RESUMEN
The Aurora-A kinase gene is frequently amplified and/or overexpressed in a variety of human cancers, leading to major efforts to develop therapeutic agents targeting this pathway. Here, we show that Aurora-A is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7 in a process that is regulated by GSK3ß. Using a series of truncated Aurora-A proteins and site-directed mutagenesis, we identified distinct FBXW7 and GSK3ß-binding sites in Aurora-A. Mutation of critical residues in either site substantially disrupts degradation of Aurora-A. Furthermore, we show that loss of Pten results in the stabilization of Aurora-A by attenuating FBXW7-dependent degradation of Aurora-A through the AKT/GSK3ß pathway. Moreover, radiation-induced tumor latency is significantly shortened in Fbxw7(+/-)Pten(+/-) mice as compared with either Fbxw7(+/-) or Pten(+/-) mice, indicating that Fbxw7 and Pten appear to cooperate in suppressing tumorigenesis. Our results establish a novel posttranslational regulatory network in which the Pten and Fbxw7 pathways appear to converge on the regulation of Aurora-A level.
Asunto(s)
Proteínas F-Box/metabolismo , Neoplasias Inducidas por Radiación/metabolismo , Fosfohidrolasa PTEN/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Aurora Quinasa A , Aurora Quinasas , Sitios de Unión/genética , Western Blotting , Línea Celular , Proteínas F-Box/genética , Proteína 7 que Contiene Repeticiones F-Box-WD , Femenino , Rayos gamma , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Células HCT116 , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Células 3T3 NIH , Neoplasias Inducidas por Radiación/genética , Neoplasias Inducidas por Radiación/patología , Fosfohidrolasa PTEN/genética , Unión Proteica , Proteínas Serina-Treonina Quinasas/genética , Factores de Tiempo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
In this study, the authors describe the development and subsequent validation of an attention-deficit/hyperactivity disorder (ADHD) scale for young adults. The authors constructed 2 parallel forms of the scale to assess items that relate directly to DSM-IV criteria. Each form comprised Inattention, Hyperactivity, and Impulsivity subscales. Confirmatory factor analyses were conducted to assess the dimensionality of the scale, and the hypothesized structure was confirmed. In addition, the measures obtained show that the scale possesses satisfactory reliability with regard to the level of internal consistency, and there was equivalence between the 2 parallel forms. Furthermore, the relevance of the scale's content and its relationship to other variables was adequate. In sum, sufficient evidence is provided regarding the validity of the measures obtained with the ADHD scale, thus illustrating that the scale could be a useful tool to assess the symptoms of ADHD in a sample of young adults from the United States.