OPPOSITE EFFECTS OF P53 ON ENZYMES OF NUCLEOTIDE-METABOLISM IN RAT1 CELLS AND THEIR SUBSTRAINS TRANSFORMED BY ONCOGENES N-RAS OR V-MOS

Effects of human exogenous p53 and its mutant forms (Ala-141, His-175, His-194, Trp-248, and His-273) on the activities of two enzymes of th e supplementary pathway of purine synthesis, adenosine deaminase (AD) and hypoxanthine phosphoribosyl transferase (HPRT), were studied in im mortalized Rat1 fibroblasts and their derivatives transformed by oncog enes N-ras or v-mos. All forms of p53 produced a 2-7.5-fold increase i n AD activity in Rat1 cells; p53 of mutant strains displayed stronger effects than the wild-type p53 (p53wt). In contrast, there was an 8-10 -fold decrease in HPRT activity upon the transduction of p53wt cDNA, w hereas mutant forms lost at least part of their ability to inhibit the enzyme. Transformation of Rat1 cells with ras and mos was also accomp anied by activation of AD (4-5- and 1.5-2-fold, respectively) and by s uppression of HPRT activity (20- and 2-fold, respectively). However, t he simultaneous expression of exogenous p53 and ras or p53 and mos res ulted not in additive, but rather in the completely opposite effect of abrupt decrease in AD activity and complete (p53wt, His-273) or parti al (His-175 and Trp-248) recovery of HPRT activity. The possible biolo gical significance and mechanisms of regulation of AD and HPRT by p53 are considered, and the role of modification of activities of enzymes mediating nucleotide metabolism in the cooperative effects of dominant oncogenes and mutant p53 species in tumor transformation are discusse d.