RESUMEN
Glioblastoma (GBM) is a highly lethal primary brain cancer with hallmark features of diffuse invasion, intense apoptosis resistance and florid necrosis, robust angiogenesis, and an immature profile with developmental plasticity. In the course of assessing the developmental consequences of central nervous system (CNS)-specific deletion of p53 and Pten, we observed a penetrant acute-onset malignant glioma phenotype with striking clinical, pathological, and molecular resemblance to primary GBM in humans. This primary, as opposed to secondary, GBM presentation in the mouse prompted genetic analysis of human primary GBM samples that revealed combined p53 and Pten mutations as the most common tumor suppressor defects in primary GBM. On the mechanistic level, the "multiforme" histopathological presentation and immature differentiation marker profile of the murine tumors motivated transcriptomic promoter-binding element and functional studies of neural stem cells (NSCs), which revealed that dual, but not singular, inactivation of p53 and Pten promotes cellular c-Myc activation. This increased c-Myc activity is associated not only with impaired differentiation, enhanced self-renewal capacity of NSCs, and tumor-initiating cells (TICs), but also with maintenance of TIC tumorigenic potential. Together, these murine studies have provided a highly faithful model of primary GBM, revealed a common tumor suppressor mutational pattern in human disease, and established c-Myc as a key component of p53 and Pten cooperative actions in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal, and tumorigenic potential.
Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Genes myc , Genes p53 , Glioblastoma/genética , Glioblastoma/patología , Células Madre Neoplásicas/patología , Fosfohidrolasa PTEN/genética , Animales , Diferenciación Celular/genética , Proliferación Celular , Transformación Celular Neoplásica/genética , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Mutantes , Ratones Transgénicos , Modelos Neurológicos , Mutación , Especificidad de la EspecieRESUMEN
Death associated protein-5 (DAP-5) is a ubiquitously expressed member of the translation initiation factor eIF4G family that lacks the eIF4E binding site. A dominant negative fragment of DAP-5 protects HeLa cells from IFNgamma-induced cell death. By employing a functional approach we examined the role of DAP-5 in human neuroblastoma cells that are sensitized for IFNgamma-induced apoptosis by tetracycline controlled MYCN expression. DAP-5 fragment transcribed at high levels and translated into a functional miniprotein of 28 kDa protected neuroblastoma cells from IFNgamma-induced apoptosis. Reduced serum levels were toxic to cells constitutively expressing DAP-5 fragment suggesting that DAP-5 protein is essential for both viability and death of human neuroblastoma cells.