دورية أكاديمية
PML restrains p53 activity and cellular senescence in clear cell renal cell carcinoma
| العنوان: | PML restrains p53 activity and cellular senescence in clear cell renal cell carcinoma |
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| المؤلفون: | Matilde Simoni, Chiara Menegazzi, Cristina Fracassi, Claudia C Biffi, Francesca Genova, Nazario Pio Tenace, Roberta Lucianò, Andrea Raimondi, Carlo Tacchetti, James Brugarolas, Davide Mazza, Rosa Bernardi |
| المصدر: | EMBO Molecular Medicine, Vol 16, Iss 6, Pp 1324-1351 (2024) |
| بيانات النشر: | Springer Nature, 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Medicine (General) LCC:Genetics |
| مصطلحات موضوعية: | PML, ccRCC, p53, Senescence, Arsenic Trioxide, Medicine (General), R5-920, Genetics, QH426-470 |
| الوصف: | Abstract Clear-cell renal cell carcinoma (ccRCC), the major subtype of RCC, is frequently diagnosed at late/metastatic stage with 13% 5-year disease-free survival. Functional inactivation of the wild-type p53 protein is implicated in ccRCC therapy resistance, but the detailed mechanisms of p53 malfunction are still poorly characterized. Thus, a better understanding of the mechanisms of disease progression and therapy resistance is required. Here, we report a novel ccRCC dependence on the promyelocytic leukemia (PML) protein. We show that PML is overexpressed in ccRCC and that PML depletion inhibits cell proliferation and relieves pathologic features of anaplastic disease in vivo. Mechanistically, PML loss unleashed p53-dependent cellular senescence thus depicting a novel regulatory axis to limit p53 activity and senescence in ccRCC. Treatment with the FDA-approved PML inhibitor arsenic trioxide induced PML degradation and p53 accumulation and inhibited ccRCC expansion in vitro and in vivo. Therefore, by defining non-oncogene addiction to the PML gene, our work uncovers a novel ccRCC vulnerability and lays the foundation for repurposing an available pharmacological intervention to restore p53 function and chemosensitivity. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1757-4684 |
| العلاقة: | https://doaj.org/toc/1757-4684Test |
| DOI: | 10.1038/s44321-024-00077-3 |
| الوصول الحر: | https://doaj.org/article/943d98c6d7a140ae919de5ddf5a741fdTest |
| رقم الانضمام: | edsdoj.943d98c6d7a140ae919de5ddf5a741fd |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 17574684 |
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| DOI: | 10.1038/s44321-024-00077-3 |