RESUMEN
Wig-1, also known as ZMAT3, is a p53 target gene that encodes an RNA-binding zinc-finger protein involved in the regulation of mRNA stability through binding to AU-rich elements (AREs). We have used microarray analysis to identify novel Wig-1 target mRNAs. We identified 2447 transcripts with >fourfold differential expression between Wig-1 and control small interfering (si)RNA-treated HCT116 cells. Several p53 target genes were among the deregulated transcripts. We found that Wig-1 regulates FAS and 14-3-3σ mRNA independently of p53. We show that Wig-1 binds to FAS mRNA 3'-UTR and decreases its stability through an ARE in the 3'-UTR. Depletion of Wig-1 was associated with increased cell death and reduced cell cycle arrest upon DNA damage. Our results suggest a role of Wig-1 as a survival factor that directs the p53 stress response toward cell cycle arrest rather than apoptosis through the regulation of FAS and 14-3-3σ mRNA levels.
Asunto(s)
Proteínas 14-3-3/genética , Biomarcadores de Tumor/genética , Proteínas Portadoras/metabolismo , Puntos de Control del Ciclo Celular , Exorribonucleasas/genética , Proteínas Nucleares/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Receptor fas/genética , Proteínas 14-3-3/metabolismo , Regiones no Traducidas 3' , Elementos Ricos en Adenilato y Uridilato , Antineoplásicos/farmacología , Apoptosis , Biomarcadores de Tumor/metabolismo , Proteínas Portadoras/genética , Línea Celular Tumoral , Cisplatino/farmacología , Exorribonucleasas/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Análisis por Micromatrices , Proteínas Nucleares/genética , Proteínas de Unión al ARN , Receptor fas/metabolismoRESUMEN
Wig-1 is a transcriptional target of the p53 tumor suppressor and encodes an mRNA stability-regulating protein. We show here that Wig-1 knockdown causes a dramatic inhibition of N-Myc expression and triggers differentiation in neuroblastoma cells carrying amplified N-Myc. Transient Wig-1 knockdown significantly delays development of N-Myc-driven tumors in mice. We also show that N-Myc expression is induced upon moderate p53-activating stress, suggesting a role of the p53-Wig-1-N-Myc axis in promoting cell cycle re-entry upon p53-induced cell cycle arrest and DNA repair. Moreover, our findings raise possibilities for the improved treatment of poor prognosis neuroblastomas that carry amplified N-Myc.
Asunto(s)
Proteínas Portadoras/metabolismo , Neoplasias/patología , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Mensajero/metabolismo , Animales , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/genética , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Reparación del ADN , Femenino , Células HCT116 , Humanos , Ratones , Ratones Desnudos , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas c-myc/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Proteínas de Unión al ARN , Trasplante Heterólogo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Wig-1 is a transcriptional target of the tumor suppressor p53 and encodes an unusual zinc-finger protein involved in post-transcriptional gene regulation. Wig-1 is expressed in all cell types investigated so far, with the highest levels in the brain, and is enriched in stem cells as compared with more differentiated cells of the same lineage. Wig-1 binds to both long double-stranded (ds) RNA and short microRNA-like dsRNA. We have shown that Wig-1 acts in a positive feedback loop that stabilizes p53 mRNA through an AU-rich element (ARE) in the p53 3'untranslated region. Our preliminary data indicate a more general effect of Wig-1 on ARE-containing mRNA. Here we shall summarize current knowledge about Wig-1 and discuss possible implications on p53 function and other cellular processes.