Oncogenic c-Myc-induced lymphomagenesis is inhibited non-redundantly by the p19Arf-Mdm2-p53 and RP-Mdm2-p53 pathways
| Autor: | J Dong, Y Zhang, N R Carlson, Xuan Meng |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Genetically modified mouse
Ribosomal Proteins Cancer Research Lymphoma Transgene Mice Transgenic Biology medicine.disease_cause Article Cell Line Proto-Oncogene Proteins c-myc chemistry.chemical_compound Mice Genetics medicine RNA polymerase I Animals Neoplasm Metastasis Molecular Biology Cyclin-Dependent Kinase Inhibitor p16 Mutation Oncogene DDX5 Proto-Oncogene Proteins c-mdm2 Neoplasms Experimental RNA Helicase A Cell Transformation Neoplastic chemistry Cancer research Tumor Suppressor Protein p53 Carcinogenesis Gene Deletion Signal Transduction |
| Zdroj: | Oncogene. 34(46) |
| ISSN: | 1476-5594 |
| Popis: | The multifaceted oncogene c-Myc plays important roles in the development and progression of human cancer. Recent in vitro and in vivo studies have shown that the p19Arf-Mdm2-p53 and the ribosomal protein (RP)-Mdm2-p53 pathways are both essential in preventing oncogenic c-Myc-induced tumorigenesis. Disruption of each pathway individually by p19Arf deletion or by Mdm2(C305F) mutation, which disrupts RP-Mdm2 binding, accelerates Eμ-myc transgene-induced pre-B/B-cell lymphoma in mice at seemingly similar paces with median survival around 10 and 11 weeks, respectively, compared to 20 weeks for Eμ-myc transgenic mice. Because p19Arf can inhibit ribosomal biogenesis through its interaction with nucleophosmin (NPM/B23), RNA helicase DDX5 and RNA polymerase I transcription termination factor (TTF-I), it has been speculated that the p19Arf-Mdm2-p53 and the RP-Mdm2-p53 pathways might be a single p19Arf-RP-Mdm2-p53 pathway, in which p19Arf activates p53 by inhibiting RP biosynthesis; thus, p19Arf deletion or Mdm2(C305F) mutation would result in similar consequences. Here, we generated mice with concurrent p19Arf deletion and Mdm2(C305F) mutation and investigated the compound mice for tumorigenesis in the absence and the presence of oncogenic c-Myc overexpression. In the absence of Eμ-myc transgene, the Mdm2(C305F) mutation did not elicit spontaneous tumors in mice, nor did it accelerate spontaneous tumors in mice with p19Arf deletion. In the presence of Eμ-myc transgene, however, Mdm2(C305F) mutation significantly accelerated p19Arf deletion-induced lymphomagenesis and promoted rapid metastasis. We found that when p19Arf-Mdm2-p53 and RP-Mdm2-p53 pathways are independently disrupted, oncogenic c-Myc-induced p53 stabilization and activation is only partially attenuated. When both pathways are concurrently disrupted, however, c-Myc-induced p53 stabilization and activation are essentially obliterated. Thus, the p19Arf-Mdm2-p53 and the RP-Mdm2-p53 are non-redundant pathways possessing similar capabilities to activate p53 upon c-Myc overexpression. |
| Databáze: | OpenAIRE |
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