Disrupting TP53 in mouse models of human cancers
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Published on: August 25, 2021
John M Parant1, Guillermina Lozano
1Department of Molecular Genetics, Section of Cancer Genetics, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4095, USA.
Abstract:
Manipulation of the mouse genome allows emulation of the genetic defects that give rise to human cancers and evaluation of the cooperating nature of different mutations in the transformation of distinct cell types. Here we review the generation of mice with specific missense mutations in p53 (TP53) and disruption of the p53 pathway by deletion of p53 inhibitors. Missense mutations in the DNA binding domain result in viable mice with gain-of-function and dominant negative phenotypes. Loss of either of the p53 inhibitors mdm2 or mdm4 gives rise to a p53-dependent embryonic lethal phenotype. A cell can thus tolerate the absence of p53 function but not excess p53 function, a characteristic that is being exploited in the treatment of human cancers.
Insights
Mouse models with altered p53 (TP53) genes mimic human cancers. Specific mutations cause gain-of-function or dominant-negative effects, while inhibiting p53 leads to embryonic lethality, offering insights for cancer therapy.
Area of Science:
- Genetics
- Cancer Biology
- Genomic Medicine
Background:
- Mouse models are crucial for understanding human cancer genetics.
- The p53 (TP53) tumor suppressor pathway is frequently altered in human cancers.
- p53 inhibitors like MDM2 and MDM4 play critical roles in regulating p53 activity.
Purpose of the Study:
- To review the generation and analysis of mouse models with specific p53 mutations and pathway disruptions.
- To investigate the functional consequences of missense mutations in p53's DNA binding domain.
- To examine the impact of deleting p53 inhibitors (mdm2, mdm4) on p53 function and embryonic development.
Main Methods:
- Generation of genetically engineered mouse models with targeted p53 mutations.
- Deletion of p53 inhibitor genes (mdm2, mdm4) in mice.
- Phenotypic analysis of resulting mouse models, including viability and cellular transformation.
Main Results:
- Missense mutations in the p53 DNA binding domain yield viable mice with gain-of-function and dominant-negative phenotypes.
- Complete loss of p53 inhibitors (mdm2 or mdm4) results in a p53-dependent embryonic lethal phenotype.
- Cells tolerate loss of p53 function but not excessive p53 activity.
Conclusions:
- Mouse models with manipulated p53 and its inhibitors provide valuable insights into cancer development.
- The differential tolerance of cells to p53 loss versus excess p53 function has therapeutic implications for human cancers.
- Understanding these genetic mechanisms in mice aids in developing targeted cancer treatments.
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