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Defective apoptosis and B-cell lymphomas in mice with p53 point mutation at Ser 23
Open accessAbstract
Phosphorylation of the p53 tumor suppressor at Ser20 (murine Ser23) has been proposed to be critical for disrupting p53 interaction with its negative regulator, MDM2, and allowing p53 stabilization. To determine the importance of Ser23 for the function of p53 in vivo, we generated a mouse in which the endogenous p53 locus was targeted to replace Ser23 with alanine. We show that, in mouse embryonic fibroblasts generated from Ser23 mutant mice, Ser23 mutation did not dramatically reduce IR-induced p53 protein stabilization or p53-dependent cell cycle arrest. However, in Ser23 mutant thymocytes and in the developing cerebellum, p53 stabilization following IR was decreased and resistance to apoptosis was observed. Homozygous Ser23 mutant animals had a reduced lifespan, but did not develop thymic lymphomas or sarcomas that are characteristic of p53-/- mice. Instead, Ser23 mutant animals died between 1 and 2 years with tumors that were most commonly of B-cell lineage. These data support an important role for Ser20/23 phosphorylation in p53 stabilization, apoptosis and tumor suppression.
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“Moreover, mouse studies show that blocking p53 phosphorylation at corresponding serine residues only caused modest defects in p53-mediated apoptosis and tumor suppression function [70–73].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [71]
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Metadata
- Authors
- MacPherson, D., Kim, J., Kim, T., Rhee, B. K., van Oostrom, C. T., DiTullio, R. A., Venere, M., Halazonetis, T. D., Bronson, R., de Vries, A., Fleming, M., & Jacks, T.
- Affiliations
- Center for Cancer Research (US)
- Sogang University (KR)
- Massachusetts Institute of Technology (US)
- The Wistar Institute (US)
- Tufts University (US)
- Boston Children's Hospital (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Jacks, Tyler
- ORCID
- Venue
- The EMBO Journal
- Published
- 2004-09-02
- Volume
- 23
- Issue
- 18
- Pages
- 3689-3699
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC517606
- OpenAlex
- W2158689768
- Cited by
- 124
- References
- 49
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 1 · 2016: 3 · 2015: 4 · 2014: 8 · 2013: 8 · 2012: 6
- FWCI
- 4.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rivm (National Institute for Public Health and the Environment) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- University of Pennsylvania
- 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, MDM2, p53 stabilization, apoptosis resistance, B-cell lymphoma, thymocytes, cerebellar development, tumor suppression, mouse model, ionizing radiation, lifespan
- MeSH terms
- Animals, Cell Cycle, Cells, Cultured, Cerebellum, DNA Damage, Female, Fibroblasts, Homozygote, Infrared Rays, Male, Mice, Inbred C57BL, Phosphorylation, Serine, Thymus Gland, Survival Rate, Tumor Suppressor Protein p53, Lymphoma, B-Cell, Apoptosis, Point Mutation, Mice, Knockout, Mice
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