Cited by 2,100Cancer-related Molecular PathwaysDNA Repair MechanismsHeat shock proteins research

DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2

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Shieh, Sheau-Yann, Ikeda, Masako, Taya, Yoichi, Prives, Carol·1997·Cell

Abstract

DNA-damaging agents signal to p53 through as yet unidentified posttranscriptional mechanisms. Here we show that phosphorylation of human p53 at serine 15 occurs after DNA damage and that this leads to reduced interaction of p53 with its negative regulator, the oncoprotein MDM2, in vivo and in vitro. Furthermore, using purified DNA-dependent protein kinase (DNA-PK), we demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of MDM2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by DNA-PK (or other protein kinases with similar specificity) in response to DNA damage.

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Crossref · 10.1016/s0092-8674(00)80416-x

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Authors
Shieh, S.-Y., Ikeda, M., Taya, Y., & Prives, C.
Affiliations
  • Columbia University (US)
  • Medical & Biological Laboratories (Japan) (JP)
  • National Cancer Center Research Institute (JP)
Corresponding author
Prives, Carol
Venue
Cell
Publisher
Elsevier BV
Published
1997-10
Volume
91
Issue
3
Pages
325-334
ISSN
0092-8674 (ISSN-L)
OpenAlex
W1978518304
Cited by
2,100
References
73
Citations by year
2026: 15 · 2025: 25 · 2024: 40 · 2023: 53 · 2022: 72 · 2021: 53 · 2020: 49 · 2019: 45 · 2018: 47 · 2017: 72 · 2016: 50 · 2015: 55 · 2014: 74 · 2013: 86 · 2012: 84
FWCI
45.42
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (CA 58316)
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, MDM2, DNA damage response, DNA-dependent protein kinase, p53-MDM2 interaction, protein conformational change
MeSH terms
Binding Sites, DNA Damage, DNA-Binding Proteins, Humans, Nuclear Proteins, Phosphorylation, Proto-Oncogene Proteins, Serine, Tumor Cells, Cultured, Transcriptional Activation, Down-Regulation, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Proto-Oncogene Proteins c-mdm2, DNA-Activated Protein Kinase

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