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Accelerated MDM2 auto‐degradation induced by DNA‐damage kinases is required for p53 activation
Open accessAbstract
p53 activation prevents the proliferation of genetically unstable cells. Conversely, p53 antagonism by its transcriptional target, the E3 ubiquitin ligase MDM2, is critical for the viability of unstressed, cycling cells. We demonstrate that MDM2 induces the degradation of p53 in both the nucleus and the cytoplasm. As p53 and MDM2 accumulate in the nuclei of stressed cells, we investigated mechanisms enabling p53 activation despite the high MDM2 levels generated during a DNA-damage response. We show that DNA damage destabilized MDM2 by a mechanism involving damage-activated kinases and MDM2 auto-ubiquitination. p53 was stable and transcriptionally active when MDM2 was unstable, but became unstable and inactive as the damage response waned and MDM2 stabilized. Importantly, blocking MDM2 destabilization in DNA-damaged cells prevented p53 target gene activation. Our data reveal that controlled MDM2 degradation is an important new step in p53 regulation.
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“However, in addition to degrading p53, Mdm2 also undergoes auto-degradation [12,13] and targets Mdmx for degradation [14–16], which is critical for optimal p53 activation after stress.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [12]
In the citing paper
“The disruption of Mdm2 oligomers might also contribute to their destabilization following DNA damage [12].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [12]
In the citing paper
“A recent study showed that DNA damage also accelerates MDM2 degradation through a mechanism that requires its own RING domain (Stommel and Wahl, 2004).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Stommel and Wahl, 2004
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Metadata
- Authors
- Stommel, J. M., & Wahl, G. M.
- Affiliations
- Salk Institute for Biological Studies (US)
- Corresponding author
- Wahl, Geoffrey M
- Venue
- The EMBO Journal
- Published
- 2004-03-18
- Volume
- 23
- Issue
- 7
- Pages
- 1547-1556
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC391059
- OpenAlex
- W2091818021
- Cited by
- 386
- References
- 54
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 9 · 2023: 13 · 2022: 10 · 2021: 16 · 2020: 13 · 2019: 19 · 2018: 10 · 2017: 9 · 2016: 8 · 2015: 15 · 2014: 21 · 2013: 13 · 2012: 24
- FWCI
- 11.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- National Institutes of Health
- National Cancer Institute (CA61449, R01CA061449)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- MDM2, p53 activation, DNA damage response, E3 ubiquitin ligase, p53 stabilization, cell cycle arrest
- MeSH terms
- Animals, Cell Line, Cell Nucleus, Cytoplasm, DNA Damage, Gene Expression Regulation, Humans, Nuclear Proteins, Proto-Oncogene Proteins, Transcription, Genetic, Transcriptional Activation, Tumor Suppressor Protein p53, Phosphatidylinositol 3-Kinases, Active Transport, Cell Nucleus, Proteasome Endopeptidase Complex, Mice, Proto-Oncogene Proteins c-mdm2, Proteasome Inhibitors
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