The C-terminal lysines fine-tune p53 stress responses in a mouse model, but are not required for stability control or transactivation
Open accessAbstract
P53 is an unstable transcription factor that is mutated in a majority of human cancers. With a significant role in initiating cell elimination programs, a network has evolved to fine-tune P53 transcriptional output and prevent errant activation. Modifications of the C terminus have long been viewed as critical binary determinants of P53 stability or activation. However, these conclusions are based on in vitro transfection or biochemical analyses where the stoichiometries between P53 and its regulators are perturbed. Therefore, we tested the importance of the C-terminal regulatory region for P53 control in mice where the seven C-terminal lysines were changed to arginine (Trp-53(7KR)). Surprisingly, the homozygous mutant mice are viable and phenotypically normal. We have functionally characterized the mutant protein in both MEFs and thymocytes, revealing the unexpected result that Trp-53(7KR) exhibits a normal half-life and functions like WT P53 in cell cycle arrest and apoptosis, and in an E1A-ras xenograft tumor suppression assay. However, a significant difference is that P53(7KR) is activated more easily by DNA damage in thymus than WT P53. Importantly, although MEFs encoding WT P53 spontaneously emerge from crisis to become immortal in a 3T3 growth protocol, we do not observe any such escape with the P53(7KR) cells. We propose that the C-terminal modifications believed to be critical for proper P53 regulation are not essential, but contribute to a fine-tuning mechanism of homeostatic control in vivo.
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Mice in which these lysines are mutated to arginine are viable and have a normal lifespan, although p53 regulation is subtly altered in some cell types.
“Furthermore, mice in which these lysines are mutated to arginine are viable and have a normal lifespan, although p53 regulation is subtly altered in some cell types [128,129].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [128]
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- Authors
- Krummel, K. A., Lee, C. J., Toledo, F., & Wahl, G. M.
- Affiliations
- Salk Institute for Biological Studies (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-07-08
- Volume
- 102
- Issue
- 29
- Pages
- 10188-10193
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1177381
- OpenAlex
- W2141576639
- Cited by
- 187
- References
- 24
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 6 · 2019: 6 · 2018: 4 · 2017: 3 · 2016: 10 · 2015: 3 · 2014: 15 · 2013: 10 · 2012: 9
- FWCI
- 8.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- National Cancer Institute (CA61449, R01CA100845, CA 100845, R01CA061449, T32CA009370)
- 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 › DNA Repair Mechanisms
- Keywords
- p53, C-terminal lysine, p53 stabilization, p53 transactivation, DNA damage response, cell cycle arrest, apoptosis, tumor suppression, thymocytes, mouse mutants, homeostatic regulation, cell immortalization
- MeSH terms
- Amino Acid Sequence, Animals, Cell Cycle, DNA Damage, Flow Cytometry, Fluorescent Antibody Technique, Gene Expression Regulation, Genotype, Lysine, Mice, Mutant Strains, Molecular Sequence Data, Mutation, Regulatory Sequences, Nucleic Acid, Thymus Gland, Transcription Factors, Blotting, Western, Tumor Suppressor Protein p53, Apoptosis, DNA Primers, Mice
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