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 cells and could conceivably comprise a subset of causal events in the carcinogenesis process. Although it has previously been shown that methylation of CpG islands in the 5'-control regions of tumor suppressor genes such as p16, Von Hippel-Lindau (VHL) syndrome gene, and the retinoblastoma (RB) gene can suppress expression and function of these gene products, the elements that control the expression of the p53 gene have not been examined in detail. In this study we examined the effect of CpG methylation in a region of the p53 promoter containing major transcription start sites. A region of the p53 promoter (from -199 to +142) containing 15 CpG dinucleotides was placed in a pCAT reporter plasmid and reporter activity was assessed in host CV-1 cells. We show for the first time that transcriptional activation of the p53 tumor suppressor gene, as assessed by a reporter plasmid construct, can be down-regulated by cytosine methylation in the basal promoter region. We believe these data suggest a role for methylation of CpG sequences in the regulation of transcription of p53. This implies that the tumor suppressor gene p53 could, therefore, contribute to carcinogenesis by inactivation via methylation of a key element in cell cycle control.
Schroeder
M
M
Toxicology Program, University of North Carolina at Chapel Hill, 27599, USA.
Mass
M J
MJ
D000818:Animals; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D015257:DNA-Cytosine Methylases / Q000378:metabolism; D019003:Deoxyribonuclease HpaII / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000235:genetics; D017930:Genes, Reporter; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007668:Kidney; D010957:Plasmids; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015533:Transcriptional Activation
C081573:DNA modification methylase SssI; D015257:DNA-Cytosine Methylases; D015500:Chloramphenicol O-Acetyltransferase; D019003:Deoxyribonuclease HpaII