RESUMEN
The mechanisms involved in oligodendroglial cell death in human demyelinating diseases are only partly understood. Here, we demonstrate that the BH3 only protein Puma, but not Noxa, is essential for oligodendroglial cell death in toxic demyelination induced by the copper chelator cuprizone. Primary oligodendrocytes derived from Noxa- or Puma-deficient mice showed comparable differentiation to wild-type cells, but Puma-deficient oligodendrocytes were less susceptible to spontaneous, staurosporine, or nitric oxide-induced cell death. Furthermore, Puma was expressed in oligodendrocytes in multiple sclerosis (MS) lesions and Puma mRNA levels were upregulated in primary human oligodendrocytes upon cell death induction by staurosporine. Our data demonstrate that Puma is pivotal for oligodendroglial cell death induced by different cell death stimuli and might play a role in oligodendroglial cell death in MS.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Oligodendroglía/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adulto , Anciano , Análisis de Varianza , Animales , Animales Recién Nacidos , Proteínas Reguladoras de la Apoptosis/deficiencia , Encéfalo/citología , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Células Cultivadas , Cuprizona/toxicidad , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/prevención & control , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Humanos , Etiquetado Corte-Fin in Situ , Interferón gamma/farmacología , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Esclerosis Múltiple/patología , Oligodendroglía/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/deficiencia , Proteínas Supresoras de Tumor/deficienciaRESUMEN
In response to DNA damage, several signaling pathways that arrest the cell cycle in G(1) and G(2) are activated. The down-regulation of mitotic genes contributes to the stable maintenance of the G(2) arrest. The human LINC or DREAM complex, together with the B-MYB transcription factor, plays an essential role in the expression of G(2)-M genes. Here, we show that DNA damage results in the p53-dependent binding of p130 and E2F4 to LINC and the dissociation of B-MYB from LINC. We find that B-MYB fails to dissociate from LINC in p53 mutant cells, that this contributes to increased G(2)-M gene expression in response to DNA damage in these cells, and, importantly, that B-MYB is required for recovery from the G(2) DNA damage checkpoint in p53-negative cells. Reanalysis of microarray expression data sets revealed that high levels of B-MYB correlate with a p53 mutant status and an advanced tumor stage in primary human breast cancer. Taken together, these data suggest that B-MYB/LINC plays an important role in the DNA damage response downstream of p53.