Widespread Overexpression of Epitope-Tagged Mdm4 Does Not Accelerate Tumor Formation In Vivo
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Mdm2 and Mdm4 are critical negative regulators of p53. A large body of evidence indicates that elevated expression of either Mdm2 or Mdm4 may favor tumor formation by inhibiting p53 tumor suppression function. To explore this possibility in vivo, we generated conditional Mdm2 and Mdm4 transgenic mice. We show that although both transgenes are designed to be expressed ubiquitously and at comparable levels, only the Mdm4 transgenic protein is produced at high levels in vivo. In contrast, exogenous Mdm2 is constitutively degraded in a proteasome-dependent manner, indicating that cells are equipped with efficient mechanisms that prevent Mdm2 accumulation in vivo. Mice that are homozygous for the Mdm4 transgene die during embryogenesis owing to severe vascular maturation defects. Importantly, this lethality is not rescued on a p53-null background, indicating that high levels of Mdm4 impact on a pathway(s) other than p53 that controls vascular and embryonic development. Mice expressing a single copy of the Mdm4 transgene are viable and, surprisingly, are not prone to spontaneous, radiation-induced or Eμ-myc-induced tumor formation. The findings have clear implications for cancer etiology as well as for cancer therapy.
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Homozygous Myc-tagged Mdmx transgene expression is embryonic lethal and cannot be rescued by p53 deletion, suggesting a p53-independent function of Mdmx in development.
“Although Mdmx inhibits p53 function, homozygous Myc-tagged Mdmx transgene expression was embryonic lethal, and this could not be rescued with deletion of p53,29 suggesting a p53-independent function of Mdmx in development.”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [29]
Normal cells tolerate small increases in Mdm2 levels.
“Small increases in Mdm2 levels in normal cells are tolerated”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as De Clercq, et al., 2010
Higher Mdm2 levels are incompatible with life in vivo and in vitro, except in some cases when p53 is also inactivated.
“higher levels are incompatible with life in vivo and in vitro, except in some cases when p53 is also inactivated”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as De Clercq, et al., 2010
MDMX levels seem to be increased in B cells that overexpress MYC before tumorigenesis.
“Intriguingly, MDMX levels seem to be increased in B cells that overexpress MYC before tumorigenesis28.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [28]
A subsequent study found no evidence for enhanced tumorigenicity following high-level MDMX transgene expression in many tissues.
“However, a subsequent study found no evidence for enhanced tumorigenicity following high-level MDMX transgene expression in many tissues28.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [28]
Marine and colleagues found that MYC-induced lymphomas were not accelerated in mice with ubiquitous overexpression of wild-type Mdmx.
“Marine and colleagues28 found that MYC-induced lymphomas were not accelerated in mice with ubiquitous overexpression of wild-type Mdmx.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [28]
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References 57 · Cited by 35
- Authors
- De Clercq, S., Gembarska, A., Denecker, G., Maetens, M., Naessens, M., Haigh, K., Haigh, J. J., & Marine, J.-C.
- Affiliations
- Laboratory for Molecular Cancer Biology
- VIB-KU Leuven Center for Cancer Biology (BE)
- Ghent University (BE)
- Corresponding author
- Marine, Jean-Christophe
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2010-11-01
- Volume
- 30
- Issue
- 22
- Pages
- 5394-5405
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2976380
- OpenAlex
- W2107116965
- Cited by
- 35
- References
- 57
- Citations by year
- 2026: 1 · 2024: 1 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 4 · 2017: 1 · 2016: 4 · 2015: 1 · 2014: 4 · 2013: 3 · 2012: 6
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Funders
- Fondation contre le Cancer
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- MDM4, MDM2, p53, transgenic mice, tumor suppression, proteasomal degradation, embryonic lethality, radiation-induced cancer, cancer therapy
- MeSH terms
- Animals, Epitopes, Embryo, Mammalian, Fibroblasts, Lymphoma, Mice, Inbred C57BL, Mice, Transgenic, Neoplasms, Proto-Oncogene Proteins, Tissue Distribution, Tumor Suppressor Protein p53, Transgenes, Ubiquitin-Protein Ligases, Mice, Proto-Oncogene Proteins c-mdm2, Kaplan-Meier Estimate
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