The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.
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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Citations
Cites
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
Bakkenist, C. J., & Kastan, M. B. (2003) · Nature · doi:10.1038/nature01368 · Cited by 3,466
Momand, J., Zambetti, G. P., Olson, D. C., George, D., & Levine, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90644-r · Cited by 3,113
Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53
Oliner, J. D., Pietenpol, J. A., Thiagalingam, S., Gyuris, J., Kinzler, K. W., & Vogelstein, B. (1993) · Nature · doi:10.1038/362857a0 · Cited by 1,474
Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53
de Oca Luna, R. M., Wagner, D. S., & Lozano, G. (1995) · Nature · doi:10.1038/378203a0 · Cited by 1,420 · cited 2×
“The importance of MDM2 in p53 regulation is evidenced by the embryonic lethality of MDM2 knockout mice, presumably due to unrestrained p53 activity (Jones et al, 1995; Montes de Oca Luna et al, 1995).”
BackgroundRescue of embryonic lethality in Mdm2-deficient mice by absence of p53
Jones, S. N., Roe, A. E., Donehower, L. A., & Bradley, A. (1995) · Nature · doi:10.1038/378206a0 · Cited by 1,280 · cited 4×
“The importance of MDM2 in p53 regulation is evidenced by the embryonic lethality of MDM2 knockout mice, presumably due to unrestrained p53 activity (Jones et al, 1995; Montes de Oca Luna et al, 1995).”
BackgroundInfluentialPost‐translational modifications and activation of p53 by genotoxic stresses
Appella, E., & Anderson, C. W. (2001) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2001.02225.x · Cited by 1,095
Mdm2 Is a RING Finger-dependent Ubiquitin Protein Ligase for Itself and p53
Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H., & Weissman, A. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8945 · Cited by 1,044
The INK4a/ARF network in tumour suppression
Sherr, C. J. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35096061 · Cited by 1,003
The MDM2 gene amplification database
Momand, J. (1998) · Nucleic Acids Research · doi:10.1093/nar/26.15.3453 · Cited by 982
Cited by
Sorted by citations
Kruse, J.-P., & Gu, W. (2009) · Cell · doi:10.1016/j.cell.2009.04.050 · Cited by 1,610
Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
Toledo, F., & Wahl, G. M. (2006) · Nature reviews. Cancer · doi:10.1038/nrc2012 · Cited by 1,286
Self-citationp53 ubiquitination: Mdm2 and beyond
Brooks, C. L., & Gu, W. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.020 · Cited by 924
“…set of experiments using the radiomimetic drug neocarzinostatin (NCS) shows that after treatment, the protein half-life of Mdm2 quickly drops from w30 min to 5 min and destabilization of Mdm2 was apparently necessary for p53 accumulation and transcriptional activation (Stommel and Wahl, 2004).”
MethodUSP10 Regulates p53 Localization and Stability by Deubiquitinating p53
Yuan, J., Luo, K., Zhang, L., Cheville, J. C., & Lou, Z. (2010) · Cell · doi:10.1016/j.cell.2009.12.032 · Cited by 637
“Furthermore, ATM-dependent phosphorylation of Mdm2 and Mdmx could destabilize these proteins and compromise their activity (Khosravi et al., 1999; Maya et al., 2001; Meulmeester et al., 2005; Pereg et al., 2005; Stommel and Wahl, 2004).”
The P53 pathway: what questions remain to be explored?
Levine, A. J., Hu, W., & Feng, Z. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401910 · Cited by 661
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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