Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability
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Mdm2 and Mdm4 are homologous RING domain-containing proteins that negatively regulate the tumor suppressor p53 under physiological and stress conditions. The RING domain of Mdm2 encodes an E3-ubiquitin ligase that promotes p53 degradation. In addition, Mdm2 and Mdm4 interact through their respective RING domains. The in vivo significance of Mdm2-Mdm4 heterodimerization in regulation of p53 function is unknown. In this study, we generated an Mdm4 conditional allele lacking the RING domain to investigate its role in Mdm2 and p53 regulation. Our results demonstrate that homozygous deletion of the Mdm4 RING domain results in prenatal lethality. Mechanistically, Mdm2-Mdm4 heterodimerization is critical for inhibiting lethal p53 activation during early embryogenesis. However, Mdm2-Mdm4 interaction is dispensable for regulating p53 activity as well as the stability of Mdm2 and p53 at later stages of development. We propose that Mdm4 is a key cofactor of Mdm2 that inhibits p53 activity primarily during early embryogenesis but is dispensable for regulating p53 and Mdm2 stability in the adult mouse.
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Mice expressing Mdmx lacking or with mutant RING domain die in utero, and p53 deletion rescues this phenotype.
“Mice engineered to express Mdmx lacking its RING domain or containing a mutant RING domain die in utero, and this phenotype was rescued with deletion of p53.50,51”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [50]
Mdm2 and Mdm4 interact through their RING domains, and this interaction is required for p53 inhibition.
“Mdm2 and Mdm4 also interact with each other through their respective RING domains, and this interaction is essential for inhibition of p53 (Figure 1).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Pant, et al., 2011
Hetero-oligomerization of MDM2 and MDMX via their RING domains is crucial for suppression of p53 activity during embryonic development.
“Hetero-oligomerization of MDM2 and MDMX via their RING domains is crucial for the suppression of p53 activity during embryonic development17,18.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [18]
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- Authors
- Pant, V., Xiong, S., Iwakuma, T., Quintás-Cardama, A., & Lozano, G.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Departments of aGenetics and
- Louisiana State University Health Sciences Center New Orleans (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-07-05
- Volume
- 108
- Issue
- 29
- Pages
- 11995-12000
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3141986
- OpenAlex
- W2066163561
- Cited by
- 134
- References
- 39
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 8 · 2019: 6 · 2018: 8 · 2017: 14 · 2016: 18 · 2015: 11 · 2014: 12 · 2013: 8 · 2012: 18
- FWCI
- 6.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA47296)
- National Cancer Institute (CA47296, CA 009299, T32CA009299, R01CA047296)
- 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, MDM4, p53, heterodimerization, RING domain, embryonic development, prenatal lethality, p53 stabilization, E3 ubiquitin ligase, tumor suppressor regulation, conditional alleles
- MeSH terms
- Animals, Cesium Radioisotopes, Genotype, Mice, Transgenic, Proto-Oncogene Proteins, Blotting, Southern, Tumor Suppressor Protein p53, DNA Primers, Gene Expression Regulation, Developmental, Reverse Transcriptase Polymerase Chain Reaction, Ubiquitin-Protein Ligases, Embryonic Development, Mice, Proto-Oncogene Proteins c-mdm2, Ubiquitination, Protein Multimerization
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