A novel mouse model of rhabdomyosarcoma underscores the dichotomy of MDM2-ALT1 function in vivo
| Autor: | Dawn S. Chandler, A K Goodwin, Bridget Sanford, P Boyaka, Thomas W. Bebee, K. M. D. La Perle, E Matsa, H Steiner, Daniel F. Comiskey, M Montes, Aixa S. Tapia-Santos, Jessica L. Grieves, Aishwarya G. Jacob |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Cancer Research Carcinogenesis Transgene Population Mice Transgenic lymphoma Biology medicine.disease_cause Article Mice splicing 03 medical and health sciences MDM2 Rhabdomyosarcoma Genetics medicine Animals Humans p53 independent education neoplasms Molecular Biology Cell Proliferation Regulation of gene expression B-Lymphocytes education.field_of_study Oncogene Proto-Oncogene Proteins c-mdm2 Neoplasms Experimental Oncogenes medicine.disease Phenotype Gene Expression Regulation Neoplastic Alternative Splicing 030104 developmental biology Immunology MCF-7 Cells NIH 3T3 Cells biology.protein Cancer research Mdm2 Female Tumor Suppressor Protein p53 Spleen Signal Transduction |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2017.282 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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