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Oncogene ; 37(1): 95-106, 2018 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-28892044

RESUMEN

Alternative splicing of the oncogene murine double minute 2 (MDM2) is induced in response to genotoxic stress. MDM2-ALT1, the major splice variant generated, is known to activate the p53 pathway and impede full-length MDM2's negative regulation of p53. Despite this perceptible tumor-suppressive role, MDM2-ALT1 is also associated with several cancers. Furthermore, expression of MDM2-ALT1 has been observed in aggressive metastatic disease in pediatric rhabdomyosarcoma (RMS), irrespective of histological subtype. Therefore, we generated a transgenic MDM2-ALT1 mouse model that would allow us to investigate the effects of this splice variant on the progression of tumorigenesis. Here we show that when MDM2-ALT1 is ubiquitously expressed in p53 null mice it leads to increased incidence of spindle cell sarcomas, including RMS. Our data provide evidence that constitutive MDM2-ALT1 expression is itself an oncogenic lesion that aggravates the tumorigenesis induced by p53 loss. On the contrary, when MDM2-ALT1 is expressed solely in B-cells in the presence of homozygous wild-type p53 it leads to significantly increased lymphomagenesis (56%) when compared with control mice (27%). However, this phenotype is observable only at later stages in life (⩾18 months). Moreover, flow cytometric analyses for B-cell markers revealed an MDM2-ALT1-associated decrease in the B-cell population of the spleens of these animals. Our data suggest that the B-cell loss is p53 dependent and is a response mounted to persistent MDM2-ALT1 expression in a wild-type p53 background. Overall, our findings highlight the importance of an MDM2 splice variant as a critical modifier of both p53-dependent and -independent tumorigenesis, underscoring the complexity of MDM2 posttranscriptional regulation in cancer. Furthermore, MDM2-ALT1-expressing p53 null mice represent a novel mouse model of fusion-negative RMS.


Asunto(s)
Carcinogénesis/genética , Regulación Neoplásica de la Expresión Génica , Ratones , Proteínas Proto-Oncogénicas c-mdm2/genética , Rabdomiosarcoma/genética , Empalme Alternativo , Animales , Linfocitos B/metabolismo , Proliferación Celular/genética , Femenino , Humanos , Células MCF-7 , Masculino , Ratones Transgénicos , Células 3T3 NIH , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Oncogenes , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Rabdomiosarcoma/patología , Transducción de Señal/genética , Bazo/citología , Bazo/patología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
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