Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Cell Commun Signal ; 18(1): 64, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32312272

RESUMO

An amendment to this paper has been published and can be accessed via the original article.

2.
Cell Commun Signal ; 14(1): 32, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27978828

RESUMO

BACKGROUND: STAT3 is increasingly becoming known for its non-transcriptional regulation of mitochondrial bioenergetic function upon activation of its S727 residue (S727-STAT3). Lengthy mitochondrial dysfunction can lead to cell death. We tested whether an integrin-FAK-STAT3 signaling pathway we recently discovered regulates mitochondrial function and cell survival, and treatments thereof. METHODS: Cultured mouse brain bEnd5 endothelial cells were treated with integrin, FAK or STAT3 inhibitors, FAK siRNA, as well as integrin and STAT3 activators. STAT3 null cells were transfected with mutant STAT3 plasmids. Outcome measures included oxygen consumption rate for mitochondrial bioenergetics, Western blotting for protein phosphorylation, mitochondrial membrane potential for mitochondrial integrity, ROS production, and cell counts. RESULTS: Vitronectin-dependent mitochondrial basal respiration, ATP production, and maximum reserve and respiratory capacities were suppressed within 4 h by RGD and αvß3 integrin antagonist peptides. Conversely, integrin ligands vitronectin, laminin and fibronectin stimulated mitochondrial function. Pharmacological inhibition of FAK completely abolished mitochondrial function within 4 h while FAK siRNA treatments confirmed the specificity of FAK signaling. WT, but not S727A functionally dead mutant STAT3, rescued bioenergetics in cells made null for STAT3 using CRISPR-Cas9. STAT3 inhibition with stattic in whole cells rapidly reduced mitochondrial function and mitochondrial pS727-STAT3. Stattic treatment of isolated mitochondria did not reduce pS727 whereas more was detected upon phosphatase inhibition. This suggests that S727-STAT3 is activated in the cytoplasm and is short-lived upon translocation to the mitochondria. FAK inhibition reduced pS727-STAT3 within mitochondria and reduced mitochondrial function in a non-transcriptional manner, as shown by co-treatment with actinomycin. Treatment with the small molecule bryostatin-1 or hepatocyte growth factor (HGF), which indirectly activate S727-STAT3, preserved mitochondrial function during FAK inhibition, but failed in the presence of the STAT3 inhibitor. FAK inhibition induced loss of mitochondrial membrane potential, which was counteracted by bryostatin, and increased superoxide and hydrogen peroxide production. Bryostatin and HGF reduced the substantial cell death caused by FAK inhibition over a 24 h period. CONCLUSION: These data suggest that extracellular matrix molecules promote STAT3-dependent mitochondrial function and cell survival through integrin-FAK signaling. We furthermore show a new treatment strategy for cell survival using S727-STAT3 activators.


Assuntos
Células Endoteliais/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Integrinas/metabolismo , Mitocôndrias/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Trifosfato de Adenosina/metabolismo , Animais , Morte Celular , Linhagem Celular Tumoral , Células Endoteliais/citologia , Metabolismo Energético , Camundongos , Fosforilação , Espécies Reativas de Oxigênio/metabolismo
3.
AJNR Am J Neuroradiol ; 44(11): 1309-1313, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37884302

RESUMO

BACKGROUND AND PURPOSE: The radiologic prevalence of superior semicircular canal dehiscence in the asymptomatic population has been widely studied, but less is known about the rates of other forms of third window dehiscence. Per the existing literature, the radiologic prevalence of cochlear-facial nerve dehiscence, for example, exceeds that seen in histologic studies, suggesting that conventional CT is unreliable for cochlear-facial dehiscence. These studies relied on nonisometric CT acquisitions, however, and underused multiplanar reformatting techniques, leading to false-positive findings. Our purpose was to determine the rate of cochlear-facial dehiscence and other non-superior semicircular canal third window dehiscences on optimized CT in asymptomatic patients. MATERIALS AND METHODS: Sixty-four-channel temporal bone CT scans from 602 patients in emergency departments were assessed for cochlear-facial and other non-superior semicircular canal third window dehiscences by using high-resolution, multiplanar oblique reformats. Confidence intervals for dehiscence prevalence were calculated using the Newcombe 95% interval confidence method. RESULTS: Of 602 patients, 500 were asymptomatic, while 102 had an imaging indication consistent with possible third window syndrome (symptomatic). Eight asymptomatic patients (1.6%) had cochlear-facial dehiscence, while 43 (8.4%) had jugular bulb-vestibular aqueduct dehiscence. There was no statistically significant difference between the prevalence of cochlear-facial dehiscence or jugular bulb-vestibular aqueduct dehiscence in asymptomatic patients compared with symptomatic patients. Cochlear-carotid canal, cochlear-internal auditory canal, and cochlear-petrosal sinus dehiscences were not observed. CONCLUSIONS: Sixty-four-channel CT with multioblique reformatting is sensitive and specific for identifying cochlear-facial dehiscence, with rates similar to those in postmortem series. Jugular bulb-vestibular aqueduct dehiscence is a common incidental finding and is unlikely to produce third window physiology. Other non-superior semicircular canal third window dehiscences are rare in asymptomatic patients.


Assuntos
Deiscência do Canal Semicircular , Humanos , Deiscência do Canal Semicircular/patologia , Prevalência , Canais Semicirculares/diagnóstico por imagem , Canais Semicirculares/patologia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Osso Temporal/diagnóstico por imagem
4.
Nat Cell Biol ; 25(3): 493-507, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36849558

RESUMO

How abnormal neurodevelopment relates to the tumour aggressiveness of medulloblastoma (MB), the most common type of embryonal tumour, remains elusive. Here we uncover a neurodevelopmental epigenomic programme that is hijacked to induce MB metastatic dissemination. Unsupervised analyses of integrated publicly available datasets with our newly generated data reveal that SMARCD3 (also known as BAF60C) regulates Disabled 1 (DAB1)-mediated Reelin signalling in Purkinje cell migration and MB metastasis by orchestrating cis-regulatory elements at the DAB1 locus. We further identify that a core set of transcription factors, enhancer of zeste homologue 2 (EZH2) and nuclear factor I X (NFIX), coordinates with the cis-regulatory elements at the SMARCD3 locus to form a chromatin hub to control SMARCD3 expression in the developing cerebellum and in metastatic MB. Increased SMARCD3 expression activates Reelin-DAB1-mediated Src kinase signalling, which results in a MB response to Src inhibition. These data deepen our understanding of how neurodevelopmental programming influences disease progression and provide a potential therapeutic option for patients with MB.


Assuntos
Neoplasias Cerebelares , Meduloblastoma , Humanos , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Meduloblastoma/genética , Fosforilação , Epigenômica , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Moléculas de Adesão Celular Neuronais/farmacologia , Neoplasias Cerebelares/genética , Epigênese Genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo
6.
Cell Signal ; 36: 154-162, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28495589

RESUMO

Excessive endoplasmic reticulum (ER) stress leads to cell loss in many diseases, e.g., contributing to endothelial cell loss after spinal cord injury. Here, we determined whether ER stress-induced mitochondrial dysfunction could be explained by interruption of the focal adhesion kinase (FAK)-mitochondrial STAT3 pathway we recently discovered. ER stress was induced in brain-derived mouse bEnd5 endothelial cells by thapsigargin or tunicamycin and caused apoptotic cell death over a 72h period. In concert, ER stress caused mitochondrial dysfunction as shown by reduced bioenergetic function, loss of mitochondrial membrane potential and increased mitophagy. ER stress caused a reduction in mitochondrial phosphorylated S727-STAT3, known to be important for maintaining mitochondrial function. Normal activation or phosphorylation of the upstream cytoplasmic FAK was also reduced, through mechanisms that involve tyrosine phosphatases and calcium signaling, as shown by pharmacological inhibitors, bisperoxovanadium (bpV) and 2-aminoethoxydiphenylborane (APB), respectively. APB mitigated the reduction in FAK and STAT3 phosphorylation, and improved endothelial cell survival caused by ER stress. Transfection of cells rendered null for STAT3 using CRISPR technology with STAT3 mutants confirmed the specific involvement of S727-STAT3 inhibition in ER stress-mediated cell loss. These data suggest that loss of FAK signaling during ER stress causes mitochondrial dysfunction by reducing the protective effects of mitochondrial STAT3, leading to endothelial cell death. We propose that stimulation of the FAK-STAT3 pathway is a novel therapeutic approach against pathological ER stress.


Assuntos
Estresse do Retículo Endoplasmático , Células Endoteliais/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Mitocôndrias/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Fosfoproteínas Fosfatases/metabolismo , Fosforilação/efeitos dos fármacos , Fosfosserina/metabolismo , Transdução de Sinais/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA