Damage-mediated Phosphorylation of Human p53 Threonine 18 through a Cascade Mediated by a Casein 1-like Kinase
Open accessAbstract
The p53 tumor suppressor protein is stabilized in response to ionizing radiation and accumulates in the nucleus. Stabilization is thought to involve disruption of the interaction between the p53 protein and Mdm2, which targets p53 for degradation. Here we show that the direct association between a p53 N-terminal peptide and Mdm2 is disrupted by phosphorylation of the peptide on Thr(18) but not by phosphorylation at other N-terminal sites, including Ser(15) and Ser(37). Thr(18) was phosphorylated in vitro by casein kinase (CK1); this process required the prior phosphorylation of Ser(15). Thr(18) was phosphorylated in vivo in response to DNA damage, and such phosphorylation required Ser(15). Our results suggest that stabilization of p53 after ionizing radiation may result, in part, from an inhibition of Mdm2 binding through a phosphorylation-phosphorylation cascade involving DNA damage-activated phosphorylation of p53 Ser(15) followed by phosphorylation of Thr(18).
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CK1-δ can also phosphorylate Thr18 of p53, which may reduce the affinity of Mdm2 for p53.
“CK1-δ can also phosphorylate Thr18 of p53, which may reduce the affinity of Mdm2 for p53 [66].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [66]
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- Authors
- Sakaguchi, K., Saito, S., Higashimoto, Y., Roy, S., Anderson, C. W., & Appella, E.
- Affiliations
- National Institutes of Health (US)
- Bose Institute (IN)
- Brookhaven National Laboratory (US)
- Corresponding author
- Appella, Ettore
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-03
- Volume
- 275
- Issue
- 13
- Pages
- 9278-9283
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2010670456
- Cited by
- 293
- References
- 43
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 7 · 2023: 7 · 2022: 8 · 2021: 3 · 2020: 2 · 2019: 8 · 2018: 10 · 2017: 12 · 2016: 8 · 2015: 11 · 2014: 13 · 2013: 8 · 2012: 11
- FWCI
- 9.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01gm052825-05)
- National Institute of General Medical Sciences (GM52825)
- 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 › Heat shock proteins research
- Keywords
- p53, casein kinase 1, MDM2, p53 stabilization, DNA damage response, ionizing radiation, phosphorylation cascade, protein-protein interaction disruption
- MeSH terms
- Amino Acid Sequence, Humans, Molecular Sequence Data, Nuclear Proteins, Phosphorylation, Protein Binding, Protein Kinases, Proto-Oncogene Proteins, Threonine, Tumor Suppressor Protein p53, Casein Kinases, Proto-Oncogene Proteins c-mdm2
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