RETENTION OF P53(VAL135) WILD-TYPE FUNCTION IN TRANSGENIC MICE

We targeted a mutant p53 gene ((val135)), previously shown to cause tu mors in transgenic mice, to the kidney and eye using a gamma-glutamylt ranspeptidase promoter. Although transgene RNA was expressed in both t issues, and mutant protein could be detected at high levels in the kid ney and was appropriately localized to the nuclei of proximal tubules, no gross or microscopic lesions developed, even when mice were held a s long as 75 weeks. When these mice were crossed with transgenic mice carrying Hras T24 (containing a codon 12 mutation) driven by the same promoter, the p53(val135) transgene partially suppressed the mutant ra s phenotype (proximal tubular hyperplasia and adenomas and carcinomas of the ciliary body and retinal pigment epithelium). The kidneys of do uble transgenic mice younger than 25 weeks showed less tubular hyperpl asia and cystic change than littermates carrying gamma-glutamyltranspe ptidase(I)ras T24 alone. By 33 weeks, there was no difference in the s everity of the kidney lesions. The eye lesions were less aggressive, a nd no malignant lesions were identified. Our findings are consistent w ith the work of others, indicating that p53(val135) is not tumorigenic under all conditions; in fact, in some circumstances, it retains some of the suppressing activity of wild-type p53.