CPG METHYLATION INACTIVATES THE TRANSCRIPTIONAL ACTIVITY OF THE PROMOTER OF THE HUMAN P53 TUMOR-SUPPRESSOR GENE

Alterations of the methylation patterns of DNA are common in cancer ce lls and could conceivably comprise a subset of causal events in the ca rcinogenesis process. Although it has previously been shown that methy lation of CpG islands in the 5'-control regions of tumor suppressor ge nes such as pie, Von Hippel-Lindau (VHL) syndrome gene, and the retino blastoma (RB) gene can suppress expression and function of these gene products, the elements that control the expression of the p53 gene hav e not been examined in detail. In this study me examined the effect of CpG methylation in a region of the p53 promoter containing major tran scription start sites. A region of the p53 promoter (from -199 to +142 ) containing 15 CpG dinucleotides was placed in a pCAT reporter plasmi d and reporter activity was assessed in host CV-1 cells. We show for t he first time that transcriptional activation of the p53 tumor suppres sor gene, as assessed by a reporter plasmid construct, can be down-reg ulated by cytosine methylation in the basal promoter region. We believ e these data suggest a role for methylation of CpG; sequences in the r egulation of transcription of p53. This implies that the tumor suppres sor gene p53 could, therefore, contribute to carcinogenesis by inactiv ation via methylation of a key element in cell cycle control. (C) 1997 Academic Press.