Functional role of Mdm2 phosphorylation by ATR in attenuation of p53 nuclear export
Abstract
Mdm2 oncoprotein plays a major role in inhibiting the p53 tumor suppressor protein. Here, we investigate phosphorylation of Mdm2 at serine 407 (S407). S407 is phosphorylated in cells after treatment with camptothecin (CPT) or hydroxyurea, inhibitors of DNA replication. S407 phosphorylation after CPT treatment is induced upon cell cycle arrest during S phase and prevented if entry into S phase of cell cycle is blocked. We found that a major kinase responsible for S407 phosphorylation is ATR, a DNA damage checkpoint protein that induces cell cycle arrest and promotes DNA repair in response to impaired DNA replication; induction of S407 phosphorylation is enhanced after expression of wild-type ATR, while it is inhibited by a dominant-negative form of ATR. Further, S407 is specifically phosphorylated by ATR in vitro. Substitution of S407 with aspartate (S407D), but not with alanine (S407A), promotes nuclear localization of p53. Taken together, our data indicate that S407 phosphorylation of Mdm2 by ATR reduces Mdm2-dependent export of p53 from nuclei to cytoplasm.
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After DNA damage, MDM2 is phosphorylated at serine 395 by ATM, serine 407 by ATR, and tyrosine 394 by c-Abl, which together with other modifications neutralizes MDM2/MDMX inhibition of p53 and sustains p53 signaling.
“Following DNA damage, MDM2 is phosphorylated on serine 395 by ATM,24 on serine 407 by ATR,36 and on tyrosine 394 by c-abl,37,47 which along with other posttranslational modifications of MDMX and p53 neutralizes the inhibitory effect of MDM2/MDMX on p53 and results in sustained p53-mediated signaling.10”
From Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist (2017) · cites this paper as [36]
MDM2 is phosphorylated by ATM, ATR, and C-Abl on sites near its C terminus.
“MDM2 is phosphorylated by ATM, ATR, and C-Abl on sites near the C terminus (Maya et al, 2001;Sionov et al, 2001;Shinozaki et al, 2003).”
From ATM activates p53 by regulating MDM2 oligomerization and E3 processivity (2009) · cites this paper as Shinozaki et al, 2003
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- Authors
- Shinozaki, T., Nota, A., Taya, Y., & Okamoto, K.
- Affiliations
- National Cancer Center Research Institute (JP)
- Japan Science and Technology Agency (JP)
- Corresponding author
- Okamoto, Koji
- ORCID
- Okamoto, Koji
- Venue
- Oncogene
- Published
- 2003-12-04
- Volume
- 22
- Issue
- 55
- Pages
- 8870-8880
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2052146604
- Cited by
- 93
- References
- 64
- Citations by year
- 2026: 2 · 2024: 4 · 2023: 7 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 5 · 2016: 8 · 2015: 4 · 2014: 5 · 2013: 7 · 2012: 5
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- 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
- MDM2, p53, ATR kinase, DNA damage checkpoint, S phase arrest, camptothecin, hydroxyurea, DNA replication inhibition
- MeSH terms
- Amino Acid Sequence, Animals, Aspartic Acid, Cell Cycle, Cell Nucleus, DNA Damage, Humans, Molecular Sequence Data, Nuclear Proteins, Phosphorylation, Proto-Oncogene Proteins, Serine, Down-Regulation, Tumor Suppressor Protein p53, S Phase, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Proto-Oncogene Proteins c-mdm2, Ataxia Telangiectasia Mutated Proteins
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