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2.
Expert Rev Neurother ; 10(4): 575-86, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20367209

RESUMO

Glioblastoma remains the most clinically challenging tumor of the CNS, as evidenced by the dismal change in overall survival over the past 50 years. However, recent advances in high-throughput screening techniques have given rise to a wealth of new information regarding the aberrant signaling pathways that drive the tumor phenotype. Two of these so-called 'oncopathways' are NF-kappaB and JAK/STAT. This review will describe the basic mechanisms of these pathways, explore the relevance of NF-kappaB and JAK/STAT signaling in glioblastoma, and look ahead to experimental compounds that will integrate our knowledge of these pathways into existing therapies.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , NF-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia , Animais , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Humanos , NF-kappa B/genética , Fator de Transcrição STAT3/genética
3.
Mol Cell Biol ; 28(21): 6632-45, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18779315

RESUMO

The NF-kappaB family mediates immune and inflammatory responses. In many cancers, NF-kappaB is constitutively activated and induces the expression of genes that facilitate tumorigenesis. ING4 is a tumor suppressor that is absent or mutated in several cancers. Herein, we demonstrate that in human gliomas, NF-kappaB is constitutively activated, ING4 expression is negligible, and NF-kappaB-regulated gene expression is elevated. We demonstrate that an ING4 and NF-kappaB interaction exists but does not prevent NF-kappaB activation, nuclear translocation, or DNA binding. Instead, ING4 and NF-kappaB bind simultaneously at NF-kappaB-regulated promoters, and this binding correlates with reductions in p65 phosphorylation, p300, and the levels of acetylated histones and H3-Me3K4, while enhancing the levels of HDAC-1 at these promoters. Using a knockdown approach, we correlate reductions in ING4 protein levels with increased basal and inducible NF-kappaB target gene expression. Collectively, these data suggest that ING4 may specifically regulate the activity of NF-kappaB molecules that are bound to target gene promoters.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Genes Neoplásicos , Glioma/genética , Proteínas de Homeodomínio/metabolismo , NF-kappa B/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Supressoras de Tumor/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Proteína p300 Associada a E1A/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/enzimologia , Histona Desacetilase 1 , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Ligação Proteica/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , RNA Interferente Pequeno/farmacologia , Fator de Transcrição RelA/metabolismo , Transcrição Gênica/efeitos dos fármacos
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