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Retention of p53val135 wild-type function in transgenic mice
D L Schaffner1, P Chévez-Barrios, S L Huang
1Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Abstract:
We targeted a mutant p53 gene (val135), previously shown to cause tumors in transgenic mice, to the kidney and eye using a gamma-glutamyltranspeptidase promoter. Although transgene RNA was expressed in both tissues, and mutant protein could be detected at high levels in the kidney and was appropriately localized to the nuclei of proximal tubules, no gross or microscopic lesions developed, even when mice were held as long as 75 weeks. When these mice were crossed with transgenic mice carrying HrasT24 (containing a codon 12 mutation) driven by the same promoter, the p53val135 transgene partially suppressed the mutant ras phenotype (proximal tubular hyperplasia and adenomas and carcinomas of the ciliary body and retinal pigment epithelium). The kidneys of double transgenic mice younger than 25 weeks showed less tubular hyperplasia and cystic change than littermates carrying gamma-glutamyltranspeptidase(I)rasT24 alone. By 33 weeks, there was no difference in the severity of the kidney lesions. The eye lesions were less aggressive, and no malignant lesions were identified. Our findings are consistent with the work of others, indicating that p53val135 is not tumorigenic under all conditions; in fact, in some circumstances, it retains some of the suppressing activity of wild-type p53.
Insights
A mutant p53 gene (p53val135) did not cause tumors in mouse kidneys or eyes. However, it partially suppressed tumors when combined with a mutant ras gene, indicating retained tumor-suppressing activity.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Mutant p53 proteins are often implicated in cancer development.
- The specific p53val135 mutation was previously shown to induce tumors in transgenic mice.
- The role of p53 mutations in tumorigenesis can be context-dependent.
Purpose of the Study:
- To investigate the tumorigenic potential of the p53val135 mutant gene in mouse kidney and eye.
- To determine if p53val135 can suppress the phenotype induced by a co-expressed mutant ras gene (HrasT24).
Main Methods:
- Targeting of the p53val135 mutant gene to kidney and eye using a gamma-glutamyltranspeptidase promoter in transgenic mice.
- Crossing p53val135 transgenic mice with HrasT24 transgenic mice.
- Histopathological analysis of kidney and eye tissues at various time points.
Main Results:
- Transgene expression and mutant p53 protein localization occurred in target tissues, but no tumors formed in p53val135 mice.
- Co-expression with HrasT24 partially suppressed proximal tubular hyperplasia and eye lesions.
- Tumorigenesis was less aggressive in double transgenic mice, with no malignant eye lesions identified.
Conclusions:
- The p53val135 mutant is not inherently tumorigenic under all conditions.
- Under specific genetic contexts, p53val135 can retain tumor-suppressing activities similar to wild-type p53.
- These findings highlight the complex and context-dependent role of p53 mutations in cancer.