DOSAGE-DEPENDENT DOMINANCE OVER WILD-TYPE P53 OF A MUTANT P53 ISOLATED FROM NASOPHARYNGEAL CARCINOMA

Mutational inactivation of p53, a tumor suppressor gene, is the most c ommon genetic alteration found in human cancer. Most mutated p53s eith er lose tumor suppressor function or gain oncogenic activity. We recen tly reported the detection of a heterozygous point mutation of p53 at codon 280 in nasopharyngeal carcinoma (NPC) (1), a high-incidence mali gnancy in southern China and southeast Asia. Given its heterozygous st ate, in which both wild-type and mutated p53 gene were expressed, p53- thr280 should function dominantly in the presence of the wild-type for m if it is to play a role in nasopharynx carcinogenesis. We tested thi s dominance hypothesis in the cells of two model systems: 1) human Sao s-2 cells lacking endogenous p53, and 2) mouse JB6 tumor promotion-res istant cells (P-) expressing endogenous wild-type p53. The results sho wed dosage-dependent dominance of p53-thr280 in controlling WT p53-dri ven transcriptional activity; in governing cell growth; and in progres sing P- phenotype to tumor promotion-sensitive (P+) phenotype. This do minant negative effect was seen at a 1:1 (WT:MU) ratio and was more st riking at a ratio of 1:3. A model is proposed to explain the dominant negative effect of mutant p53. We conclude from this study that p53-th r280 is likely to be dominant in the heterozygous state found in NPC a nd that this dominant-negative mutated p53 may contribute to the genes is of NPC or of other carcinomas in which both mutant and wild-type p5 3 are expressed.