Benzo[a]pyrene activates the human p53 gene through induction of nuclear factor kappaB activity.
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 kappaB motif, is essential for both the p53 basal promoter activity and p53 promoter activation induced by B[a]P. Nuclear factor kappaB (NF-kappaB) proteins have been revealed to be activated in B[a]P-induced p53 expression. Activated NF-kappaB 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 IkappaBalpha completely inhibited NF-kappaB 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-kappaB activity.
Pei
X H
XH
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Nakanishi
Y
Y
Takayama
K
K
Bai
F
F
Hara
N
N
D016475:3T3 Cells; D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D015152:Blotting, Northern; D002273:Carcinogens / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D020672:I-kappa B Proteins; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D011401:Promoter Regions, Genetic; D013379:Substrate Specificity; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
D002273:Carcinogens; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D016159:Tumor Suppressor Protein p53; D000072000:NF-KappaB Inhibitor alpha; D001564:Benzo(a)pyrene; D015500:Chloramphenicol O-Acetyltransferase