ArticleProceedings of the National Academy of Sciences of the United States of America2021
Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Top 100 most-cited articles on apoptosis of non-small cell lung cancer over the past two decades: a bibliometrics analysis.Frontiers in immunology · 2024Pooled it
- Cellular senescence and regulated cell death in cancer: mechanisms, cross-regulatory networks and therapeutic implications.Journal of hematology & oncology · 2026Review
- p53 Drives Lung Cancer Regression through a TSC2/TFEB-dependent Senescence Program.Cancer discovery · 2026Article
- Omics-aided design genome editing strategy for challenging human immortalized cell models.PloS one · 2026Article
- Transcriptional remodeling shapes therapeutic vulnerability to necroptosis in acute lymphoblastic leukemia.Blood · 2025Article
- Death-ision: the link between cellular resilience and cancer resistance to treatments.Molecular cancer · 2025Review
- Oncogenic and microenvironmental signals drive cell type specific apoptosis resistance in juvenile myelomonocytic leukemia.Cell death & disease · 2025Article
- The three barriers senescent tumor cells must overcome to relapse.Cancer heterogeneity and plasticity · 2025Article
- Selective metabolic regulations by p53 mutant variants in pancreatic cancer.Journal of experimental & clinical cancer research : CR · 2024Article
- Determinants of p53 DNA binding, gene regulation, and cell fate decisions.Cell death and differentiation · 2024Review
- Venetoclax Combined with Intensive Chemotherapy: A New Hope for Refractory and/or Relapsed Acute Myeloid Leukemia?Journal of clinical medicine · 2024Review
- Opinion: more mouse models and more translation needed for ALS.Molecular neurodegeneration · 2023Review
- Identification of Key Biomarkers Associated with Immunogenic Cell Death and Their Regulatory Mechanisms in Severe Acute Pancreatitis Based on WGCNA and Machine Learning.International journal of molecular sciences · 2023Article
- BCL-xL inhibition potentiates cancer therapies by redirecting the outcome of p53 activation from senescence to apoptosis.Cell reports · 2022Article
- A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-XL Antiapoptotic Protein in Kidney Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Article
- From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs.Open biology · 2022Review
- Comparing the Secretomes of Chemorefractory and Chemoresistant Ovarian Cancer Cell Populations.Cancers · 2022Review
- Partial p53 reactivation is sufficient to induce cancer regression.Journal of experimental & clinical cancer research : CR · 2022Article
- It's Getting Complicated-A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy.Frontiers in cell and developmental biology · 2022Review
- The possible alleviating effect of garlic supplement on the neural retina in a rat model of hypercholesterolemia: a histological and immunohistochemical study.European journal of histochemistry : EJH · 2021Article
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Authors and funding
11 authors.
Funding
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.
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