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Nucleic Acids Res ; 35(16): 5439-51, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17702766

RESUMO

Toxic nitric oxide (NO) levels can regulate gene expression. Using a novel protein/DNA array, we show that toxic NO levels regulate the binding of trans-factors to various cis-elements in neuroblastoma cells, including CRE and those recognized by the transcription factors AP1, AP2, Brn-3a, EGR, E2F1 and SP1. Functionality of some of the cis-elements was confirmed by electro mobility shift and reporter assays. Interestingly, CREB, AP-1, Brn-3a, EGR and E2F1 can control mammalian cell viability. NO induced the anti-apoptotic Bcl-2 protein and its mRNA prior to the onset of death of 30-60% of the cells. Promoter analysis of the bcl-2 gene confirmed the involvement of a CRE in NO-dependent bcl-2 transcription. Neuroblastoma cells over-expressing bcl-2 became much more resistant to NO-induced apoptosis; conversely, Bcl-2 knockdown cells were rendered markedly more sensitive to NO. Together these results suggest that Bcl-2 counteracts NO-induced apoptosis in a fraction of the cell population. Thus, NO stimulates the binding of many trans-factors to their cognate cis-elements, some of which can regulate cell viability through transcriptional activation of target genes. Our results emphasize that a DNA/protein array approach can reveal novel, global transcription factor activities stimulated by cell death-regulating molecules.


Assuntos
Apoptose/genética , Óxido Nítrico/metabolismo , Elementos de Resposta , Fatores de Transcrição/metabolismo , Ativação Transcricional , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular , AMP Cíclico/metabolismo , Genes bcl-2 , Humanos , Neuroblastoma , Análise de Sequência com Séries de Oligonucleotídeos , Análise Serial de Proteínas
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