Ser18 and 23 phosphorylation is required for p53‐dependent apoptosis and tumor suppression
Open accessAbstract
Mouse p53 is phosphorylated at Ser18 and Ser23 after DNA damage. To determine whether these two phosphorylation events have synergistic functions in activating p53 responses, we simultaneously introduced Ser18/23 to Ala mutations into the endogenous p53 locus in mice. While partial defects in apoptosis are observed in p53S18A and p53S23A thymocytes exposed to IR, p53-dependent apoptosis is essentially abolished in p53S18/23A thymocytes, indicating that these two events have critical and synergistic roles in activating p53-dependent apoptosis. In addition, p53S18/23A, but not p53S18A, could completely rescue embryonic lethality of Xrcc4(-/-) mice that is caused by massive p53-dependent neuronal apoptosis. However, certain p53-dependent functions, including G1/S checkpoint and cellular senescence, are partially retained in p53(S18/23A) cells. While p53(S18A) mice are not cancer prone, p53S18/23A mice developed a spectrum of malignancies distinct from p53S23A and p53(-/-) mice. Interestingly, Xrcc4(-/-)p53S18/23A mice fail to develop tumors like the pro-B cell lymphomas uniformly developed in Xrcc4(-/-) p53(-/-) animals, but exhibit developmental defects typical of accelerated ageing. Therefore, Ser18 and Ser23 phosphorylation is important for p53-dependent suppression of tumorigenesis in certain physiological context.
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Blocking mouse p53 phosphorylation on S18 and S23 only partially reduced p53 stabilization after DNA damage and caused partial defects in apoptosis and tumour suppression.
“Studies in mouse models showed that blocking mouse p53 phosphorylation on S18 and S23 (equivalents of human p53 S15 and S20) only partially reduced p53 stabilization after DNA damage, and causes partial defects in apoptosis and tumour suppression functions (Chao et al, 2006).”
From ATM activates p53 by regulating MDM2 oligomerization and E3 processivity (2009) · cites this paper as Chao et al, 2006
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References 34 · Cited by 158
- Authors
- Chao, C., Herr, D., Chun, J., & Xu, Y.
- Affiliations
- University of California San Diego (US)
- Scripps Research Institute (US)
- Corresponding author
- Xu, Yang
- Venue
- The EMBO Journal
- Published
- 2006-06-01
- Volume
- 25
- Issue
- 11
- Pages
- 2615-2622
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1478190
- OpenAlex
- W2122904921
- Cited by
- 158
- References
- 34
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 6 · 2019: 6 · 2018: 5 · 2017: 2 · 2016: 5 · 2015: 8 · 2014: 14 · 2013: 9 · 2012: 10
- FWCI
- 8.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (MH51699)
- National Institute of Mental Health (MH-51699, R01MH051699, MH01723, K02MH001723)
- National Cancer Institute (R01CA094254, CA94254)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- p53, p53-dependent apoptosis, tumor suppression, XRCC4, DNA damage response, thymocytes, embryonic lethality, neuronal apoptosis, G1/S checkpoint, cellular senescence, accelerated aging, TP53 mutation
- MeSH terms
- Animals, Cells, Cultured, DNA Damage, DNA-Binding Proteins, Embryo, Mammalian, Male, Mutation, Neoplasms, Phosphorylation, Serine, Thymus Gland, Survival Rate, Tumor Suppressor Protein p53, Apoptosis, Mice, Knockout, Cell Proliferation, Mice
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