Prostate-specific expression of p53(R172L) differentially regulates p21, Bax, and mdm2 to inhibit prostate cancer progression and prolong survival.
Loss of heterozygosity or mutation at the p53 tumor suppressor gene locus is frequently associated with advanced human prostate cancer. Hence, replacement p53 gene therapy may prove to be efficacious for this disease. While many mutations result in p53 molecules with oncogenic properties, other variants may possess wild-type properties with increased tumor suppressor activity. We have chosen to investigate the activity of a naturally occurring variant p53 molecule, p53(R172L), carrying an arginine-to-leucine mutation at codon 172. We demonstrate that p53(R172L) can differentially activate expression of genes involved in cell cycle control and apoptosis in vitro. Transgenic mice expressing a subphysiological level of a p53(R172L) minigene (PB-p53(R172L)) in the prostate epithelium were generated and bred to the transgenic adenocarcinoma mouse prostate (TRAMP) model of prostate cancer. While PB-p53(R172L) transgenic mice developed normally with no detectable prostate gland phenotype, we observed a significant increase in the apoptotic index in the prostate glands of TRAMP x PB-p53(R172L) F1 mice. We noted an increase in the expression of Bax in the bigenic mice concomitant with the reduced incidence and rate of tumor growth and increased survival. While low-level expression of the p53(R172L) variant had no obvious influence on normal prostate tissue, it was able to significantly inhibit prostate cancer progression in the context of a genetically predisposed model system. This suggests that additional tumor-related events specifically influence the ability of the variant p53(R172L) molecule to inhibit tumor growth. These studies support gene therapy strategies employing specific p53 variants.
Hernandez, I; Maddison, LA; Wei, Y; DeMayo, F; Petras, T; Li, B; Gingrich, JR; Rosen, JM; Greenberg, NM
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