A modified p53 overcomes mdm2-mediated oncogenic transformation: A potential cancer therapeutic agent

The antiproliferative activities of wild-type (wt) p53 are inhibited by mdm 2 (murine double minute2) oncogene product, We tested growth suppression ac tivity of p53 14/19, an engineered p53 variant, which does not bind mdm2 an d is completely resistant to the inhibition by mdm2, p53 14/19, unlike wt p 53, suppressed the growth of cancer tells that contain amplified mdm2 oncog ene efficiently by direct DNA transfection or adenovirus-mediated gene tran sfer. in addition, p53 14/19 also inhibited the growth of several different cancer cell lines expressing low levels of mdm2 oncogene product as effici ently as wt p53, We further examined the antioncogenic potencies of p53 14/ 19 in the rat embryo fibroblast cotransformation assay, Addition of wt p53 failed to cause any significant decrease in ms plus mdm2 foci counts, In co ntrast, cotransfection of p53 14/19 with ras and mdm2 significantly reduced foci number. In similar experiments, cotransfection of wt p53 or 14/19 p53 resulted in significant inhibition of oncogenic transformation in rat embr yo fibroblast mediated by an activated ras plus c-myc, adenovirus EIA, or h uman papillomavirus E7 oncogenes, Therefore, these results suggest that p53 14/19 modified tumor suppressor gene may be a promising therapeutic agent for human cancers that express abnormally high levels of mdm2 oncogene prod uct.