Anti-diol epoxide of benzo[a]pyrene induces transient Mdm2 and p53 Ser15 phosphorylation, while anti-diol epoxide of dibenzo[a,l]pyrene induces a nontransient p53 Ser15 phosphorylation.
The polycyclic aromatic hydrocarbons (PAHs) dibenzo[a,l]pyrene (DBP) and benzo[a]pyrene (BP) are environmental contaminants and potent carcinogens. DBP is several orders of magnitude more mutagenic/carcinogenic than BP. This can be ascribed to differences in DNA binding efficiency of their ultimate carcinogenic bay- and fjord-region diol epoxide (DE) intermediates, differences in structural features of the DNA adducts and differences in DNA adduct recognition and the subsequent downstream signaling. In this study, we have characterized the effect of the ultimate carcinogenic DEs, (+)-anti-BPDE and (-)-anti-DBPDE following short exposure times, on Mdm2 and p53 pathway in A549 human lung epithelial carcinoma cells. In contrast to (-)-anti-DBPDE, (+)-anti-BPDE induces stabilization of phosphorylated Mdm2. (+)-anti-BPDE-induced effects on Mdm2 were transient and correlated with transient p53 Ser15 phosphorylation. DNA adducts of (-)-anti-DBPDE are more refractory to removal by nucleotide excision repair (NER) than adducts of (+)-anti-BPDE and do not induce Mdm2 phosphorylation. This suggests a role of phosphorylated Mdm2 in the repair process. In addition, (-)-anti-DBPDE, in contrast to (+)-anti-BPDE, induced prolonged p53 Ser15 phosphorylation as well as phosphorylation of p53 at Ser46, a phosphorylation site associated with apoptosis. It is also concluded that p53 Ser15 phosphorylation and antibody 2A10-site specific Mdm2 alterations are induced by nonidentical signaling pathways by the bay- and fjord-region DE. These differences may reflect the different carcinogenic potential of these compounds.
Pääjärvi
Gerd
G
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Jernström
Bengt
B
Seidel
Albrecht
A
Stenius
Ulla
U
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology*; D001580:Benzopyrenes / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology; D045744:Cell Line, Tumor; D004852:Epoxy Compounds / Q000494:pharmacology*; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D001580:Benzopyrenes; D002273:Carcinogens; D004852:Epoxy Compounds; D016159:Tumor Suppressor Protein p53; D012694:Serine; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C041517:dibenzo(a,l)pyrene