Title |
Tumour suppressor protein p53 regulates the stress activated bilirubin oxidase cytochrome P450 2A6
|
---|---|
Published in |
Toxicology & Applied Pharmacology, September 2015
|
DOI | 10.1016/j.taap.2015.08.021 |
Pubmed ID | |
Authors |
Hao Hu, Ting Yu, Satu Arpiainen, Matti A. Lang, Jukka Hakkola, A'edah Abu-Bakar |
Abstract |
Human cytochrome P450 (CYP) 2A6 enzyme has been proposed to play a role in cellular defence against chemical-induced oxidative stress. The encoding gene is regulated by various stress activated transcription factors. This paper demonstrates that p53 is a novel transcriptional regulator of the gene. Sequence analysis of the CYP2A6 promoter revealed six putative p53 binding sites in a 3 kb proximate promoter region. The site closest to transcription start site (TSS) is highly homologous with the p53 consensus sequence. Transfection with various stepwise deletions of CYP2A6-5'-Luc constructs-down to -160 bp from the TSS-showed p53 responsiveness in p53 overexpressed C3A cells. However, a further deletion from -160 to -74 bp, including the putative p53 binding site, totally abolished the p53 responsiveness. Electrophoretic mobility shift assay with a probe containing the putative binding site showed specific binding of p53. A point mutation at the binding site abolished both the binding and responsiveness of the recombinant gene to p53. Up-regulation of the endogenous p53 with benzo[α]pyrene-a well-known p53 activator-increased the expression of the p53 responsive positive control and the CYP2A6-5'-Luc construct containing the intact p53 binding site but not the mutated CYP2A6-5'-Luc construct. Finally, inducibility of the native CYP2A6 gene by benzo[α]pyrene was demonstrated by dose-dependent increases in CYP2A6 mRNA and protein levels along with increased p53 levels in the nucleus. Collectively, the results indicate that p53 protein is a regulator of the CYP2A6 gene in C3A cells and further support the putative cytoprotective role of CYP2A6. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 22 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Bachelor | 5 | 23% |
Student > Ph. D. Student | 4 | 18% |
Researcher | 2 | 9% |
Student > Master | 2 | 9% |
Lecturer | 1 | 5% |
Other | 3 | 14% |
Unknown | 5 | 23% |
Readers by discipline | Count | As % |
---|---|---|
Pharmacology, Toxicology and Pharmaceutical Science | 6 | 27% |
Biochemistry, Genetics and Molecular Biology | 5 | 23% |
Agricultural and Biological Sciences | 3 | 14% |
Medicine and Dentistry | 1 | 5% |
Unknown | 7 | 32% |