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Nucleic Acids Res ; 36(13): 4222-32, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18583365

RESUMO

MYCN activation, mainly by gene amplification, is one of the most frequent molecular events in neuroblastoma (NB) oncogenesis, and is associated with increased malignancy and decreased neuronal differentiation propensity. The frequency of concomitant loss of heterozygosity at the 1p36.3 locus, which harbours the p53 anti-oncogene homologue TP73, indicates that MYCN and p73 alterations may cooperate in the pathogenesis of NB. We have previously shown that p73 isoforms are deregulated in NB tumours and that TAp73 co-operates synergistically with p53 for apoptosis of NB cells, whereas DeltaNp73 activates the expression of neuronal differentiation genes such as BTG2. Herein, using both ectopic expression and RNA interference-mediated silencing of p73 in MYCN amplified NB cells, we show that p73alpha isoforms inhibit MYCN expression at both transcript and protein levels, in spite of transactivator effects on MYCN promoter. To explain this paradox, we found that TAp73alpha exerts negative post-transcriptional effects leading to reduced MYCN mRNA stability. RNA immunoprecipitation experiments suggest that this dominant inhibitory post-transcriptional effect could be due to an interaction between the p73 protein and MYCN mRNA, a hypothesis also raised for the regulation of certain genes by the p53 protein.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Neuroblastoma/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Oncogênicas/genética , Estabilidade de RNA , RNA Mensageiro/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Linhagem Celular Tumoral , Genes myc , Humanos , Proteína Proto-Oncogênica N-Myc , Neuroblastoma/metabolismo , Proteínas Nucleares/biossíntese , Proteínas Oncogênicas/biossíntese , Proteínas Oncogênicas/metabolismo , Regiões Promotoras Genéticas , Isoformas de Proteínas/metabolismo , Ativação Transcricional , Proteína Tumoral p73
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