Tissue-specific differences of p53 inhibition by Mdm2 and Mdm4
Open accessAbstract
The function of the p53 tumor suppressor to inhibit proliferation or initiate apoptosis is often abrogated in tumor cells. Mdm2 and its homolog, Mdm4, are critical inhibitors of p53 that are often overexpressed in human tumors. In mice, loss of Mdm2 or Mdm4 leads to embryonic lethal phenotypes that are completely rescued by concomitant loss of p53. To examine the role of Mdm2 and Mdm4 in a temporal and tissue-specific manner and to determine the relationships of these inhibitors to each other, we generated conditional alleles. We deleted Mdm2 and Mdm4 in cardiomyocytes, since proliferation and apoptosis are important processes in heart development. Mice lacking Mdm2 in the heart were embryonic lethal and showed defects at the time recombination occurred. A critical number of cardiomyocytes were lost by embryonic day 13.5, resulting in heart failure. This phenotype was completely rescued by deletion of p53. Mice lacking Mdm4 in the heart were born at the correct ratio and appeared to be normal. Our studies provide the first direct evidence that Mdm2 can function in the absence of Mdm4 to regulate p53 activity in a tissue-specific manner. Moreover, Mdm4 cannot compensate for the loss of Mdm2 in heart development.
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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 [34]
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 [34]
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 [34]
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- [34]Vousden, K. H. 2000. p53: death star. Cell 103:691-694. [DOI] [PubMed] [Google Scholar] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. Supplementary Materials [Supplemental material] molcellb_26_1_192__index.html (920B, html) molcellb_26_1_192__Supplemental_Figure.TIF (2.4MB, TIF) molcellb_26_1_192__FIG_legend.doc (23.5KB, doc)
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Self-citation
- Authors
- Grier, J. D., Xiong, S., Elizondo-Fraire, A. C., Parant, J. M., & Lozano, G.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2006-01-01
- Volume
- 26
- Issue
- 1
- Pages
- 192-198
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1317622
- OpenAlex
- W2128306207
- Cited by
- 149
- References
- 34
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 5 · 2017: 15 · 2016: 13 · 2015: 9 · 2014: 10 · 2013: 9 · 2012: 12
- FWCI
- 2.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (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 › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- p53, MDM2, MDM4, p53 inhibitors, tissue-specific gene deletion, cardiomyocytes, heart development, embryonic lethality, heart failure, conditional alleles, apoptosis, cell proliferation, tumor suppressor
- MeSH terms
- Alleles, Animals, Embryo, Mammalian, Genes, Lethal, Heart, Heart Defects, Congenital, Proto-Oncogene Proteins, Tumor Suppressor Protein p53, Apoptosis, Gene Deletion, Myocytes, Cardiac, Ubiquitin-Protein Ligases, Embryonic Development, Cell Proliferation, Mice, Proto-Oncogene Proteins c-mdm2
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