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Pesquisa : D12.776.476.400.842.374 [Categoria DeCS]
Referências encontradas : 61 [refinar]
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[PMID]:28073913
[Au] Autor:Papaioannou G; Petit ET; Liu ES; Baccarini M; Pritchard C; Demay MB
[Ad] Endereço:From the Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.
[Ti] Título:Raf Kinases Are Essential for Phosphate Induction of ERK1/2 Phosphorylation in Hypertrophic Chondrocytes and Normal Endochondral Bone Development.
[So] Source:J Biol Chem;292(8):3164-3171, 2017 Feb 24.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hypophosphatemia causes rickets by impairing hypertrophic chondrocyte apoptosis. Phosphate induction of MEK1/2-ERK1/2 phosphorylation in hypertrophic chondrocytes is required for phosphate-mediated apoptosis and growth plate maturation. MEK1/2 can be activated by numerous molecules including Raf isoforms. A- and B-Raf ablation in chondrocytes does not alter skeletal development, whereas ablation of C-Raf decreases hypertrophic chondrocyte apoptosis and impairs vascularization of the growth plate. However, ablation of C-Raf does not impair phosphate-induced ERK1/2 phosphorylation , but leads to rickets by decreasing VEGF protein stability. To determine whether Raf isoforms are required for phosphate-induced hypertrophic chondrocyte apoptosis, mice lacking all three Raf isoforms in chondrocytes were generated. Raf deletion caused neonatal death and a significant expansion of the hypertrophic chondrocyte layer of the growth plate, accompanied by decreased cleaved caspase-9. This was associated with decreased phospho-ERK1/2 immunoreactivity in the hypertrophic chondrocyte layer and impaired vascular invasion. These data further demonstrated that Raf kinases are required for phosphate-induced ERK1/2 phosphorylation in cultured hypertrophic chondrocytes and perform essential, but partially redundant roles in growth plate maturation.
[Mh] Termos MeSH primário: Condrócitos/metabolismo
Condrogênese
Lâmina de Crescimento/crescimento & desenvolvimento
Proteína Quinase 1 Ativada por Mitógeno/metabolismo
Proteína Quinase 3 Ativada por Mitógeno/metabolismo
Proteínas Proto-Oncogênicas A-raf/metabolismo
Proteínas Proto-Oncogênicas B-raf/metabolismo
Proteínas Proto-Oncogênicas c-raf/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose
Desenvolvimento Ósseo
Células Cultivadas
Condrócitos/citologia
Condrócitos/patologia
Lâmina de Crescimento/metabolismo
Camundongos Endogâmicos C57BL
Fosfatos/metabolismo
Fosforilação
Isoformas de Proteínas/metabolismo
Quinases raf/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phosphates); 0 (Protein Isoforms); EC 2.7.11.1 (Braf protein, mouse); EC 2.7.11.1 (Proto-Oncogene Proteins A-raf); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); EC 2.7.11.1 (Proto-Oncogene Proteins c-raf); EC 2.7.11.1 (raf Kinases); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
[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:170112
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.763342


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[PMID]:27240957
[Au] Autor:Zhang Q; Matsui H; Horiuchi H; Liang X; Sasaki K
[Ad] Endereço:Department of Oral Implantology, State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, Sichuan, China; Department of Advanced Prosthetic Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan.
[Ti] Título:A-Raf and C-Raf differentially regulate mechanobiological response of osteoblasts to guide mechanical stress-induced differentiation.
[So] Source:Biochem Biophys Res Commun;476(4):438-444, 2016 08 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Regulation of osteoblast activity by mechanical stress is important for bone remodeling. However, the precise mechanotransduction mechanism that triggers the anabolic reaction of osteoblasts is largely unknown. In this study, we performed RNA interference (RNAi) screening to identify the signaling molecules upstream of ERK, which was responsible for osteogenesis. Of twenty-two mitogen-activated protein kinase (MAPK) kinase kinases (MAP3Ks), we identified A-Raf and C-Raf as upstream MAP3Ks of the mechanical stretch-activated ERK pathway. Subsequently we screened the mechanosensitive cation channel, and identified P2X7 as an upstream molecule of the ERK pathway. Intriguingly, P2X7 functioned as an upstream activator of A-Raf but not of C-Raf. Furthermore, A-Raf contributed to mechanical stretch-induced osteoblast differentiation. In contrast, C-Raf but not A-Raf protected osteoblasts from mechanical stretch-induced apoptosis. These results suggested that A-Raf and C-Raf were involved in mechanobiological osteogenesis in a distinct way: A-Raf was responsible for osteogenesis while C-Raf for anti-apoptotic protection and promotion.
[Mh] Termos MeSH primário: Osteoblastos/citologia
Proteínas Proto-Oncogênicas A-raf/metabolismo
Proteínas Proto-Oncogênicas c-raf/metabolismo
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular/fisiologia
Linhagem Celular
Sobrevivência Celular
MAP Quinase Quinase Quinases/genética
MAP Quinase Quinase Quinases/metabolismo
Camundongos
Proteínas Quinases Ativadas por Mitógeno/genética
Proteínas Quinases Ativadas por Mitógeno/metabolismo
Osteoblastos/fisiologia
Proteínas Proto-Oncogênicas A-raf/genética
Proteínas Proto-Oncogênicas c-raf/genética
Interferência de RNA
Receptores Purinérgicos P2X7/genética
Receptores Purinérgicos P2X7/metabolismo
Estresse Mecânico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Receptors, Purinergic P2X7); EC 2.7.11.1 (Proto-Oncogene Proteins A-raf); EC 2.7.11.1 (Proto-Oncogene Proteins c-raf); EC 2.7.11.24 (Mitogen-Activated Protein Kinases); EC 2.7.11.25 (MAP Kinase Kinase Kinases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171126
[Lr] Data última revisão:
171126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160601
[St] Status:MEDLINE


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[PMID]:26508523
[Au] Autor:An S; Yang Y; Ward R; Liu Y; Guo XX; Xu TR
[Ad] Endereço:a Faculty of Life Science and Technology , Kunming University of Science and Technology , Kunming , Yunnan , China and.
[Ti] Título:A-Raf: A new star of the family of raf kinases.
[So] Source:Crit Rev Biochem Mol Biol;50(6):520-31, 2015.
[Is] ISSN:1549-7798
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The Ras-Raf-MEK-MAPK (mitogen-activated protein kinase)-signaling pathway plays a key role in the regulation of many cellular functions, including cell proliferation, differentiation and transformation, by transmitting signals from membrane receptors to various cytoplasmic and nuclear targets. One of the key components of this pathway is the serine/threonine protein kinase, Raf. The Raf family kinases (A-Raf, B-Raf and C-Raf) have been intensively studied since being identified in the early 1980s as retroviral oncogenes, especially with respect to the discovery of activating mutations of B-Raf in a large number of tumors which led to intensified efforts to develop drugs targeting Raf kinases. This also resulted in a rapid increase in our knowledge of the biological functions of the B-Raf and C-Raf isoforms, which may in turn be contrasted with the little that is known about A-Raf. The biological functions of A-Raf remain mysterious, although it appears to share some of the basic properties of the other two isoforms. Recently, emerging evidence has begun to reveal the functions of A-Raf, of which some are kinase-independent. These include the inhibition of apoptosis by binding to MST2, acting as safeguard against oncogenic transformation by suppressing extracellular signal-regulated kinases (ERK) activation and playing a role in resistance to Raf inhibitors. In this review, we discuss the regulation of A-Raf protein expression, and the roles of A-Raf in apoptosis and cancer, with a special focus on its role in resistance to Raf inhibitors. We also describe the scaffold functions of A-Raf and summarize the unexpected complexity of Raf signaling.
[Mh] Termos MeSH primário: Neoplasias/genética
Proteínas Proto-Oncogênicas A-raf/genética
Proteínas Proto-Oncogênicas A-raf/metabolismo
[Mh] Termos MeSH secundário: Animais
Resistência a Medicamentos Antineoplásicos
Endocitose
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Mutação
Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
Mapas de Interação de Proteínas
Isoformas de Proteínas/análise
Isoformas de Proteínas/antagonistas & inibidores
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Proteínas Proto-Oncogênicas A-raf/análise
Proteínas Proto-Oncogênicas A-raf/antagonistas & inibidores
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Protein Isoforms); 0 (Protein Kinase Inhibitors); EC 2.7.11.1 (Proto-Oncogene Proteins A-raf)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:151126
[Lr] Data última revisão:
151126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151029
[St] Status:MEDLINE
[do] DOI:10.3109/10409238.2015.1102858


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[PMID]:26310448
[Au] Autor:Sauvanet C; Garbett D; Bretscher A
[Ad] Endereço:Department of Molecular Biology and Genetics, Weill Institute for Molecular and Cell Biology, Cornell University, Ithaca, NY 14853.
[Ti] Título:The function and dynamics of the apical scaffolding protein E3KARP are regulated by cell-cycle phosphorylation.
[So] Source:Mol Biol Cell;26(20):3615-27, 2015 Oct 15.
[Is] ISSN:1939-4586
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We examine the dynamics and function of the apical scaffolding protein E3KARP/NHERF2, which consists of two PDZ domains and a tail containing an ezrin-binding domain. The exchange rate of E3KARP is greatly enhanced during mitosis due to phosphorylation at Ser-303 in its tail region. Whereas E3KARP can substitute for the function of the closely related scaffolding protein EBP50/NHERF1 in the formation of interphase microvilli, E3KARP S303D cannot. Moreover, the S303D mutation enhances the in vivo dynamics of the E3KARP tail alone, whereas in vitro the interaction of E3KARP with active ezrin is unaffected by S303D, implicating another factor regulating dynamics in vivo. A-Raf is found to be required for S303 phosphorylation in mitotic cells. Regulation of the dynamics of EBP50 is known to be dependent on its tail region but modulated by PDZ domain occupancy, which is not the case for E3KARP. Of interest, in both cases, the mechanisms regulating dynamics involve the tails, which are the most diverged region of the paralogues and probably evolved independently after a gene duplication event that occurred early in vertebrate evolution.
[Mh] Termos MeSH primário: Ciclo Celular/fisiologia
Fosfoproteínas/metabolismo
Trocadores de Sódio-Hidrogênio/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Células CACO-2
Técnicas de Cultura de Células
Ciclo Celular/genética
Proteínas do Citoesqueleto/metabolismo
Seres Humanos
Espectrometria de Massas
Mitose/fisiologia
Proteínas Associadas à Matriz Nuclear/metabolismo
Domínios PDZ/genética
Fosfoproteínas/genética
Fosforilação
Filogenia
Ligação Proteica
Proteínas Proto-Oncogênicas A-raf/metabolismo
Trocadores de Sódio-Hidrogênio/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Cytoskeletal Proteins); 0 (Nuclear Matrix-Associated Proteins); 0 (Phosphoproteins); 0 (Sodium-Hydrogen Exchangers); 0 (ezrin); 0 (sodium-hydrogen exchanger regulatory factor); EC 2.7.11.1 (Proto-Oncogene Proteins A-raf)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150828
[St] Status:MEDLINE
[do] DOI:10.1091/mbc.E15-07-0498


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[PMID]:25996975
[Au] Autor:Watanabe-Takano H; Takano K; Hatano M; Tokuhisa T; Endo T
[Ad] Endereço:Department of Biology, Graduate School of Science, Chiba University, Inage-ku, Chiba, Japan; Biomedical Research Center, Chiba University, Chuo-ku, Chiba, Japan; Japan Society for the Promotion of Science (JSPS), Chiyoda-ku, Tokyo, Japan.
[Ti] Título:DA-Raf-Mediated Suppression of the Ras--ERK Pathway Is Essential for TGF-ß1-Induced Epithelial-Mesenchymal Transition in Alveolar Epithelial Type 2 Cells.
[So] Source:PLoS One;10(5):e0127888, 2015.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Myofibroblasts play critical roles in the development of idiopathic pulmonary fibrosis by depositing components of extracellular matrix. One source of lung myofibroblasts is thought to be alveolar epithelial type 2 cells that undergo epithelial-mesenchymal transition (EMT). Rat RLE-6TN alveolar epithelial type 2 cells treated with transforming growth factor-ß1 (TGF-ß1) are converted into myofibroblasts through EMT. TGF-ß induces both canonical Smad signaling and non-canonical signaling, including the Ras-induced ERK pathway (Raf-MEK-ERK). However, the signaling mechanisms regulating TGF-ß1-induced EMT are not fully understood. Here, we show that the Ras-ERK pathway negatively regulates TGF-ß1-induced EMT in RLE-6TN cells and that DA-Raf1 (DA-Raf), a splicing isoform of A-Raf and a dominant-negative antagonist of the Ras-ERK pathway, plays an essential role in EMT. Stimulation of the cells with fibroblast growth factor 2 (FGF2), which activated the ERK pathway, prominently suppressed TGF-ß1-induced EMT. An inhibitor of MEK, but not an inhibitor of phosphatidylinositol 3-kinase, rescued the TGF-ß1-treated cells from the suppression of EMT by FGF2. Overexpression of a constitutively active mutant of a component of the Ras-ERK pathway, i.e., H-Ras, B-Raf, or MEK1, interfered with EMT. Knockdown of DA-Raf expression with siRNAs facilitated the activity of MEK and ERK, which were only weakly and transiently activated by TGF-ß1. Although DA-Raf knockdown abrogated TGF-ß1-induced EMT, the abrogation of EMT was reversed by the addition of the MEK inhibitor. Furthermore, DA-Raf knockdown impaired the TGF-ß1-induced nuclear translocation of Smad2, which mediates the transcription required for EMT. These results imply that intrinsic DA-Raf exerts essential functions for EMT by antagonizing the TGF-ß1-induced Ras-ERK pathway in RLE-6TN cells.
[Mh] Termos MeSH primário: Células Epiteliais Alveolares/metabolismo
Transição Epitelial-Mesenquimal
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Proteínas Proto-Oncogênicas A-raf/metabolismo
Transdução de Sinais
Fator de Crescimento Transformador beta1/metabolismo
Proteínas ras/metabolismo
[Mh] Termos MeSH secundário: Células Epiteliais Alveolares/efeitos dos fármacos
Animais
Linhagem Celular
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Transição Epitelial-Mesenquimal/genética
Fator 2 de Crescimento de Fibroblastos/farmacologia
Expressão Gênica
Técnicas de Silenciamento de Genes
Camundongos
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas Proto-Oncogênicas A-raf/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
Ratos
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Transforming Growth Factor beta1); 103107-01-3 (Fibroblast Growth Factor 2); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (DA-Raf1 protein, mouse); EC 2.7.11.1 (Proto-Oncogene Proteins A-raf); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.6.5.2 (ras Proteins)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150522
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0127888


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[PMID]:25674762
[Au] Autor:Lee J; Jeong S; Park JH; Lee CR; Ku CR; Kang SW; Jeong JJ; Nam KH; Shin DY; Lee EJ; Chung WY; Jo YS
[Ad] Endereço:From the Department of Surgery (JL, CRL, SWK, JJJ, KHN, WYC); Department of Internal Medicine, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (SJ, CRK, DYS, EJL, YSJ); and Department of Surgery, Yonsei University Wonju College of Medicine, Kangwon (JHP), Korea.
[Ti] Título:Aberrant expression of COT is related to recurrence of papillary thyroid cancer.
[So] Source:Medicine (Baltimore);94(6):e548, 2015 Feb.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aberrant expression of Cancer Osaka Thyroid Oncogene mitogen-activated protein kinase kinase kinase 8 (COT) (MAP3K8) is a driver of resistance to B-RAF inhibition. However, the de novo expression and clinical implications of COT in papillary thyroid cancer (PTC) have not been investigated.The aim of this study is to investigate the expression of A-, B-, C-RAF, and COT in PTC (n = 167) and analyze the clinical implications of aberrant expression of these genes.Quantitative polymerase chain reaction (qPCR) and immunohistochemical staining (IHC) were performed on primary thyroid cancers. Expression of COT was compared with clinicopathological characteristics including recurrence-free survival. Datasets from public repository (NCBI) were subjected to Gene Set Enrichment Analysis (GSEA).qPCR data showed that the relative mRNA expression of A-, B-, C-RAF and COT of PTC were higher than normal tissues (all P < 0.01). In addition, the expression of COT mRNA in PTC showed positive correlation with A- (r = 0.4083, P < 0.001), B- (r = 0.2773, P = 0.0003), and C-RAF (r = 0.5954, P < 0.001). The mRNA expressions of A-, B,- and C-RAF were also correlated with each other (all P < 0.001). In IHC, the staining intensities of B-RAF and COT were higher in PTC than in normal tissue (P < 0.001). Interestingly, moderate-to-strong staining intensities of B-RAF and COT were more frequent in B-RAF-positive PTC (P < 0.001, P = 0.013, respectively). In addition, aberrant expression of COT was related to old age at initial diagnosis (P = 0.045) and higher recurrence rate (P = 0.025). In multivariate analysis, tumor recurrence was persistently associated with moderate-to-strong staining of COT after adjusting for age, sex, extrathyroidal extension, multifocality, T-stage, N-stage, TNM stage, and B-RAF mutation (odds ratio, 4.662; 95% confidence interval 1.066 - 21.609; P = 0.045). Moreover, moderate-to-strong COT expression in PTC was associated with shorter recurrence-free survival (mean follow-up duration, 14.2 ±â€Š4.1 years; P = 0.0403). GSEA indicated that gene sets related to B-RAF-RAS (P < 0.0001, false discovery rate [FDR] q-value = 0.000) and thyroid differentiation (P = 0.048, FDR q-value = 0.05) scores were enriched in lower COT expression group and gene sets such as T-cell receptor signaling pathway and Toll-like receptor signaling pathway are coordinately upregulated in higher COT expression group (both, P < 0.0001, FDR q-value = 0.000).Aberrant expression of A-, B-, and C-RAF, and COT is frequent in PTC; increased expression of COT is correlated with recurrence of PTC.
[Mh] Termos MeSH primário: Carcinoma Papilar/genética
MAP Quinase Quinase Quinases/genética
Recidiva Local de Neoplasia/genética
Proteínas Proto-Oncogênicas A-raf/genética
Proteínas Proto-Oncogênicas B-raf/genética
Proteínas Proto-Oncogênicas c-raf/genética
Proteínas Proto-Oncogênicas/genética
Neoplasias da Glândula Tireoide/genética
[Mh] Termos MeSH secundário: Adulto
Fatores Etários
Western Blotting
Carcinoma Papilar/mortalidade
DNA/análise
Feminino
Seres Humanos
Imuno-Histoquímica
Masculino
RNA Mensageiro/análise
Reação em Cadeia da Polimerase em Tempo Real
Neoplasias da Glândula Tireoide/mortalidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Proto-Oncogene Proteins); 0 (RNA, Messenger); 9007-49-2 (DNA); EC 2.7.11.1 (Proto-Oncogene Proteins A-raf); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); EC 2.7.11.1 (Proto-Oncogene Proteins c-raf); EC 2.7.11.25 (MAP Kinase Kinase Kinases); EC 2.7.11.25 (MAP3K8 protein, human)
[Em] Mês de entrada:1504
[Cu] Atualização por classe:151028
[Lr] Data última revisão:
151028
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:150213
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000000548


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[PMID]:25608663
[Au] Autor:Sia D; Losic B; Moeini A; Cabellos L; Hao K; Revill K; Bonal D; Miltiadous O; Zhang Z; Hoshida Y; Cornella H; Castillo-Martin M; Pinyol R; Kasai Y; Roayaie S; Thung SN; Fuster J; Schwartz ME; Waxman S; Cordon-Cardo C; Schadt E; Mazzaferro V; Llovet JM
[Ad] Endereço:1] Barcelona-Clínic Liver Cancer Group (HCC Translational Research Laboratory, Liver Unit, Hepato-biliary Surgery), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona 08036, Spain [2] Gastrointestinal Surgery and Liver T
[Ti] Título:Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma.
[So] Source:Nat Commun;6:6087, 2015 Jan 22.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Intrahepatic cholangiocarcinoma (iCCA) is a fatal bile duct cancer with dismal prognosis and limited therapeutic options. By performing RNA- and exome-sequencing analyses, we report a novel fusion event, FGFR2-PPHLN1 (16%), and damaging mutations in the ARAF oncogene (11%). Here we demonstrate that the chromosomal translocation t(10;12)(q26;q12) leading to FGFR2-PPHLN1 fusion possesses transforming and oncogenic activity, which is successfully inhibited by a selective FGFR2 inhibitor in vitro. Among the ARAF mutations, N217I and G322S lead to activation of the pathway and N217I shows oncogenic potential in vitro. Screening of a cohort of 107 iCCA patients reveals that FGFR2 fusions represent the most recurrent targetable alteration (45%, 17/107), while they are rarely present in other primary liver tumours (0/100 of hepatocellular carcinoma (HCC); 1/21 of mixed iCCA-HCC). Taken together, around 70% of iCCA patients harbour at least one actionable molecular alteration (FGFR2 fusions, IDH1/2, ARAF, KRAS, BRAF and FGF19) that is amenable for therapeutic targeting.
[Mh] Termos MeSH primário: Antígenos de Neoplasias/genética
Neoplasias dos Ductos Biliares/genética
Colangiocarcinoma/genética
Sequenciamento de Nucleotídeos em Larga Escala/métodos
Mutação
Proteínas Nucleares/genética
Proteínas Proto-Oncogênicas A-raf/genética
Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética
[Mh] Termos MeSH secundário: Células 3T3
Idoso
Sequência de Aminoácidos
Animais
Sequência de Bases
Linhagem Celular Tumoral
Estudos de Coortes
Exoma
Éxons
Feminino
Seres Humanos
Hibridização in Situ Fluorescente
Masculino
Camundongos
Meia-Idade
Dados de Sequência Molecular
Análise de Sequência com Séries de Oligonucleotídeos
Proteínas Recombinantes de Fusão/química
Análise de Sequência de RNA
Homologia de Sequência de Aminoácidos
Translocação Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antigens, Neoplasm); 0 (Nuclear Proteins); 0 (PPHLN1 protein, human); 0 (Recombinant Fusion Proteins); EC 2.7.10.1 (FGFR2 protein, human); EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 2); EC 2.7.11.1 (Proto-Oncogene Proteins A-raf)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:150503
[Lr] Data última revisão:
150503
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150123
[St] Status:MEDLINE
[do] DOI:10.1038/ncomms7087


  8 / 61 MEDLINE  
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[PMID]:25097033
[Au] Autor:Mooz J; Oberoi-Khanuja TK; Harms GS; Wang W; Jaiswal BS; Seshagiri S; Tikkanen R; Rajalingam K
[Ad] Endereço:Cell death signalling group, Institute of Biochemistry II, Goethe University Medical School, Frankfurt 60590, Germany. Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, Building 708, Mainz 55131, Germany.
[Ti] Título:Dimerization of the kinase ARAF promotes MAPK pathway activation and cell migration.
[So] Source:Sci Signal;7(337):ra73, 2014 Aug 05.
[Is] ISSN:1937-9145
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The RAF family of kinases mediates RAS signaling, and RAF inhibitors can be effective for treating tumors with BRAF(V600E) mutant protein. However, RAF inhibitors paradoxically accelerate metastasis in RAS-mutant tumors and become ineffective in BRAF(V600E) tumors because of reactivation of downstream mitogen-activated protein kinase (MAPK) signaling. We found that the RAF isoform ARAF has an obligatory role in promoting MAPK activity and cell migration in a cell type-dependent manner. Knocking down ARAF prevented the activation of MAPK kinase 1 (MEK1) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and decreased the number of protrusions from tumor cell spheroids in three-dimensional culture that were induced by BRAF(V600E)-specific or BRAF/CRAF inhibitors (GDC-0879 and sorafenib, respectively). RAF inhibitors induced the homodimerization of ARAF and the heterodimerization of BRAF with CRAF and the scaffolding protein KSR1. In a purified protein solution, recombinant proteins of the three RAF isoforms competed for binding to MEK1. In cells in culture, overexpressing mutants of ARAF that could not homodimerize impaired the interaction between ARAF and endogenous MEK1 and thus prevented the subsequent activation of MEK1 and ERK1/2. Our findings reveal a new role for ARAF in directly activating the MAPK cascade and promoting tumor cell invasion and suggest a new therapeutic target for RAS- and RAF-mediated cancers.
[Mh] Termos MeSH primário: Movimento Celular/fisiologia
Sistema de Sinalização das MAP Quinases/fisiologia
Modelos Moleculares
Proteínas Proto-Oncogênicas A-raf/metabolismo
[Mh] Termos MeSH secundário: Análise de Variância
Ligação Competitiva
Western Blotting
Dimerização
Eletroforese em Gel de Poliacrilamida
Ativação Enzimática/genética
Técnicas de Silenciamento de Genes
Células HEK293
Seres Humanos
Indenos/farmacologia
MAP Quinase Quinase 1/metabolismo
Sistema de Sinalização das MAP Quinases/genética
Invasividade Neoplásica
Niacinamida/análogos & derivados
Niacinamida/farmacologia
Compostos de Fenilureia/farmacologia
Proteínas Proto-Oncogênicas A-raf/química
Proteínas Proto-Oncogênicas A-raf/genética
Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores
Pirazóis/farmacologia
RNA Interferente Pequeno/genética
Imagem com Lapso de Tempo
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (2-(4-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol); 0 (Indenes); 0 (Phenylurea Compounds); 0 (Pyrazoles); 0 (RNA, Small Interfering); 25X51I8RD4 (Niacinamide); 9ZOQ3TZI87 (sorafenib); EC 2.7.11.1 (Proto-Oncogene Proteins A-raf); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); EC 2.7.11.1 (Proto-Oncogene Proteins c-raf); EC 2.7.12.2 (MAP Kinase Kinase 1)
[Em] Mês de entrada:1503
[Cu] Atualização por classe:160513
[Lr] Data última revisão:
160513
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140807
[St] Status:MEDLINE
[do] DOI:10.1126/scisignal.2005484


  9 / 61 MEDLINE  
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[PMID]:24847881
[Au] Autor:Mazur PK; Reynoird N; Khatri P; Jansen PW; Wilkinson AW; Liu S; Barbash O; Van Aller GS; Huddleston M; Dhanak D; Tummino PJ; Kruger RG; Garcia BA; Butte AJ; Vermeulen M; Sage J; Gozani O
[Ad] Endereço:1] Department of Pediatrics, Stanford University School of Medicine, California 94305, USA [2] Department of Genetics, Stanford University School of Medicine, California 94305, USA [3].
[Ti] Título:SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer.
[So] Source:Nature;510(7504):283-7, 2014 Jun 12.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Deregulation of lysine methylation signalling has emerged as a common aetiological factor in cancer pathogenesis, with inhibitors of several histone lysine methyltransferases (KMTs) being developed as chemotherapeutics. The largely cytoplasmic KMT SMYD3 (SET and MYND domain containing protein 3) is overexpressed in numerous human tumours. However, the molecular mechanism by which SMYD3 regulates cancer pathways and its relationship to tumorigenesis in vivo are largely unknown. Here we show that methylation of MAP3K2 by SMYD3 increases MAP kinase signalling and promotes the formation of Ras-driven carcinomas. Using mouse models for pancreatic ductal adenocarcinoma and lung adenocarcinoma, we found that abrogating SMYD3 catalytic activity inhibits tumour development in response to oncogenic Ras. We used protein array technology to identify the MAP3K2 kinase as a target of SMYD3. In cancer cell lines, SMYD3-mediated methylation of MAP3K2 at lysine 260 potentiates activation of the Ras/Raf/MEK/ERK signalling module and SMYD3 depletion synergizes with a MEK inhibitor to block Ras-driven tumorigenesis. Finally, the PP2A phosphatase complex, a key negative regulator of the MAP kinase pathway, binds to MAP3K2 and this interaction is blocked by methylation. Together, our results elucidate a new role for lysine methylation in integrating cytoplasmic kinase-signalling cascades and establish a pivotal role for SMYD3 in the regulation of oncogenic Ras signalling.
[Mh] Termos MeSH primário: Transformação Celular Neoplásica/metabolismo
Histona-Lisina N-Metiltransferase/metabolismo
Lisina/metabolismo
MAP Quinase Quinase Quinase 2/metabolismo
MAP Quinase Quinase Quinases/metabolismo
Proteína Oncogênica p21(ras)/metabolismo
[Mh] Termos MeSH secundário: Adenocarcinoma/enzimologia
Adenocarcinoma/genética
Adenocarcinoma/metabolismo
Adenocarcinoma/patologia
Animais
Linhagem Celular Tumoral
Transformação Celular Neoplásica/genética
Transformação Celular Neoplásica/patologia
Modelos Animais de Doenças
Seres Humanos
Neoplasias Pulmonares/enzimologia
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/metabolismo
Neoplasias Pulmonares/patologia
MAP Quinase Quinase Quinase 2/química
MAP Quinase Quinase Quinases/química
Metilação
Camundongos
Proteínas Quinases Ativadas por Mitógeno/metabolismo
Proteína Oncogênica p21(ras)/genética
Neoplasias Pancreáticas/enzimologia
Neoplasias Pancreáticas/genética
Neoplasias Pancreáticas/metabolismo
Neoplasias Pancreáticas/patologia
Proteína Fosfatase 2/antagonistas & inibidores
Proteína Fosfatase 2/metabolismo
Proteínas Proto-Oncogênicas A-raf/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 2.1.1.43 (Histone-Lysine N-Methyltransferase); EC 2.1.1.43 (SMYD3 protein, human); EC 2.1.1.43 (Smyd3 protein, mouse); EC 2.7.11.1 (Proto-Oncogene Proteins A-raf); EC 2.7.11.24 (Mitogen-Activated Protein Kinases); EC 2.7.11.25 (MAP Kinase Kinase Kinase 2); EC 2.7.11.25 (MAP Kinase Kinase Kinases); EC 2.7.11.25 (MAP3K2 protein, human); EC 2.7.11.25 (Map3k2 protein, mouse); EC 3.1.3.16 (Protein Phosphatase 2); EC 3.6.5.2 (Oncogene Protein p21(ras)); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1407
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140523
[St] Status:MEDLINE
[do] DOI:10.1038/nature13320


  10 / 61 MEDLINE  
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[PMID]:24843139
[Au] Autor:Watanabe-Takano H; Takano K; Sakamoto A; Matsumoto K; Tokuhisa T; Endo T; Hatano M
[Ad] Endereço:Departments of Biomedical Science andDepartment of Biology, Graduate School of Science andJapan Society for the Promotion of Science, Chiyoda-ku, Tokyo 102-0083, Japan; and.
[Ti] Título:DA-Raf-dependent inhibition of the Ras-ERK signaling pathway in type 2 alveolar epithelial cells controls alveolar formation.
[So] Source:Proc Natl Acad Sci U S A;111(22):E2291-300, 2014 Jun 03.
[Is] ISSN:1091-6490
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Alveolar formation is coupled to the spatiotemporally regulated differentiation of alveolar myofibroblasts (AMYFs), which contribute to the morphological changes of interalveolar walls. Although the Ras-ERK signaling pathway is one of the key regulators for alveolar formation in developing lungs, the intrinsic molecular and cellular mechanisms underlying its role remain largely unknown. By analyzing the Ras-ERK signaling pathway during postnatal development of lungs, we have identified a critical role of DA-Raf1 (DA-Raf)-a dominant-negative antagonist for the Ras-ERK signaling pathway-in alveolar formation. DA-Raf-deficient mice displayed alveolar dysgenesis as a result of the blockade of AMYF differentiation. DA-Raf is predominantly expressed in type 2 alveolar epithelial cells (AEC2s) in developing lungs, and DA-Raf-dependent MEK1/2 inhibition in AEC2s suppresses expression of tissue inhibitor of matalloprotienase 4 (TIMP4), which prevents a subsequent proteolytic cascade matrix metalloproteinase (MMP)14-MMP2. Furthermore, MMP14-MMP2 proteolytic cascade regulates AMYF differentiation and alveolar formation. Therefore, DA-Raf-dependent inhibition of the Ras-ERK signaling pathway in AEC2s is required for alveolar formation via triggering MMP2 activation followed by AMYF differentiation. These findings reveal a pivotal role of the Ras-ERK signaling pathway in the dynamic regulation of alveolar development.
[Mh] Termos MeSH primário: Sistema de Sinalização das MAP Quinases/fisiologia
Proteínas Proto-Oncogênicas A-raf/metabolismo
Alvéolos Pulmonares/crescimento & desenvolvimento
Alvéolos Pulmonares/metabolismo
Mucosa Respiratória/crescimento & desenvolvimento
Mucosa Respiratória/metabolismo
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular/fisiologia
Feminino
Regulação da Expressão Gênica no Desenvolvimento
Técnicas de Introdução de Genes
MAP Quinase Quinase 1/metabolismo
MAP Quinase Quinase 2/metabolismo
Masculino
Metaloproteinase 14 da Matriz/metabolismo
Metaloproteinase 2 da Matriz/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Proteínas Proto-Oncogênicas A-raf/genética
Proteínas Proto-Oncogênicas c-raf/metabolismo
Alvéolos Pulmonares/citologia
Mucosa Respiratória/citologia
Inibidores Teciduais de Metaloproteinases/genética
Inibidores Teciduais de Metaloproteinases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Mmp14 protein, mouse); 0 (Tissue Inhibitor of Metalloproteinases); 0 (tissue inhibitor of metalloproteinase-4); EC 2.7.11.1 (DA-Raf1 protein, mouse); EC 2.7.11.1 (Proto-Oncogene Proteins A-raf); EC 2.7.11.1 (Proto-Oncogene Proteins c-raf); EC 2.7.12.2 (MAP Kinase Kinase 1); EC 2.7.12.2 (MAP Kinase Kinase 2); EC 2.7.12.2 (Map2k1 protein, mouse); EC 2.7.12.2 (Map2k2 protein, mouse); EC 3.4.24.24 (Matrix Metalloproteinase 2); EC 3.4.24.24 (Mmp2 protein, mouse); EC 3.4.24.80 (Matrix Metalloproteinase 14)
[Em] Mês de entrada:1408
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140521
[St] Status:MEDLINE
[do] DOI:10.1073/pnas.1321574111



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