Carcinogenesis Advance Access originally published online on September 30, 2004
Carcinogenesis 2005 26(1):201-208; doi:10.1093/carcin/bgh289
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Carcinogenesis vol.26 no.1 © Oxford University Press 2005; all rights reserved.
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TCDD activates Mdm2 and attenuates the p53 response to DNA damaging agents
1 Institute of Environmental Medicine, Karolinska Institutet, Box 210, 17177 Stockholm, Sweden, 2 Laboratory of Toxicology, Department of Environmental Health, National Public Health Institute, FIN-70701 Kuopio, Finland and 3 Department of Food and Environmental Hygiene, University of Helsinki, FIN-00014 Helsinki, Finland and National Veterinary and Food Research Institute, Kuopio, Finland
4 To whom correspondence should be addressed Email: johan.hogberg{at}imm.ki.se
In this study we investigated the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the p53 response to DNA damaging agents. Pre-treatment of rats with TCDD attenuated the p53 liver response to diethylnitrosamine (DEN) and reduced levels of p53 and Ser15 phosphorylated p53. In addition, there were more slowly migrating p53 species, forming a ladder, which suggests an increased ubiquination of p53 in TCDD-pre-treated rats. Terminal deoxynucleotidyl transferase-mediated X-dUTP nick-end labelling analysis indicated decreased apoptosis rates in the livers of these rats. Studies on aryl hydrocarbon receptor (AhR) knockout mice and their wild-type littermates confirmed this effect in AhR +/+ but not in AhR –/– mice, indicating that this effect may be AhR-mediated. Quantitative RT-PCR analysis revealed no increased mRNA levels in TCDD-treated rats, but immunohistological studies indicated that TCDD modulated Mdm2 protein levels, and in particular, increased nuclear levels in rat hepatocytes in situ. In vitro studies employing HepG2 cells confirmed the in vivo data. Thus, TCDD increased basal levels of Mdm2 protein, but not mRNA, and attenuated the p53 response to a variety of genotoxic and cytotoxic agents. The increase in Mdm2 protein levels was accompanied by rapid and highly sensitive phosphorylation of Mdm2 at Ser166, which has been associated to active Mdm2. In summary, TCDD is a potent inhibitor of p53 that may influence the liver's ability to handle genotoxic agents in a safe way, and may play a role in TCDD-induced carcinogenesis.
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