A threshold mechanism mediates p53 cell fate decision between growth arrest and apoptosis.
Open accessAbstract
The p53 tumor suppressor responds to certain cellular stresses by inducing transcriptional programs that can lead to growth arrest or apoptosis. However, the molecular mechanisms responsible for choosing between these two cell fates are not well understood. Previous studies have suggested that p53 selectively activates proarrest target genes, due to the higher affinity of p53 for their promoters compared with proapoptotic genes. Here we show using microarray and chromatin immunoprecipitation that p53 binds to and transcriptionally activates both its proarrest and proapoptotic target genes proportionally to induced p53 expression levels. Further, we provide evidence that to trigger apoptosis, cells must overcome an apoptotic threshold, whose height is determined by expression levels of p53 and its targets, the duration of their expression and the cellular context. We demonstrate in multiple cells lines that below this threshold, expression levels of p53 and its targets were sufficient to induce arrest but not apoptosis. Above this threshold, p53 and its targets triggered extensive apoptosis. Moreover, lowering this threshold with inhibitors of antiapoptotic Bcl-2 family proteins sensitized cells to p53-induced apoptosis. These findings argue that agents that lower the apoptotic threshold should increase the efficacy of p53-mediated cancer therapy.
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The switch between cell cycle arrest and apoptosis in response to DNA damage is largely dictated by the cell reaching threshold p53 protein levels.
“The switch between cell cycle arrest and apoptosis in response to DNA damage, is largely dictated by the cell reaching threshold p53 protein levels (Kracikova et al., 2013; Paek et al., 2016).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Kracikova et al., 2013
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- Authors
- Kracikova, M., Akiri, G., George, A., Sachidanandam, R., & Aaronson, S. A.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Aaronson, S A
- Venue
- Cell Death & Differentiation
- Published
- 2013-01-11
- Volume
- 20
- Issue
- 4
- Pages
- 576-588
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC3595483
- OpenAlex
- W2070990294
- Cited by
- 261
- References
- 49
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 8 · 2023: 12 · 2022: 19 · 2021: 22 · 2020: 14 · 2019: 24 · 2018: 13 · 2017: 41 · 2016: 20 · 2015: 31 · 2014: 25 · 2013: 11
- FWCI
- 15.52
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (9724504)
- Breast Cancer Research Foundation
- New York State Department of Health
- National Institutes of Health
- National Cancer Institute (R24CA095823, P01CA080058)
- National Center for Research Resources (1 S10RR0 9145-01)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- p53, growth arrest, apoptosis, cell fate determination, transcriptional activation, p53 target genes, Bcl-2 family proteins, anti-apoptotic proteins, p53 inhibitors, cancer therapy
- MeSH terms
- Antibiotics, Antineoplastic, Cell Line, Doxorubicin, Doxycycline, Epithelial Cells, Humans, Imidazoles, Piperazines, Promoter Regions, Genetic, Protein Binding, Transcriptional Activation, Down-Regulation, Up-Regulation, Tumor Suppressor Protein p53, Apoptosis, Proto-Oncogene Proteins c-bcl-2, G1 Phase Cell Cycle Checkpoints
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