Lung specific expression of a human mutant p53 affects cell proliferation in transgenic mice.

The human mutant p53(273H) has been shown in vitro to have both dominant-negative and gain-of-function properties, as well as to retain partial DNA-binding and transcriptional activation functions. We have developed a line of transgenic mice in which the human mutant p53(273H) is expressed in a lung specific manner (p53 (+/+/TG)). Crossing of the transgenic mice with p53 knockout mice led to generate mice with various genetic backgrounds. To evaluate the influence of p53 mutants in cell proliferation in mice lung tissue, we analyzed cell proliferation rate by Bromodeoxyuridine (BrdU) labeling and by expression of proliferating cell nuclear antigen (PCNA). BrdU analysis showed a 3.7-fold increase in the number of BrdU positive cells in the (p53 (-/+/TG)) mice compared to the (p53 (-/+)) mice, whereas no difference was observed in proliferation rate in the p53 (-/-/TG) lungs as compared to p53 (-/-) lungs. After the mice were treated with gamma-irradiation, BrdU positive cells were absent from both the p53 (-/+/TG) and p53 (-/+) mice, whereas a decrease in the rate of cell proliferation occurred in p53 (-/-/TG) lungs as compared to p53 (-/-) lungs. Real time PCR results indicated that the p53(273H) mutant did not retain the function to activate expression of p21 (WAF1/CIP1) in the transgenic mice. The above results indicate that overexpression of the human mutant p53(273H) in vivo results in an increase in basal proliferation rate which requires the presence of wild type p53. Mutant p53(273H) may affect cell proliferation by interrupting murine endogenous p53 function.