Mutated forms of p53 are often expressed in a variety of human
tumors. In addition to loss of function of the p53
tumor suppressor, mutant p53s contribute to malignant process by acquisition of novel functions that enhance transformed properties of cells and resistance to anticancer
therapy in vitro, and increase tumorigenecity, invasiveness and metastatic ability in vivo. Searching for genes that change expression in response to p53 gain of function mutants may give a clue to the mechanisms underlying their oncogenic effects. Recently by subtraction hybridization cloning we found that the
dUTPase gene is transcriptionally upregulated in p53-null mouse fibroblasts expressing the exogenous human
tumor-derived His175 p53 mutant. Here we show that conditional expression of His175 and Trp248 hot-spot p53 mutants in p53-negative mouse 10(1) fibroblasts and human SK-OV3 and H1299
tumor cells results in increase in
dUTPase gene transcription, an important marker predicting the efficacy of
cancer therapy with fluoropyrimidine drugs. Using
tetracycline-regulated retroviral vectors for conditional expression of p53 mutants, we found that transcription of the
dUTPase gene is increased within 24 h after
tetracycline withdrawal, and the cells acquire higher resistance to
5-FU. Additional inactivation of the N-terminal transcription activation domain of mutant p53 (substitutions in
amino-acid residues 22 and 23) results in abrogation of both induction of
dUTPase transcripts and
5-FU resistance.