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Genetic interactions between the Wilms' tumor 1 gene and the p53 gene
Aswin L Menke1, Alan R Clarke, Andrea Leitch
1Central Hematologie Laboratory, University Medical Centre St. Radboud, 6500 HB, Nijmegen, the Netherlands.
Abstract:
In recent years, a number of proteins have been identified that can modify the activities of the Wilms' Tumor 1 (WT1) proteins. One of these modifiers is the p53 protein. To investigate a genetic interaction between the p53 gene and the wt1 gene, we have crossed their respective knockout mice. The absence of p53 appears to have no gross effect on the phenotype of wt1-null mice. Both wt1-null and double-null embryos develop pericardial bleeding and die in utero. In adult p53-null mice, wt1-heterozygosity (wt1het) predisposes to an earlier onset of lymphomagenesis and the development of kidney abnormalities resembling oncocytoma in humans. wt1-heterozygosity alone predisposes to the development of glomerular sclerosis.
Insights
The p53 gene does not affect Wilms' Tumor 1 (WT1) null mice, but WT1 heterozygosity in p53 null mice leads to earlier lymphoma and kidney tumors.
Area of Science:
- Molecular biology
- Genetics
- Developmental biology
Background:
- The Wilms' Tumor 1 (WT1) protein plays a crucial role in embryonic development and tumor suppression.
- The p53 protein is a well-known tumor suppressor involved in cell cycle regulation and apoptosis.
- Interactions between WT1 and p53 may influence cellular processes and disease development.
Purpose of the Study:
- To investigate the genetic interaction between the p53 and WT1 genes.
- To determine the phenotypic consequences of combined p53 and WT1 gene deficiencies.
Main Methods:
- Generation of p53-null and WT1-null knockout mice.
- Cross-breeding of p53-knockout and WT1-knockout mice to create double-null (p53-/-; WT1-/-) and various heterozygous/null combinations.
- Phenotypic analysis of embryos and adult mice, including assessment of survival, developmental abnormalities, lymphomagenesis, and kidney pathologies.
Main Results:
- Absence of p53 did not alter the embryonic lethality or pericardial bleeding phenotype of WT1-null mice.
- WT1 heterozygosity in adult p53-null mice accelerated lymphomagenesis and induced kidney abnormalities resembling human oncocytoma.
- WT1 heterozygosity alone predisposed to glomerular sclerosis.
Conclusions:
- p53 is not essential for the embryonic functions of WT1.
- A genetic interaction exists between p53 and WT1, where p53 deficiency exacerbates WT1-related pathologies in adult mice, including lymphomagenesis and kidney disease.
- These findings highlight a complex interplay between p53 and WT1 in tumorigenesis and kidney development.