Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration
| العنوان: | Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration |
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| المؤلفون: | Tyler Jacks, Jeremy Ryan, Nadya Dimitrova, Jesse R. Zamudio, Mary Clare Beytagh, Yadira M. Soto-Feliciano, Anthony Letai, David M. Feldser, Lucius Xuan, Francisco J. Sánchez-Rivera, Michael T. Hemann |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | p53, Cell cycle checkpoint, Lung Neoplasms, Cell, Priming (immunology), Adenocarcinoma of Lung, Cell fate determination, Biology, chemistry.chemical_compound, Mice, Cell Line, Tumor, medicine, Animals, Humans, cell fate, Multidisciplinary, Navitoclax, apoptosis, Sarcoma, Cell Cycle Checkpoints, Cell Biology, Cell cycle, Biological Sciences, Mitochondria, medicine.anatomical_structure, chemistry, Apoptosis, Cell culture, cell cycle arrest, Cancer research, Tumor Suppressor Protein p53 |
| الوصف: | Significance It has long been observed that activation of p53 can yield two main cell fates: either apoptotic cell death or cell cycle arrest. However, what determines this cell fate remains to be fully elucidated. Here we show that the state of mitochondrial priming prior to activation of p53 can determine cell fate. Highly primed cells commit to apoptosis, while less-primed cells commit to cell cycle arrest. We show that modulation of priming in either direction can alter cell fate; increasing priming in poorly primed cells yields apoptosis, while decreasing priming in highly primed cells yields arrest. Drugs that increase priming enforce an apoptotic fate, suggesting a p53-independent strategy for augmenting efficacy of cancer chemotherapy drugs that kill via p53. Reactivation of p53 in established tumors typically results in one of two cell fates, cell cycle arrest or apoptosis, but it remains unclear how this cell fate is determined. We hypothesized that high mitochondrial priming prior to p53 reactivation would lead to apoptosis, while low priming would lead to survival and cell cycle arrest. Using a panel of Kras-driven, p53 restorable cell lines derived from genetically engineered mouse models of lung adenocarcinoma and sarcoma (both of which undergo cell cycle arrest upon p53 restoration), as well as lymphoma (which instead undergo apoptosis), we show that the level of mitochondrial apoptotic priming is a critical determinant of p53 reactivation outcome. Cells with high initial priming (e.g., lymphomas) lacked sufficient reserve antiapoptotic capacity and underwent apoptosis after p53 restoration. Forced BCL-2 or BCL-XL expression reduced priming and resulted in survival and cell cycle arrest. Cells with low initial priming (e.g., lung adenocarcinoma and sarcoma) survived and proceeded to arrest in the cell cycle. When primed by inhibition of their antiapoptotic proteins using genetic (BCL-2 or BCL-XL deletion or BAD overexpression) or pharmacologic (navitoclax) means, apoptosis resulted upon p53 restoration in vitro and in vivo. These data demonstrate that mitochondrial apoptotic priming is a key determining factor of cell fate upon p53 activation. Moreover, it is possible to enforce apoptotic cell fate following p53 activation in less primed cells using p53-independent drugs that increase apoptotic priming, including BH3 mimetic drugs. |
| تدمد: | 1091-6490 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f784b16e4c9e4bdec96388c74b59405cTest https://pubmed.ncbi.nlm.nih.gov/34074758Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f784b16e4c9e4bdec96388c74b59405c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 |
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