RESUMEN
Centrosomal protein 55 (Cep55), which is localized to the centrosome in interphase cells and recruited to the midbody during cytokinesis, is a regulator required for the completion of cell abscission. Up-regulation of Cep55 and inactivation of p53 occur in the majority of human cancers, raising the possibility of a link between these two genes. In this study we evaluated the role of p53 in Cep55 regulation. We demonstrated that Cep55 expression levels are well correlated with cancer cell growth rate and that p53 is able to negatively regulate Cep55 protein and promoter activity. Down-regulation of expression of Cep55 was accompanied by repression of polo-like kinase 1 (Plk1) levels due to p53 induction. Overexpression of Plk1 and knockdown of p53 expression both enhanced the post-translational protein stability of Cep55. BI 2356, a selective Plk1 inhibitor, however, prevented Cep55 accumulation in p53 knockdown cells while persistently keeping Plk1 levels elevated. Our results, therefore, indicate the existence of a p53-Plk1-Cep55 axis in which p53 negatively regulates expression of Cep55, through Plk1 which, in turn, is a positive regulator of Cep55 protein stability.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Centrosoma/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/genética , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Femenino , Técnicas de Silenciamiento del Gen , Células HeLa , Humanos , Masculino , Neoplasias/genética , Neoplasias/patología , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Estabilidad Proteica , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Pteridinas/farmacología , Proteína p53 Supresora de Tumor/genética , Quinasa Tipo Polo 1RESUMEN
Centrosomal protein 55 (Cep55), located in the centrosome in interphase cells and recruited to the midbody during cytokinesis, is essential for completion of cell abscission. Northern blot previously showed that a high level of Cep55 is predominantly expressed in the testis. In the present study, we examined the spatial and temporal expression patterns of Cep55 during mouse testis maturation. We found that Cep55, together with pericentrin, another centrosomal protein, were localized to the intercellular bridges (IBs) interconnecting spermatogenic cells in a syncytium. The IBs were elaborated as a double ring structure formed by an inner ring decorated by Cep55 or pericentrin and an outer ring of mitotic kinesin-like protein 1 (MKLP1) in the male germ cell in early postnatal stages and adulthood. In addition, Cep55 and pericentrin were also localized to the acrosome region and flagellum neck and middle piece in elongated spermatids, respectively. These results suggest that Cep55 and pericentrin are required for the stable bridge between germ cells during spermatogenesis and spermiogenesis.