The influence of TP53 status on the metabolic activation of environmental carcinogens

• Applicant: Dr. Annette Krais
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 215680516

The p53 protein is an important tumour suppressor that is inactivated in many cancers. Exposure to environmental carcinogens has been linked to tumour development and various carcinogens have been found to be associated with different characteristic mutations in TP53. Recent findings have indicated that the cellular TP53 status can influence the metabolism of different environmental carcinogens, suggesting a possible role for TP53 in the regulation of xenobiotic-metabolising enzymes (XMEs). In order to investigate the role of TP53 in xenobiotic metabolism a panel of isogenic cell lines will be used that differ only with respect to their endogenous TP53 status. E.g. HCT116 cells having wild-type (WT) TP53, heterozygous TP53, complete knock-out of TP53, or mutant TP53 will be treated with environmental carcinogens from different chemical classes (e.g. polycyclic or nitro-polycyclic aromatic hydrocarbons, heterocyclic aromatic amines). These cells will be characterised for (i) their capability to metabolically activate the carcinogens by the measurement of DNA adducts, (ii) their expression and induction of XMEs, in particular cytochrome P450 (CYP) enzymes, both at the gene and protein level, and (iii) their expression of transcription factors involved in metabolism regulation such as the aryl hydrocarbon receptor. The role of CYP isoenzymes will also be investigated by treatment of cells with activated reactive intermediates and results will be compared to those obtained with their parent compounds. Further, selected test compounds will be investigated in vivo using p53-WT and p53-null mice. Finally, the influence of the TP53 status on other cellular processes such as epigenetic changes will be explored. Suggesting a novel role of p53 in carcinogen metabolism, this project will provide significant insights into the mechanism of p53 function in chemical carcinogenesis, information that may ultimately assist in developing strategies for cancer prevention.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Dr. David Phillips