RESUMEN
MicroRNAs (miRNAs) carry out post-transcriptional control of a multitude of cellular processes. Aberrant expression of miRNA can lead to diseases, including cancer. Gliomas are aggressive brain tumors that are thought to arise from transformed glioma-initiating neural stem cells (giNSCs). With the use of giNSCs and human glioblastoma cells, we investigated the function of miRNAs in gliomas. We identified pro-neuronal miR-128 as a candidate glioma tumor suppressor miRNA. Decreased expression of miR-128 correlates with aggressive human glioma subtypes. With a combination of molecular, cellular and in vivo approaches, we characterize miR-128's tumor suppressive role. miR-128 represses giNSC growth by enhancing neuronal differentiation. miR-128 represses growth and mediates differentiation by targeting oncogenic receptor tyrosine kinases (RTKs) epithelial growth factor receptor and platelet-derived growth factor receptor-α. Using an autochthonous glioma mouse model, we demonstrated that miR-128 repressed gliomagenesis. We identified miR-128 as a glioma tumor suppressor that targets RTK signaling to repress giNSC self-renewal and enhance differentiation.
Asunto(s)
Neoplasias Encefálicas/genética , Receptores ErbB/genética , Genes Supresores de Tumor , Glioma/genética , MicroARNs/fisiología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Animales , Diferenciación Celular/genética , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Desnudos , Ratones SCID , Células-Madre Neurales/fisiologíaRESUMEN
A 140.7-kb segment of zebrafish genomic DNA known to contain odorant receptor (OR) genes was fully sequenced to characterize more completely the organization of this gene cluster. A total of 20 OR genes were identified in this region. The most highly related genes are grouped in closest proximity to one another and in the same transcriptional orientation, indicating that a series of tandem duplications was responsible for the expansion of the OR gene family in teleost fish. Our analysis also revealed sequences that may be involved in the transcriptional regulation of OR genes within the cluster.
Asunto(s)
Genoma , Familia de Multigenes , Receptores Odorantes/genética , Pez Cebra/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Elementos Transponibles de ADN , Modelos Genéticos , Datos de Secuencia Molecular , Filogenia , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido Nucleico , Transcripción GenéticaRESUMEN
We have characterized the organization and expression of odorant receptor genes clustered within approximately 100 kb of the zebrafish genome. Physical analysis of this genomic region reveals that the receptor genes are tightly linked in tandem arrays. The expression patterns of these genes were evaluated during development as well as in the adult olfactory epithelium. Highly related genes from this array are expressed individually in different olfactory neurons, suggesting that the discriminatory capacity of the vertebrate olfactory system has been maximized by segregating the most similar receptors into distinct cellular pathways. Furthermore, genes from this cluster are activated at different times of development. Together, these results indicate that genomically linked odorant receptor genes are not coordinately regulated.