Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development
Open accessAbstract
Loss of Mdm2 or Mdm4 leads to embryo lethal phenotypes that are p53-dependent. To determine whether Mdm2 and Mdm4 inhibit p53 function redundantly in a more restricted cell type, conditional alleles were crossed to a neuronal specific Cre transgene to delete Mdm2 and Mdm4 in the CNS. Mice lacking Mdm2 in the CNS developed hydranencephaly at embryonic day 12.5 due to apoptosis, whereas Mdm4 deletion showed a proencephaly phenotype at embryonic day 17.5 because of cell cycle arrest and apoptosis. The deletion of both genes, strikingly, contributed to an even earlier and more severe CNS phenotype. Additionally, Mdm2 and Mdm4 had a gene dosage effect, because loss of three of the four Mdm alleles also showed a more accelerated CNS phenotype than deletion of either gene alone. All phenotypes were rescued by deletion of p53. Thus, these in vivo data demonstrate the importance of Mdm4 independent of Mdm2 in inhibition of p53.
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In smooth muscle cells, loss of Mdmx has no phenotype.
“However, in other cases, such as smooth muscle cells, loss of Mdmx has no phenotype.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [40]
Mdm2 and Mdmx contribute to p53 regulation to different extents in different tissues in vivo.
“Mdm2 and Mdmx seem to contribute to p53 regulation to different extents in different tissues in vivo (Table 1; [32–40]).”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [40]
In some tissues and cell types, such as the central nervous system and proliferative intestinal cells, there is a requirement for both Mdm2 and Mdmx.
“Clearly in some tissues and cell types [such as the central nervous system (CNS) and proliferative intestinal cells], there is a requirement for both Mdm2 and Mdmx.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [40]
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 [109]
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Self-citation
- Authors
- Xiong, S., Van Pelt, C. S., Elizondo-Fraire, A. C., Liu, G., & Lozano, G.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Veterinary Medicine and Surgery, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030
- Departments of *Molecular Genetics and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-02-21
- Volume
- 103
- Issue
- 9
- Pages
- 3226-3231
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1413885
- OpenAlex
- W1967632402
- Cited by
- 155
- References
- 43
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 5 · 2022: 3 · 2020: 6 · 2019: 2 · 2018: 4 · 2017: 8 · 2016: 9 · 2015: 5 · 2014: 7 · 2013: 7 · 2012: 15
- FWCI
- 8.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA-16672, CA47296, R01CA047296, P30CA016672)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- MDM2, MDM4, p53, p53 inhibition, central nervous system development, hydranencephaly, apoptosis, cell cycle arrest, gene dosage effect, conditional gene deletion, embryonic lethality
- MeSH terms
- Animals, Animals, Newborn, Central Nervous System, Female, Genes, Lethal, Mice, Transgenic, Phenotype, Proto-Oncogene Proteins, Tumor Suppressor Protein p53, Apoptosis, Gene Expression Regulation, Developmental, Ubiquitin-Protein Ligases, Mice, Proto-Oncogene Proteins c-mdm2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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