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Pesquisa : D12.644.360.024.316 [Categoria DeCS]
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[PMID]:28468300
[Au] Autor:Sp N; Kang DY; Joung YH; Park JH; Kim WS; Lee HK; Song KD; Park YM; Yang YM
[Ad] Endereço:Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea. nipinsp@gmail.com.
[Ti] Título:Nobiletin Inhibits Angiogenesis by Regulating Src/FAK/STAT3-Mediated Signaling through PXN in ER⁺ Breast Cancer Cells.
[So] Source:Int J Mol Sci;18(5), 2017 Apr 30.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Tumor angiogenesis is one of the major hallmarks of tumor progression. Nobiletin is a natural flavonoid isolated from citrus peel that has anti-angiogenic activity. Steroid receptor coactivator (Src) is an intracellular tyrosine kinase so that focal adhesion kinase (FAK) binds to Src to play a role in tumor angiogenesis. Signal transducer and activator of transcription 3 (STAT3) is a marker for tumor angiogenesis which interacts with Src. Paxillin (PXN) acts as a downstream target for both FAK and STAT3. The main goal of this study was to assess inhibition of tumor angiogenesis by nobiletin in estrogen receptor positive (ER⁺) breast cancer cells via Src, FAK, and STAT3-mediated signaling through PXN. Treatment with nobiletin in MCF-7 and T47D breast cancer cells inhibited angiogenesis markers, based on western blotting and RT-PCR. Validation of in vitro angiogenesis in the human umbilical vein endothelial cells (HUVEC) endothelial cell line proved the anti-angiogenic activity of nobiletin. Electrophoretic mobility shift assay and the ChIP assay showed that nobiletin inhibits STAT3/DNA binding activity and STAT3 binding to a novel binding site of the gene promoter. We also investigated the migration and invasive ability of nobiletin in ER⁺ cells. Nobiletin inhibited tumor angiogenesis by regulating Src, FAK, and STAT3 signaling through PXN in ER⁺ breast cancer cells.
[Mh] Termos MeSH primário: Inibidores da Angiogênese/farmacologia
Flavonas/farmacologia
Proteína-Tirosina Quinases de Adesão Focal/metabolismo
Paxilina/metabolismo
Receptores Estrogênicos/metabolismo
Fator de Transcrição STAT3/metabolismo
Quinases da Família src/metabolismo
[Mh] Termos MeSH secundário: Proliferação Celular
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos
Células Endoteliais da Veia Umbilical Humana/metabolismo
Células Endoteliais da Veia Umbilical Humana/fisiologia
Seres Humanos
Células MCF-7
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Flavones); 0 (Paxillin); 0 (Receptors, Estrogen); 0 (STAT3 Transcription Factor); D65ILJ7WLY (nobiletin); EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases); EC 2.7.10.2 (src-Family Kinases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180202
[Lr] Data última revisão:
180202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE


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[PMID]:29212004
[Au] Autor:Deschout H; Platzman I; Sage D; Feletti L; Spatz JP; Radenovic A
[Ad] Endereço:Laboratory of Nanoscale Biology, Institute of Bioengineering, School of Engineering, EPFL, Lausanne, Switzerland.
[Ti] Título:Investigating Focal Adhesion Substructures by Localization Microscopy.
[So] Source:Biophys J;113(11):2508-2518, 2017 Dec 05.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cells rely on focal adhesions (FAs) to carry out a variety of important tasks, including motion, environmental sensing, and adhesion to the extracellular matrix. Although attaining a fundamental characterization of FAs is a compelling goal, their extensive complexity and small size, which can be below the diffraction limit, have hindered a full understanding. In this study we have used single-molecule localization microscopy (SMLM) to investigate integrin ß3 and paxillin in rat embryonic fibroblasts growing on two different extracellular matrix-representing substrates (i.e., fibronectin-coated substrates and specifically biofunctionalized nanopatterned substrates). To quantify the substructure of FAs, we developed a clustering method based on expectation maximization of a Gaussian mixture that accounts for localization uncertainty and background. Analysis of our SMLM data indicates that the structures within FAs, characterized as a Gaussian mixture, typically have areas between 0.01 and 1 µm , contain 10-100 localizations, and can exhibit substantial eccentricity. Our approach based on SMLM opens new avenues for studying structural and functional biology of molecular assemblies that display substantial varieties in size, shape, and density.
[Mh] Termos MeSH primário: Adesões Focais/metabolismo
Microscopia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Fibroblastos/citologia
Fibroblastos/metabolismo
Integrina beta3/metabolismo
Modelos Biológicos
Paxilina/metabolismo
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Integrin beta3); 0 (Paxillin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180119
[Lr] Data última revisão:
180119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171207
[St] Status:MEDLINE


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[PMID]:28739717
[Au] Autor:Sobkowicz AD; Sanders AJ; Mason MD; Jiang WG
[Ad] Endereço:Cardiff China Medical Research Collaborative (CCMRC), Cardiff University School of Medicine, Cardiff, U.K.
[Ti] Título:Potential Implication of Paxillin in Cancer Establishment Within the Bone Environment.
[So] Source:Anticancer Res;37(8):4255-4268, 2017 08.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Bone metastases are a common feature of advanced prostatic malignancies. They are characterised by a unique prevalence of osteoblastic phenotype and a poor prognosis. Paxillin is a 68-kDa signal transduction adaptor and scaffold protein that contains motifs involved in the mediation of protein-protein interactions. The state of paxillin phosphorylation is central to determining a cell's ability to adhere, detach and migrate and hence has been linked to processes such as wound repair and tumour metastasis. The current study explored the impact of paxillin suppression on prostate and breast cancer cell function and their responsiveness to hepatocyte growth factor (HGF) and bone matrix extract (BME) in order to assess its potential to influence bone colonization and homing. MATERIALS AND METHODS: Hammerhead ribozyme transgenes were used to knockdown the expression of paxillin in breast and prostate cancer cell lines. The impact on the cell growth, migration, adhesion and invasion was assessed using in vitro functional assays. In order to explore potential mechanisms, focal adhesion kinase (FAK) inhibitor was also used. RESULTS: Knockdown of paxillin expression was observed in all tested cell lines following transfection with the ribozyme transgene. The knockdown of paxillin increased proliferation and invasiveness of LNCaP cells, with no effect on their attachment abilities. The opposite, however, is true for PC-3 cells where, following knockdown, cellular attachment was significantly reduced, while no significant changes in growth and invasiveness were detected. In the MDA-MB-231 breast cancer knockdown model, cells had little difference in proliferative rates and generally increased attachment and reduced invasive abilities. Treatments with HGF and BME had differential effects on targeted cells when compared to controls. CONCLUSION: These data suggest that paxillin appears to influence major cell functions in a diverse range of prostate and breast cancer models. The responsiveness of cells to environmental factors such as HGF or BME may be influenced by paxillin status, although this seems to be dependent on cell type.
[Mh] Termos MeSH primário: Neoplasias Ósseas/tratamento farmacológico
Extratos Celulares/administração & dosagem
Fator de Crescimento de Hepatócito/administração & dosagem
Paxilina/genética
[Mh] Termos MeSH secundário: Matriz Óssea/química
Neoplasias Ósseas/genética
Neoplasias Ósseas/patologia
Neoplasias Ósseas/secundário
Neoplasias da Mama/tratamento farmacológico
Neoplasias da Mama/genética
Neoplasias da Mama/patologia
Extratos Celulares/química
Linhagem Celular Tumoral
Movimento Celular/genética
Proliferação Celular/efeitos dos fármacos
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Técnicas de Silenciamento de Genes
Seres Humanos
Masculino
Invasividade Neoplásica/genética
Paxilina/antagonistas & inibidores
Neoplasias da Próstata/tratamento farmacológico
Neoplasias da Próstata/genética
Neoplasias da Próstata/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Extracts); 0 (HGF protein, human); 0 (Paxillin); 67256-21-7 (Hepatocyte Growth Factor)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE


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[PMID]:28592635
[Au] Autor:Owen LM; Adhikari AS; Patel M; Grimmer P; Leijnse N; Kim MC; Notbohm J; Franck C; Dunn AR
[Ad] Endereço:Biophysics, Stanford University, Stanford, CA 94305.
[Ti] Título:A cytoskeletal clutch mediates cellular force transmission in a soft, three-dimensional extracellular matrix.
[So] Source:Mol Biol Cell;28(14):1959-1974, 2017 Jul 07.
[Is] ISSN:1939-4586
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The ability of cells to impart forces and deformations on their surroundings underlies cell migration and extracellular matrix (ECM) remodeling and is thus an essential aspect of complex, metazoan life. Previous work has resulted in a refined understanding, commonly termed the molecular clutch model, of how cells adhering to flat surfaces such as a microscope coverslip transmit cytoskeletally generated forces to their surroundings. Comparatively less is known about how cells adhere to and exert forces in soft, three-dimensional (3D), and structurally heterogeneous ECM environments such as occur in vivo. We used time-lapse 3D imaging and quantitative image analysis to determine how the actin cytoskeleton is mechanically coupled to the surrounding matrix for primary dermal fibroblasts embedded in a 3D fibrin matrix. Under these circumstances, the cytoskeletal architecture is dominated by contractile actin bundles attached at their ends to large, stable, integrin-based adhesions. Time-lapse imaging reveals that α-actinin-1 puncta within actomyosin bundles move more quickly than the paxillin-rich adhesion plaques, which in turn move more quickly than the local matrix, an observation reminiscent of the molecular clutch model. However, closer examination did not reveal a continuous rearward flow of the actin cytoskeleton over slower moving adhesions. Instead, we found that a subset of stress fibers continuously elongated at their attachment points to integrin adhesions, providing stable, yet structurally dynamic coupling to the ECM. Analytical modeling and numerical simulation provide a plausible physical explanation for this result and support a picture in which cells respond to the effective stiffness of local matrix attachment points. The resulting dynamic equilibrium can explain how cells maintain stable, contractile connections to discrete points within ECM during cell migration, and provides a plausible means by which fibroblasts contract provisional matrices during wound healing.
[Mh] Termos MeSH primário: Adesões Focais/metabolismo
Adesões Focais/fisiologia
Fibras de Estresse/fisiologia
[Mh] Termos MeSH secundário: Citoesqueleto de Actina/metabolismo
Actinina/metabolismo
Actinas/metabolismo
Actomiosina/metabolismo
Fenômenos Biomecânicos/fisiologia
Adesão Celular
Movimento Celular
Citoesqueleto/metabolismo
Matriz Extracelular/metabolismo
Matriz Extracelular/fisiologia
Fibroblastos/metabolismo
Seres Humanos
Integrinas/metabolismo
Paxilina/metabolismo
Fibras de Estresse/metabolismo
Imagem com Lapso de Tempo/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ACTN1 protein, human); 0 (Actins); 0 (Integrins); 0 (Paxillin); 11003-00-2 (Actinin); 9013-26-7 (Actomyosin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170609
[St] Status:MEDLINE
[do] DOI:10.1091/mbc.E17-02-0102


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[PMID]:28553938
[Au] Autor:Yuan JH; Liu XN; Wang TT; Pan W; Tao QF; Zhou WP; Wang F; Sun SH
[Ad] Endereço:Department of Medical Genetics, Second Military Medical University, Shanghai 200433, China.
[Ti] Título:The MBNL3 splicing factor promotes hepatocellular carcinoma by increasing PXN expression through the alternative splicing of lncRNA-PXN-AS1.
[So] Source:Nat Cell Biol;19(7):820-832, 2017 Jul.
[Is] ISSN:1476-4679
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Understanding the roles of splicing factors and splicing events during tumorigenesis would open new avenues for targeted therapies. Here we identify an oncofetal splicing factor, MBNL3, which promotes tumorigenesis and indicates poor prognosis of hepatocellular carcinoma patients. MBNL3 knockdown almost completely abolishes hepatocellular carcinoma tumorigenesis. Transcriptomic analysis revealed that MBNL3 induces lncRNA-PXN-AS1 exon 4 inclusion. The transcript lacking exon 4 binds to coding sequences of PXN mRNA, causes dissociation of translation elongation factors from PXN mRNA, and thereby inhibits PXN mRNA translation. In contrast, the transcript containing exon 4 preferentially binds to the 3' untranslated region of PXN mRNA, protects PXN mRNA from microRNA-24-AGO2 complex-induced degradation, and thereby increases PXN expression. Through inducing exon 4 inclusion, MBNL3 upregulates PXN, which mediates the pro-tumorigenic roles of MBNL3. Collectively, these data demonstrate detailed mechanistic links between an oncofetal splicing factor, a splicing event and tumorigenesis, and establish splicing factors and splicing events as potential therapeutic targets.
[Mh] Termos MeSH primário: Processamento Alternativo
Carcinoma Hepatocelular/metabolismo
Neoplasias Hepáticas/metabolismo
Paxilina/metabolismo
RNA Longo não Codificante/metabolismo
Proteínas de Ligação a RNA/metabolismo
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas
Animais
Proteínas Argonauta/genética
Proteínas Argonauta/metabolismo
Sítios de Ligação
Carcinoma Hepatocelular/genética
Proteínas de Transporte/metabolismo
Proliferação Celular
Éxons
Perfilação da Expressão Gênica/métodos
Regulação Neoplásica da Expressão Gênica
Células Hep G2
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Neoplasias Hepáticas/genética
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Nus
MicroRNAs/genética
MicroRNAs/metabolismo
Proteína Homeobox Nanog/genética
Proteína Homeobox Nanog/metabolismo
Fator 3 de Transcrição de Octâmero/genética
Fator 3 de Transcrição de Octâmero/metabolismo
Paxilina/genética
Ligação Proteica
Interferência de RNA
RNA Longo não Codificante/genética
Proteínas de Ligação a RNA/genética
Fatores de Transcrição SOXB1/genética
Fatores de Transcrição SOXB1/metabolismo
Fatores de Tempo
Transfecção
Carga Tumoral
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (Argonaute Proteins); 0 (Carrier Proteins); 0 (EIF2C2 protein, human); 0 (MBNL3 protein, human); 0 (MBNL3 protein, mouse); 0 (MIRN24 microRNA, human); 0 (MicroRNAs); 0 (NANOG protein, human); 0 (Nanog Homeobox Protein); 0 (Octamer Transcription Factor-3); 0 (POU5F1 protein, human); 0 (PXN protein, human); 0 (PXN-AS1 non-coding RNA, human); 0 (Paxillin); 0 (RNA, Long Noncoding); 0 (RNA-Binding Proteins); 0 (SOX2 protein, human); 0 (SOXB1 Transcription Factors)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170913
[Lr] Data última revisão:
170913
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170530
[St] Status:MEDLINE
[do] DOI:10.1038/ncb3538


  6 / 1651 MEDLINE  
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[PMID]:28485208
[Au] Autor:Nagasato AI; Yamashita H; Matsuo M; Ueda K; Kioka N
[Ad] Endereço:a Division of Applied Life Sciences, Graduate School of Agriculture , Kyoto University , Kyoto , Japan.
[Ti] Título:The distribution of vinculin to lipid rafts plays an important role in sensing stiffness of extracellular matrix.
[So] Source:Biosci Biotechnol Biochem;81(6):1136-1147, 2017 Jun.
[Is] ISSN:1347-6947
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Extracellular matrix (ECM) stiffness regulates cell differentiation, survival, and migration. Our previous study has shown that the interaction of the focal adhesion protein vinculin with vinexin α plays a critical role in sensing ECM stiffness and regulating stiffness-dependent cell migration. However, the mechanism how vinculin-vinexin α interaction affects stiffness-dependent cell migration is unclear. Lipid rafts are membrane microdomains that are known to affect ECM-induced signals and cell behaviors. Here, we show that vinculin and vinexin α can localize to lipid rafts. Cell-ECM adhesion, intracellular tension, and a rigid ECM promote vinculin distribution to lipid rafts. The disruption of lipid rafts with Methyl-ß-cyclodextrin impaired the ECM stiffness-mediated regulation of vinculin behavior and rapid cell migration on rigid ECM. These results indicate that lipid rafts play an important role in ECM-stiffness regulation of cell migration via vinculin.
[Mh] Termos MeSH primário: Matriz Extracelular/metabolismo
Fibroblastos/metabolismo
Adesões Focais/metabolismo
Microdomínios da Membrana/metabolismo
Proteínas Musculares/metabolismo
Vinculina/metabolismo
[Mh] Termos MeSH secundário: Animais
Fenômenos Biomecânicos
Caveolina 1/genética
Caveolina 1/metabolismo
Adesão Celular/efeitos dos fármacos
Linhagem Celular
Movimento Celular/efeitos dos fármacos
Embrião de Mamíferos
Matriz Extracelular/efeitos dos fármacos
Matriz Extracelular/ultraestrutura
Fibroblastos/efeitos dos fármacos
Fibroblastos/ultraestrutura
Adesões Focais/efeitos dos fármacos
Adesões Focais/ultraestrutura
Regulação da Expressão Gênica
Dureza
Microdomínios da Membrana/efeitos dos fármacos
Microdomínios da Membrana/ultraestrutura
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Camundongos
Proteínas Musculares/genética
Paxilina/genética
Paxilina/metabolismo
Ligação Proteica
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Transdução de Sinais
Vinculina/genética
beta-Ciclodextrinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Caveolin 1); 0 (Membrane Proteins); 0 (Muscle Proteins); 0 (Paxillin); 0 (Protein Isoforms); 0 (Pxn protein, mouse); 0 (Sh3d4 protein, mouse); 0 (beta-Cyclodextrins); 0 (flotillins); 0 (methyl-beta-cyclodextrin); 125361-02-6 (Vinculin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170703
[Lr] Data última revisão:
170703
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170510
[St] Status:MEDLINE
[do] DOI:10.1080/09168451.2017.1289074


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[PMID]:28423510
[Au] Autor:Cui S; Wang J; Wu Q; Qian J; Yang C; Bo P
[Ad] Endereço:Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, Yangzhou, China.
[Ti] Título:Genistein inhibits the growth and regulates the migration and invasion abilities of melanoma cells via the FAK/paxillin and MAPK pathways.
[So] Source:Oncotarget;8(13):21674-21691, 2017 Mar 28.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Genistein is one of the main components of soy-based foods, which are widely known for their many benefits, including anti-cancer, anti-inflammatory, and antioxidant effects. In this study, we investigated the anti-metastasis effects of genistein on B16F10 melanoma cells. Our results showed that genistein strongly inhibited B16F10 cell proliferation and induced apoptosis in time- and concentration-dependent manners. Genistein altered the morphology of B16F10 cells to an elongated shape with slim pseudopodia-like protrusions. Moreover, genistein inhibited the invasion and migration abilities of B16F10 cells in a dose-dependent manner. On one hand, a high concentration of genistein (100 µM) significantly inhibited cell adhesion and migration, as shown by wound healing assays and transwell-migration and invasion assays. Furthermore, the expression levels of p-FAK, p-paxillin, tensin-2, vinculin, and α-actinin were decreased by genistein. As a result, genistein is believed to strongly downregulate the migration and invasion abilities of B16F10 cells via the FAK/paxillin pathway. Moreover, p-p38, p-ERK, and p-JNK levels were also dramatically decreased by treatment with genistein. Finally, genistein significantly decreased the gene expression of FAK, paxillin, vimentin, and epithelial-to-mesenchymal transition-related transcription factor Snail, as shown by real-time PCR (qPCR) analysis. On the other hand, a lower concentration of genistein (12.5 µM) significantly promoted both invasion and migration by activating the FAK/paxillin and MAPK signaling cascades. Taken together, this study showed for the first time that genistein exerts dual functional effects on melanoma cells. Our findings suggest that genistein regulates the FAK/paxillin and MAPK signaling pathways in a highly concentration-dependent manner. Patients with melanoma should therefore be cautious of consuming soy-based foods in their diets.
[Mh] Termos MeSH primário: Anticarcinógenos/farmacologia
Genisteína/farmacologia
Melanoma Experimental/patologia
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Western Blotting
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Imunofluorescência
Quinase 1 de Adesão Focal/efeitos dos fármacos
Quinase 1 de Adesão Focal/metabolismo
Marcação In Situ das Extremidades Cortadas
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Camundongos
Invasividade Neoplásica/patologia
Paxilina/efeitos dos fármacos
Paxilina/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticarcinogenic Agents); 0 (Paxillin); 0 (Pxn protein, mouse); DH2M523P0H (Genistein); EC 2.7.10.2 (Focal Adhesion Kinase 1); EC 2.7.10.2 (Ptk2 protein, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15535


  8 / 1651 MEDLINE  
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[PMID]:28408355
[Au] Autor:Shih YP; Yuan SY; Lo SH
[Ad] Endereço:Department of Biochemistry and Molecular Medicine, California-Davis, Sacramento, CA 95817, USA.
[Ti] Título:Down-regulation of DLC1 in endothelial cells compromises the angiogenesis process.
[So] Source:Cancer Lett;398:46-51, 2017 Jul 10.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:DLC1 is a RhoGAP-containing tumor suppressor that inhibits angiogenesis by repressing VEGF production in epithelial cells. Here we report the roles of DLC1 in endothelial cells. Silencing of DLC1 (siDLC1) enhances cell migration but reduces tube formation activities of human umbilical vein endothelial cells (HUVECs). Biochemically, RhoA activity and paxillin protein level are markedly increased in siDLC1 HUVECs. Although further silencing of RhoA restores the cell migration phenotype, the tube formation defect and up-regulated paxillin level remain unchanged. On the other hand, paxillin knockdown rescues tube formation and migration phenotypes but not the up-regulated RhoA activity. These results indicate that DLC1 regulates endothelial cell migration through RhoA and paxillin independently and controls tube formation mainly via paxillin. To further determine endothelial DLC1's function, we have generated endothelial specific knockout mice (DLC1-Tek). DLC1-Tek mice appear to be normal and healthy but their angiogenesis processes are compromised as shown in gel plug and aortic ring sprouting assays. Analysis of endothelial cells isolated from DLC1-Tek mice has further affirmed the cellular and biochemical phenotypes established in siDLC1 HUVECs. Our studies have demonstrated a positive regulatory role of endothelial DLC1 in angiogenesis.
[Mh] Termos MeSH primário: Células Endoteliais/metabolismo
Proteínas Ativadoras de GTPase/metabolismo
Neovascularização Fisiológica
Proteínas Supressoras de Tumor/metabolismo
[Mh] Termos MeSH secundário: Animais
Movimento Celular
Células Cultivadas
Regulação para Baixo
Proteínas Ativadoras de GTPase/deficiência
Proteínas Ativadoras de GTPase/genética
Genótipo
Células Endoteliais da Veia Umbilical Humana/metabolismo
Seres Humanos
Camundongos Knockout
Paxilina/metabolismo
Fenótipo
Interferência de RNA
Transdução de Sinais
Transfecção
Proteínas Supressoras de Tumor/deficiência
Proteínas Supressoras de Tumor/genética
Proteínas rho de Ligação ao GTP/metabolismo
Proteína rhoA de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DLC-1 (deleted in liver cancer) protein, mouse); 0 (DLC1 protein, human); 0 (GTPase-Activating Proteins); 0 (PXN protein, human); 0 (Paxillin); 0 (Pxn protein, mouse); 0 (Tumor Suppressor Proteins); 124671-05-2 (RHOA protein, human); EC 3.6.5.2 (RhoA protein, mouse); EC 3.6.5.2 (rho GTP-Binding Proteins); EC 3.6.5.2 (rhoA GTP-Binding Protein)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170415
[St] Status:MEDLINE


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[PMID]:28381423
[Au] Autor:Mekhdjian AH; Kai F; Rubashkin MG; Prahl LS; Przybyla LM; McGregor AL; Bell ES; Barnes JM; DuFort CC; Ou G; Chang AC; Cassereau L; Tan SJ; Pickup MW; Lakins JN; Ye X; Davidson MW; Lammerding J; Odde DJ; Dunn AR; Weaver VM
[Ad] Endereço:Department of Chemical Engineering, Stanford University, Stanford, CA 94305.
[Ti] Título:Integrin-mediated traction force enhances paxillin molecular associations and adhesion dynamics that increase the invasiveness of tumor cells into a three-dimensional extracellular matrix.
[So] Source:Mol Biol Cell;28(11):1467-1488, 2017 Jun 01.
[Is] ISSN:1939-4586
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metastasis requires tumor cells to navigate through a stiff stroma and squeeze through confined microenvironments. Whether tumors exploit unique biophysical properties to metastasize remains unclear. Data show that invading mammary tumor cells, when cultured in a stiffened three-dimensional extracellular matrix that recapitulates the primary tumor stroma, adopt a basal-like phenotype. Metastatic tumor cells and basal-like tumor cells exert higher integrin-mediated traction forces at the bulk and molecular levels, consistent with a motor-clutch model in which motors and clutches are both increased. Basal-like nonmalignant mammary epithelial cells also display an altered integrin adhesion molecular organization at the nanoscale and recruit a suite of paxillin-associated proteins implicated in invasion and metastasis. Phosphorylation of paxillin by Src family kinases, which regulates adhesion turnover, is similarly enhanced in the metastatic and basal-like tumor cells, fostered by a stiff matrix, and critical for tumor cell invasion in our assays. Bioinformatics reveals an unappreciated relationship between Src kinases, paxillin, and survival of breast cancer patients. Thus adoption of the basal-like adhesion phenotype may favor the recruitment of molecules that facilitate tumor metastasis to integrin-based adhesions. Analysis of the physical properties of tumor cells and integrin adhesion composition in biopsies may be predictive of patient outcome.
[Mh] Termos MeSH primário: Adesão Celular/fisiologia
Integrinas/metabolismo
Paxilina/metabolismo
[Mh] Termos MeSH secundário: Mama/metabolismo
Neoplasias da Mama/patologia
Linhagem Celular Tumoral
Matriz Extracelular/metabolismo
Feminino
Proteína-Tirosina Quinases de Adesão Focal/metabolismo
Seres Humanos
Metástase Neoplásica/fisiopatologia
Fosforilação
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Integrins); 0 (Paxillin); EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170407
[St] Status:MEDLINE
[do] DOI:10.1091/mbc.E16-09-0654


  10 / 1651 MEDLINE  
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[PMID]:28373581
[Au] Autor:Dragoni S; Hudson N; Kenny BA; Burgoyne T; McKenzie JA; Gill Y; Blaber R; Futter CE; Adamson P; Greenwood J; Turowski P
[Ad] Endereço:Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.
[Ti] Título:Endothelial MAPKs Direct ICAM-1 Signaling to Divergent Inflammatory Functions.
[So] Source:J Immunol;198(10):4074-4085, 2017 May 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lymphocyte transendothelial migration (TEM) is critically dependent on intraendothelial signaling triggered by adhesion to ICAM-1. Here we show that endothelial MAPKs ERK, p38, and JNK mediate diapedesis-related and diapedesis-unrelated functions of ICAM-1 in cerebral and dermal microvascular endothelial cells (MVECs). All three MAPKs were activated by ICAM-1 engagement, either through lymphocyte adhesion or Ab-mediated clustering. MAPKs were involved in ICAM-1-dependent expression of TNF-α in cerebral and dermal MVECs, and CXCL8, CCL3, CCL4, VCAM-1, and cyclooxygenase 2 (COX-2) in cerebral MVECs. Endothelial JNK and to a much lesser degree p38 were the principal MAPKs involved in facilitating diapedesis of CD4 lymphocytes across both types of MVECs, whereas ERK was additionally required for TEM across dermal MVECs. JNK activity was critical for ICAM-1-induced F-actin rearrangements. Furthermore, activation of endothelial ICAM-1/JNK led to phosphorylation of paxillin, its association with VE-cadherin, and internalization of the latter. Importantly ICAM-1-induced phosphorylation of paxillin was required for lymphocyte TEM and converged functionally with VE-cadherin phosphorylation. Taken together we conclude that during lymphocyte TEM, ICAM-1 signaling diverges into pathways regulating lymphocyte diapedesis, and other pathways modulating gene expression thereby contributing to the long-term inflammatory response of the endothelium.
[Mh] Termos MeSH primário: Células Endoteliais/metabolismo
Inflamação/metabolismo
Molécula 1 de Adesão Intercelular/metabolismo
Proteínas Quinases Ativadas por Mitógeno/metabolismo
Transdução de Sinais
Migração Transendotelial e Transepitelial
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Mh] Termos MeSH secundário: Actinas/metabolismo
Encéfalo/irrigação sanguínea
Linfócitos T CD4-Positivos/imunologia
Linfócitos T CD4-Positivos/fisiologia
Movimento Celular
Células Cultivadas
Quimiocina CCL3/genética
Quimiocina CCL3/imunologia
Quimiocina CCL4/genética
Quimiocina CCL4/imunologia
Ciclo-Oxigenase 2/genética
Ciclo-Oxigenase 2/metabolismo
Derme/irrigação sanguínea
Células Endoteliais/imunologia
Endotélio Vascular/citologia
Endotélio Vascular/imunologia
Endotélio Vascular/metabolismo
Ativação Enzimática
Seres Humanos
Inflamação/imunologia
Interleucina-8/genética
Interleucina-8/imunologia
Sistema de Sinalização das MAP Quinases
Microvasos
Paxilina/metabolismo
Fosforilação
Fator de Necrose Tumoral alfa/metabolismo
Molécula 1 de Adesão de Célula Vascular/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (CCL3 protein, human); 0 (CCL4 protein, human); 0 (Chemokine CCL3); 0 (Chemokine CCL4); 0 (ICAM1 protein, human); 0 (IL8 protein, human); 0 (Interleukin-8); 0 (PXN protein, human); 0 (Paxillin); 0 (Tumor Necrosis Factor-alpha); 0 (Vascular Cell Adhesion Molecule-1); 126547-89-5 (Intercellular Adhesion Molecule-1); EC 1.14.99.1 (Cyclooxygenase 2); EC 1.14.99.1 (PTGS2 protein, human); EC 2.7.11.24 (Mitogen-Activated Protein Kinases); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170405
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1600823



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