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1.
Cell Adh Migr ; 15(1): 58-73, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33724150

RESUMO

Neuroblastoma is a highly metastatic tumor that emerges from neural crest cell progenitors. Focal Adhesion Kinase (FAK) is a regulator of cell migration that binds to the receptor Neogenin-1 and is upregulated in neuroblastoma. Here, we show that Netrin-1 ligand binding to Neogenin-1 leads to FAK autophosphorylation and integrin ß1 activation in a FAK dependent manner, thus promoting neuroblastoma cell migration. Moreover, Neogenin-1, which was detected in all tumor stages and was required for neuroblastoma cell migration, was found in a complex with integrin ß1, FAK, and Netrin-1. Importantly, Neogenin-1 promoted neuroblastoma metastases in an immunodeficient mouse model. Taken together, these data show that Neogenin-1 is a metastasis-promoting protein that associates with FAK, activates integrin ß1 and promotes neuroblastoma cell migration.


Assuntos
Integrina beta1 , Neuroblastoma , Animais , Adesão Celular , Movimento Celular , Quinase 1 de Adesão Focal/genética , Proteína-Tirosina Quinases de Adesão Focal , Proteínas de Membrana , Camundongos , Netrina-1
2.
Cell Adh Migr ; 13(1): 33-40, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30160193

RESUMO

Neuroblastoma (NB) is the most common pediatric extracranial solid tumor. It arises during development of the sympathetic nervous system. Netrin-4 (NTN4), a laminin-related protein, has been proposed as a key factor to target NB metastasis, although there is controversy about its function. Here, we show that NTN4 is broadly expressed in tumor, stroma and blood vessels of NB patient samples. Furthermore, NTN4 was shown to act as a cell adhesion molecule required for the migration induced by Neogenin-1 (NEO1) in SK-N-SH neuroblastoma cells. Therefore, we propose that NTN4, by forming a ternary complex with Laminin γ1 (LMγ1) and NEO1, acts as an essential extracellular matrix component, which induces the migration of SK-N-SH cells.


Assuntos
Movimento Celular , Regulação Neoplásica da Expressão Gênica , Laminina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Netrinas/metabolismo , Neuroblastoma/patologia , Receptores de Superfície Celular/metabolismo , Adesão Celular , Feminino , Humanos , Lactente , Masculino , Neuroblastoma/metabolismo , Células Tumorais Cultivadas
3.
Semin Cell Dev Biol ; 80: 43-49, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-28899716

RESUMO

Historically, ROS have been considered toxic molecules, especially when their intracellular concentration reaches high values. However, physiological levels of ROS support crucial cellular processes, acting as second messengers able to regulate intrinsic signaling pathways. Specifically, both the central and peripheral nervous systems are especially susceptible to changes in the redox state, developing either a defense or adaptive response depending on the concentration, source and duration of the pro-oxidative stimuli. In this review, we summarize classical and modern concepts regarding ROS physiology, with an emphasis on the role of the NADPH oxidase (NOX) complex, the main enzymatic and regulated source of ROS in the nervous system. We discuss how ROS and redox state contribute to neurogenesis, polarization and maturation of neurons, providing a context for the spatio-temporal conditions in which ROS modulate neural fate, discriminating between "oxidative distress", and "oxidative eustress". Finally, we present a brief discussion about the "physiological range of ROS concentration", and suggest that these values depend on several parameters, including cell type, developmental stage, and the source and type of pro-oxidative molecule.


Assuntos
Sistema Nervoso/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Humanos , Oxirredução , Transdução de Sinais/fisiologia
4.
J Neurosci ; 36(43): 11107-11119, 2016 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-27798190

RESUMO

Physiological levels of ROS support neurite outgrowth and axonal specification, but the mechanisms by which ROS are able to shape neurons remain unknown. Ca2+, a broad intracellular second messenger, promotes both Rac1 activation and neurite extension. Ca2+ release from the endoplasmic reticulum, mediated by both the IP3R1 and ryanodine receptor (RyR) channels, requires physiological ROS levels that are mainly sustained by the NADPH oxidase (NOX) complex. In this work, we explore the contribution of the link between NOX and RyR-mediated Ca2+ release toward axonal specification of rat hippocampal neurons. Using genetic approaches, we find that NOX activation promotes both axonal development and Rac1 activation through a RyR-mediated mechanism, which in turn activates NOX through Rac1, one of the NOX subunits. Collectively, these data suggest a feedforward mechanism that integrates both NOX activity and RyR-mediated Ca2+ release to support cellular mechanisms involved in axon development. SIGNIFICANCE STATEMENT: High levels of ROS are frequently associated with oxidative stress and disease. In contrast, physiological levels of ROS, mainly sustained by the NADPH oxidase (NOX) complex, promote neuronal development and axonal growth. However, the mechanisms by which ROS shape neurons have not been described. Our work suggests that NOX-derived ROS promote axonal growth by regulating Rac1 activity, a molecular determinant of axonal growth, through a ryanodine receptor (RyR)-mediated Ca2+ release mechanism. In addition, Rac1, one of the NOX subunits, was activated after RyR-mediated Ca2+ release, suggesting a feedforward mechanism between NOX and RyR. Collectively, our data suggest a novel mechanism that is instrumental in sustaining physiological levels of ROS required for axonal growth of hippocampal neurons.


Assuntos
Orientação de Axônios/fisiologia , Sinalização do Cálcio/fisiologia , Retroalimentação Fisiológica/fisiologia , NADPH Oxidases/metabolismo , Neurônios/fisiologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipocampo/fisiologia , Hipocampo/ultraestrutura , Masculino , Plasticidade Neuronal/fisiologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
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