High Expression of <i>PPM1D</i> Induces Tumors Phenotypically Similar to <i>TP53</i> Loss-of-Function Mutations in Mice
<i>PPM1D</i> is a negative regulator of p53 and genomic aberrations resulting in increased activity of <i>PPM1D</i> have been observed in cancers of different origins, indicating that <i>PPM1D</i> has oncogenic properties. We established a transgenic mouse model o...
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| Autores principales: | , , , , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/4e7642724943438284674a8797264157 |
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| Sumario: | <i>PPM1D</i> is a negative regulator of p53 and genomic aberrations resulting in increased activity of <i>PPM1D</i> have been observed in cancers of different origins, indicating that <i>PPM1D</i> has oncogenic properties. We established a transgenic mouse model overexpressing <i>PPM1D</i> and showed that these mice developed a wide variety of cancers. <i>PPM1D</i>-expressing mice developed tumors phenotypically and genetically similar to tumors in mice with dysfunctional p53. T-cell lymphoblastic lymphoma was the most frequent cancer observed in these mice (55%) followed by adenocarcinomas (24%), leukemia (12%) and other solid tumors including neuroblastoma. Characterization of T-cell lymphomas in mice overexpressing <i>PPM1D</i> demonstrates <i>Pten</i>-deletion and p53-accumulation similar to mice with p53 loss-of-function. Also, <i>Notch1</i> mutations which are recurrently observed in T-cell acute lymphoblastic lymphoma (T-ALL) were frequently detected in <i>PPM1D-</i>transgenic mice. Hence, <i>PPM1D</i> acts as an oncogenic driver in connection with cellular stress, suggesting that the <i>PPM1D</i> gene status and expression levels should be investigated in <i>TP53</i> wild-type tumors. |
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