Regulation of the c-met proto-oncogene promoter by p53

In the present study, we have investigated the possible involvement of p53 in the transcriptional regulation of the c-met gene. Cotransfection of vari ous c-met promoter reporter vectors with p53 expression plasmids demonstrat ed that only wild-type p53 but not tumor-derived mutant forms of p53 result ed in a significant enhancement of c-met promoter activity. Functional assa ys revealed that the p53 responsive element in the c-met promoter region is located at position -278 to -216 and confers p53 responsiveness not only i n the context of the c-met promoter but also in the context of a heterologo us promoter. Electrophoretic mobility shift assays using purified recombina nt p53 protein showed that the p53 binding element identified within the c- met promoter specifically binds to p53 protein. Induction of p53 by UV irra diation in RKO cells that express wildtype p53 increased the level of the e ndogenous c-met gene product and p21(WAF1/CIP1), a known target of p53 regu lation. On the other hand, in RKO cells in which the function of p53 is imp aired either by stable transfection of a dominant negative form of p53 or b y HPV-E6 viral protein, no induction of the endogenous c-met gene or p21(WA F1/CIP1) was noted by UV irradiation. These results suggest that the c-met gene is also a target of p53 gene regulation.