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A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
Published on: July 6, 2017
Distinct downstream targets manifest p53-dependent pathologies in mice
1Department of Genetics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
Mdm2, the principal negative regulator of p53, is critical for survival, a fact clearly demonstrated by the p53-dependent death of germline or conditional mice following deletion of Mdm2. On the other hand, Mdm2 hypomorphic (Mdm2Puro/Δ7-12) or heterozygous (Mdm2+/-) mice that express either 30 or 50% of normal Mdm2 levels, respectively, are viable but present distinct phenotypes because of increased p53 activity. Mdm2 levels are also transcriptionally regulated by p53. We evaluated the significance of this reciprocal relationship in a new hypomorphic mouse model inheriting an aberrant Mdm2 allele with insertion of the neomycin cassette and deletion of 184-bp sequence in intron 3. These mice also carry mutations in the Mdm2 P2-promoter and thus express suboptimal levels of Mdm2 entirely encoded from the P1-promoter. Resulting mice exhibit abnormalities in skin pigmentation and reproductive tissue architecture, and are subfertile. Notably, all these phenotypes are rescued on a p53-null background. Furthermore, these phenotypes depend on distinct p53 downstream activities as genetic ablation of the pro-apoptotic gene Puma reverts the reproductive abnormalities but not skin hyperpigmentation, whereas deletion of cell cycle arrest gene p21 does not rescue either phenotype. Moreover, p53-mediated upregulation of Kitl influences skin pigmentation. Altogether, these data emphasize tissue-specific p53 activities that regulate cell fate.
Insights
Mice with reduced Mdm2 levels show skin and reproductive issues due to increased p53 activity. These phenotypes are p53-dependent and linked to specific downstream gene functions.
Area of Science:
- Molecular Biology
- Genetics
- Developmental Biology
Background:
- Mdm2 is a key negative regulator of the tumor suppressor p53.
- Mdm2 and p53 have a reciprocal regulatory relationship.
- Mice lacking Mdm2 die due to p53-dependent apoptosis, while hypomorphic mice are viable with distinct phenotypes.
Purpose of the Study:
- To investigate the significance of the Mdm2-p53 reciprocal relationship using a novel hypomorphic mouse model.
- To analyze the tissue-specific roles of p53 downstream effectors in Mdm2-deficient phenotypes.
Main Methods:
- Generation of a new Mdm2 hypomorphic mouse model with a modified Mdm2 allele and P2-promoter mutations.
- Phenotypic analysis of resulting mice, including skin pigmentation and reproductive abnormalities.
- Genetic ablation of p53 downstream genes (Puma, p21) and assessment of phenotype rescue.
- Analysis of p53-mediated upregulation of Kitl in relation to skin pigmentation.
Main Results:
- The novel Mdm2 hypomorphic mice exhibit skin hyperpigmentation and reproductive tissue abnormalities, leading to subfertility.
- All observed phenotypes are rescued in a p53-null background, confirming p53 dependency.
- Genetic ablation of Puma rescues reproductive abnormalities but not skin hyperpigmentation.
- Deletion of p21 does not rescue either phenotype, indicating distinct p53 downstream activities.
Conclusions:
- The study highlights tissue-specific functions of p53 in regulating cell fate.
- Mdm2-p53 interactions play crucial roles in maintaining normal skin pigmentation and reproductive tissue architecture.
- Distinct p53 downstream pathways, involving Puma and Kitl, mediate specific phenotypic outcomes.
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