Increased Radioresistance and Accelerated B Cell Lymphomas in Mice with Mdmx Mutations that Prevent Modifications by DNA-Damage-Activated Kinases
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Mdmx is a critical negative regulator of the p53 pathway that is stoichiometrically limiting in some tissues. Posttranslational modification and degradation of Mdmx after DNA damage have been proposed to be essential for p53 activation. We tested this model in vivo, where critical stoichiometric relationships are preserved. We generated an Mdmx mutant mouse in which three conserved serines (S341, S367, S402) targeted by DNA-damage-activated kinases were replaced by alanines to investigate whether modifications of these residues are important for Mdmx degradation and p53 activation. The mutant mice were remarkably resistant to radiation, and very susceptible to Myc-induced lymphomagenesis. These data demonstrate that Mdmx downregulation is crucial for effective p53-mediated radiation responses and tumor suppression in vivo.
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In Mdmx3SA, Mdm2 remains bound to Mdmx, but degradation of Mdmx is significantly reduced.
“In Mdmx3SA, Mdm2 remains bound to Mdmx, but degradation of Mdmx is significantly reduced.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [30]
In Mdmx3SA mice, damage-induced Mdmx degradation is attenuated and p53 stabilization is significantly reduced compared with wild-type mice.
“When these serines are mutated to alanine in vivo (Mdmx3SA mice), damage-induced Mdmx degradation is attenuated. Furthermore, p53 stabilization is significantly reduced in Mdmx3SA compared with wild type mice [30].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [30]
Phosphorylation of Mdmx at C-terminal serine residues (Ser-341, 367, and 402 in mouse) by damage-activated kinases leads to its Mdm2-dependent degradation.
“Phosphorylation of Mdmx at C-terminal serine residues by damage-activated kinases (Ser-341, 367 and 402 in mouse) leads to its Mdm2-dependent degradation.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [30]
Because p53 activation is weakened in Mdmx3SA mice, these animals are more prone to tumors driven by c-Myc, through uncontrolled cell growth.
“However, the attenuated p53 activation in Mdmx3SA mice predisposes them to c-Myc-induced tumorigenesis due to deregulated cell proliferation.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [30]
After DNA damage, the fold increase in p53 target genes is similar in Mdmx3SA and wild-type mice.
“Interestingly, the fold induction of p53 gene targets after DNA damage was similar between Mdmx3SA and wild type mice, but due to reduced basal p53 activity, the absolute transcript levels of p53 target genes ( p21 and puma) were lower in Mdmx3SA mice.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [30]
Mdmx3SA mice show strong resistance to radiation and can survive a dose of ionizing radiation that is normally lethal.
“This renders the mice remarkably radio-resistant, as they survive an ordinarily lethal dose of ionizing radiation.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [30]
In Mdmx3SA mice, p53 activity before genotoxic stress is about half its normal level.
“In Mdmx3SA mice, (see above) there is an approximately 50% reduction of basal p53 activity prior to genotoxic stress [30].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [30]
After DNA damage, the absolute transcript levels of p21 and puma are lower in Mdmx3SA mice than in wild-type mice because their basal p53 activity is reduced.
“Interestingly, the fold induction of p53 gene targets after DNA damage was similar between Mdmx3SA and wild type mice, but due to reduced basal p53 activity, the absolute transcript levels of p53 target genes ( p21 and puma) were lower in Mdmx3SA mice.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [30]
Reprogramming is more efficient when Mdmx3SA fibroblasts are used.
“A higher efficiency can be achieved using Mdmx3SA fibroblasts, once again illustrating the crucial function of post-translational modification for fine-tuning p53 activity in biological systems.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [30]
Wahl and colleagues reported a dramatic acceleration of MYC-induced lymphomas in the presence of the MDMX3SA mutant.
“By contrast, Wahl and colleagues46 reported a dramatic acceleration of MYC-induced lymphomas in the presence of the MDMX3SA mutant.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [46]
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- Authors
- Wang, Y. V., Leblanc, M., Wade, M., Jochemsen, A. G., & Wahl, G. M.
- Affiliations
- Salk Institute for Biological Studies (US)
- Leiden University Medical Center (NL)
- Corresponding author
- Wahl, Geoffrey M.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 16
- Issue
- 1
- Pages
- 33-43
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC2758524
- OpenAlex
- W2043411325
- Cited by
- 79
- References
- 66
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 1 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 6 · 2017: 7 · 2016: 5 · 2015: 5 · 2014: 5 · 2013: 5 · 2012: 14
- FWCI
- 5.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1513 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA100845, CA61449)
- 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 › Cell death mechanisms and regulation
- Keywords
- MDMX, p53, radioresistance (biology), B-cell lymphoma, p53 activation, tumor suppression, radiation response
- MeSH terms
- Animals, Codon, DNA Damage, Female, Genotype, Homozygote, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Recombination, Genetic, Serine, Blotting, Southern, Gene Expression Regulation, Neoplastic, Polymerase Chain Reaction, Tumor Suppressor Protein p53, Lymphoma, B-Cell, Conserved Sequence, Genetic Predisposition to Disease, Mice, Proto-Oncogene Proteins c-mdm2
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