Benzo[a]pyrene activates the human p53 gene through induction of nuclear factor κB activity

Abstract

p53 is known to be recruited in response to DNA-damaging genotoxic stress and plays an important role in maintaining the integrity of the genome. In the present study, the effect of a potent lung cancer carcinogen, benzo[a]pyrene (B[a]P) on p53 expression was investigated. We showed that exposure of A549 and NIH 3T3 cells to B[a]P resulted in an increase in p53 mRNA levels and in p53 promoter activation, indicating that B[a]P-induced p53 expression is partly regulated at the transcriptional level. The p53 promoter region which extends from -58 to -43, overlapping the κB motif, is essential for both the p53 basal promoter activity and p53 promoter activation induced by B[a]P. Nuclear factor κB (NF-κB) proteins have been revealed to be activated in B[a]P-induced p53 expression. Activated NF-κB complexes were shown to contain predominantly p50 and p65 subunit components in A549 cells and p65 subunit in NIH 3T3 cells. In addition, the overexpression of IκBα completely inhibited NF-κB activation, p53 promoter transactivation and the stimulatory effect on p53 transcription induced by B[a]P. We therefore conclude that B[a]P transcriptionally activates the human p53 gene through the induction of NF-κB activity.