The intestinal epithelium compensates for p53-mediated cell death and guarantees organismal survival
Open accessAbstract
Mdm2 is the major inhibitor of the p53 tumor suppressor. Loss of Mdm2 in mice or in specific tissues of the mouse always yields p53-dependent lethal phenotypes. However, the role of Mdm2 in tissues with high turnover capacity is unknown. We have engineered mice lacking Mdm2 in the intestinal epithelium using the Cre/LoxP system. Loss of Mdm2 (Mdm2(intDelta)) results in viable animals, but neonates display multiple intestinal abnormalities such as hyperplasia, enterocyte vacuolization, and inflammation. These defects correlate with a drastic increase in p53-dependent apoptosis in highly proliferative and differentiated cells. Unexpectedly, the observed phenotypes disappear with age. The tissue selects against Mdm2-null cells and increases its proliferative capacity. Additionally, the intestinal stem and progenitor cell populations are enriched leading to an increase in crypt fission events. Enhanced proliferation is achieved by activation of the canonical Wnt and EGFR-mediated Ras/MAPK pathways. While Mdm2 is a critical inhibitor of p53 in the intestinal epithelium, the tissue employs a series of processes that compensate for cell death.
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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 [38]
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 [38]
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 [38]
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- Authors
- Valentin-Vega, Y. A., Okano, H., & Lozano, G.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Keio University (JP)
- Corresponding author
- Lozano, G
- Venue
- Cell Death & Differentiation
- Published
- 2008-07-18
- Volume
- 15
- Issue
- 11
- Pages
- 1772-1781
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC2742618
- OpenAlex
- W2061031835
- Cited by
- 58
- References
- 42
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 6 · 2016: 2 · 2015: 1 · 2014: 4 · 2013: 4 · 2012: 8
- FWCI
- 3.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (CA-16 672, CA47296)
- 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 › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- MDM2, p53, intestinal epithelium, p53-dependent apoptosis, intestinal hyperplasia, intestinal inflammation, intestinal stem cells, crypt fission, Wnt signaling, EGFR, RAS/MAPK pathway, cell proliferation, tissue homeostasis
- MeSH terms
- Animals, Cell Differentiation, DNA, Epithelial Cells, Intestinal Mucosa, Survival Analysis, Tumor Suppressor Protein p53, Cell Death, ras Proteins, MAP Kinase Signaling System, Cell Proliferation, Wnt Proteins, Mice, Proto-Oncogene Proteins c-mdm2, ErbB Receptors
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