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Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration.

ABSTRACT: 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.

SUBMITTER: Sanchez-Rivera FJ

PROVIDER: S-EPMC8201929 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration.

Sánchez-Rivera Francisco J FJ Ryan Jeremy J Soto-Feliciano Yadira M YM Clare Beytagh Mary M Xuan Lucius L Feldser David M DM Hemann Michael T MT Zamudio Jesse J Dimitrova Nadya N Letai Anthony A Jacks Tyler T

Proceedings of the National Academy of Sciences of the United States of America 20210601 23

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 ...[more]

PMID: 34074758

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Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration.

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Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration.

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