cell growth and survival of NF1-deficient cells have become dependent on hyperactivation of the mTOR pathway, and the tumorigenic properties of these cells have become dependent on LAMTOR1. Taken together, our findings may provide novel insights into therapeutic approaches targeting NF1-deficient tumors.
[Mh] Termos MeSH primário: Proteínas de Transporte/metabolismo
Edição de Genes/métodos
Neoplasias/metabolismo
Neurofibromina 1/metabolismo
Proteômica/métodos
Serina-Treonina Quinases TOR/metabolismo
[Mh] Termos MeSH secundário: Sistemas CRISPR-Cas
Proteínas de Transporte/genética
Proliferação Celular
Sobrevivência Celular
Células HEK293
Células HeLa
Seres Humanos
Espectrometria de Massas
Neoplasias/genética
Neurofibromina 1/genética
Mapas de Interação de Proteínas
Transdução de Sinais
Serina-Treonina Quinases TOR/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Neurofibromin 1); 0 (p27RF-Rho protein, human); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170930
[Lr] Data última revisão:
170930
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170209
[St] Status:MEDLINE
[do] DOI:10.1074/mcp.M116.064543



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