REDUCTION OF P53 GENE DOSAGE DOES NOT INCREASE INITIATION OR PROMOTION BUT ENHANCES MALIGNANT PROGRESSION OF CHEMICALLY-INDUCED SKIN TUMORS

The availability of p53 knockout mice generated by gene targeting has enabled us to investigate the functional role of the p53 tumor suppres sor gene in initiation, promotion, and progression of carcinogenesis i n vivo, using mouse skin as a model system. The number, size, and grow th rate of benign papillomas were not increased in the p53 heterozygou s mice in comparison with wild type. The p53 null mice showed a reduce d yield of papillomas, but these underwent much more rapid malignant p rogression, with some poorly differentiated carcinomas developing afte r only 10 weeks of promotion. Progression rate was also greater in het erozygous than in wild-type mice and was associated with loss of the r emaining wild-type allele. Most tumors from all groups had activating mutations in the H-ras gene. Absence of p53, therefore, does not augme nt the frequency of initiation or the rate of promotion but greatly en hances malignant progression.