Abstract
The tumour suppressor gene TP53 is mutated in more than 50 % of human tumours, making it one of the most important cancer genes. We have investigated the role of TP53 in cytochrome P450 (CYP)-mediated metabolic activation of three polycyclic aromatic hydrocarbons (PAHs) in a panel of isogenic colorectal HCT116 cells with differing TP53 status. Cells that were TP53(+/+), TP53(+/−), TP53(−/−), TP53(R248W/+) or TP53(R248W/−) were treated with benzo[a]pyrene (BaP), dibenz[a,h]anthracene and dibenzo[a,l]pyrene, and the formation of DNA adducts was measured by 32P-postlabelling analysis. Each PAH formed significantly higher DNA adduct levels in TP53(+/+) cells than in the other cell lines. There were also significantly lower levels of PAH metabolites in the culture media of these other cell lines. Bypass of the need for metabolic activation by treating cells with the corresponding reactive PAH-diol-epoxide metabolites resulted in similar adduct levels in all cell lines, which confirms that the influence of p53 is on the metabolism of the parent PAHs. Western blotting showed that CYP1A1 protein expression was induced to much greater extent in TP53(+/+) cells than in the other cell lines. CYP1A1 is inducible via the aryl hydrocarbon receptor (AHR), but we did not find that expression of AHR was dependent on p53; rather, we found that BaP-induced CYP1A1 expression was regulated through p53 binding to a p53 response element in the CYP1A1 promoter region, thereby enhancing its transcription. This study demonstrates a new pathway for CYP1A1 induction by environmental PAHs and reveals an emerging role for p53 in xenobiotic metabolism.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-014-1409-1) contains supplementary material, which is available to authorized users.
Highlights
The TP53 tumour suppressor gene, which encodes the protein p53, is mutated in over 50 % of human tumours and is one of the most important cancer genes (Olivier et al 2010). p53, often described as the guardian of the genome, is involved in multiple cellular functions; amongst these is the response to cellular stress induced by various types of DNA damage, thereby delaying DNA synthesis or cell division to allow DNA repair or inducing apoptosis
CYP1A1 is inducible via the aryl hydrocarbon receptor (AHR), but we did not find that expression of AHR was dependent on p53; rather, we found that BaP-induced CYP1A1 expression was regulated through p53 binding to a p53 response element in the CYP1A1 promoter region, thereby enhancing its transcription
We investigated whether p53 impacts on the regulation of XME expression such as CYP1A1 via the aryl hydrocarbon receptor (AHR) or whether the expression of XMEs such as CYP1A1 may be transcriptionally regulated by direct binding of p53 to the regulatory regions of the XME genes (Goldstein et al 2013)
Summary
The TP53 tumour suppressor gene, which encodes the protein p53, is mutated in over 50 % of human tumours and is one of the most important cancer genes (Olivier et al 2010). p53, often described as the guardian of the genome, is involved in multiple cellular functions; amongst these is the response to cellular stress induced by various types of DNA damage, thereby delaying DNA synthesis or cell division to allow DNA repair or inducing apoptosis. The TP53 tumour suppressor gene, which encodes the protein p53, is mutated in over 50 % of human tumours and is one of the most important cancer genes (Olivier et al 2010). In normal, unstressed cells, p53 protein expression is kept low via ubiquitin-mediated proteolysis that is regulated by the E3 ubiquitin ligase MDM2. In addition to its role in the DNA damage response, p53 has been found to regulate metabolic pathways such as glycolysis and oxidative phosphorylation thereby linking p53 to cancer, and to other diseases such as diabetes and obesity, and to other physiological processes such as ageing (Maddocks and Vousden 2011). It has been observed that abrogation of p53 activity by knockout or knockdown of TP53 in human cells in vitro affects carcinogen activation (Hockley et al 2008; Simoes et al 2008) and drug metabolism (Goldstein et al 2013), but as yet little is known about the mechanism of this phenomenon
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
