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 various c-met promoter reporter vectors with p53 expression plasmids demonstrated that only wild-type p53 but not tumor-derived mutant forms of p53 resulted in a significant enhancement of c-met promoter activity. Functional assays 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 in the context of the c-met promoter but also in the context of a heterologous promoter. Electrophoretic mobility shift assays using purified recombinant p53 protein showed that the p53 binding element identified within the c-met promoter specifically binds to p53 protein. Induction of p53 by UV irradiation in RKO cells that express wild-type p53 increased the level of the endogenous c-met gene product and p21(WAF1/CIP1), a known target of p53 regulation. On the other hand, in RKO cells in which the function of p53 is impaired either by stable transfection of a dominant negative form of p53 or by HPV-E6 viral protein, no induction of the endogenous c-met gene or p21(WAF1/CIP1) was noted by UV irradiation. These results suggest that the c-met gene is also a target of p53 gene regulation.