Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53
Abstract
The p53 protein can inhibit cell cycling or induce apoptosis, and is thus a critical regulator of tumorigenesis. This protein is negatively regulated by a physical interaction with MDM2, an E3 ubiquitin ligase. This interaction is critical for cell viability; loss of Mdm2 causes cell death in vitro and in vivo in a p53-dependent manner. The recently discovered MDM2-related protein MDM4 (also known as MDMX) has some of the same properties as MDM2. MDM4 binds and inhibits p53 transcriptional activity in vitro. Unlike MDM2, however, MDM4 does not cause nuclear export or degradation of p53 (refs. 9,10). To study MDM4 function in vivo, we deleted Mdm4 in mice. Mdm4-null mice died at 7.5-8.5 dpc, owing to loss of cell proliferation and not induction of apoptosis. To assess the importance of p53 in the death of Mdm4-/- embryos, we crossed in the Trp53-null allele. The loss of Trp53 completely rescued the Mdm4-/- embryonic lethality. Thus, MDM2 and MDM4 are nonoverlapping critical regulators of p53 in vivo. These data define a new pathway of p53 regulation and raise the possibility that increased MDM4 levels and the resulting inactivation of p53 contribute to the development of human tumors.
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Mice lacking Mdm4 have embryonic lethal phenotypes that are completely rescued by p53 deletion.
“Mice lacking Mdm4 exhibit embryonic lethal phenotypes that are also completely rescued by p53 deletion (Finch, et al., 2002; Migliorini, et al., 2002; Parant, et al., 2001).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Parant, et al., 2001
MDM2 and MDMX are the two major negative regulators of p53.
“Mouse genetic models strongly suggest that MDM2 and MDMX are the two major p53 antagonists in vivo107,108”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [108]
Mouse genetic models strongly suggest that MDM2 and MDMX are the two major p53 antagonists in vivo and that they exert non-overlapping inhibitory activities towards p53.
“Mouse genetic models strongly suggest that MDM2 and MDMX are the two major p53 antagonists in vivo107,108 and that they exert non-overlapping inhibitory activities towards p53 (Refs 24,109).”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [108]
MDMX-null mice die in utero in a p53-dependent manner, and this lethality is rescued by crossing into a p53-null background.
“Several studies showed that MDMX-null mice also die in utero in a p53-dependent fashion, which can be rescued by crossing into the p53-null background (Finch et al, 2002;Migliorini et al, 2002;Parant et al, 2002).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Parant et al, 2002
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- Authors
- Parant, J., Chavez-Reyes, A., Little, N. A., Yan, W., Reinke, V., Jochemsen, A. G., & Lozano, G.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Leiden University Medical Center (NL)
- Corresponding author
- Lozano, Guillermina
- Venue
- Nature Genetics
- Published
- 2001-08-20
- Volume
- 29
- Issue
- 1
- Pages
- 92-95
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1598779357
- Cited by
- 517
- References
- 19
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 15 · 2023: 15 · 2022: 13 · 2021: 20 · 2020: 20 · 2019: 14 · 2018: 15 · 2017: 22 · 2016: 34 · 2015: 14 · 2014: 35 · 2013: 18 · 2012: 23
- FWCI
- 7.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- 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 › Ubiquitin and proteasome pathways
- Keywords
- MDM4, MDM2, p53 regulation, Trp53, embryonic lethality, cell proliferation, E3 ubiquitin ligase, tumor suppressor, p53 inactivation
- MeSH terms
- Animals, Base Sequence, Embryo, Mammalian, Genes, Lethal, Nuclear Proteins, Precipitin Tests, Proto-Oncogene Proteins, Blotting, Western, Polymerase Chain Reaction, Genes, p53, Tumor Suppressor Protein p53, DNA Primers, Mice, Knockout, In Situ Nick-End Labeling, Mice, Proto-Oncogene Proteins c-mdm2
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