Tumour suppressor protein p53 regulates the stress activated bilirubin oxidase cytochrome P450 2A6

Hu, Hao, Yu, Ting, Arpiainen, Satu, Lang, Matti A., Hakkola, Jukka and Abu-Bakar, A'edah (2015) Tumour suppressor protein p53 regulates the stress activated bilirubin oxidase cytochrome P450 2A6. Toxicology and Applied Pharmacology, 289 1: 30-39. doi:10.1016/j.taap.2015.08.021

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Author Hu, Hao
Yu, Ting
Arpiainen, Satu
Lang, Matti A.
Hakkola, Jukka
Abu-Bakar, A'edah
Title Tumour suppressor protein p53 regulates the stress activated bilirubin oxidase cytochrome P450 2A6
Journal name Toxicology and Applied Pharmacology   Check publisher's open access policy
ISSN 1096-0333
Publication date 2015-11-15
Sub-type Article (original research)
DOI 10.1016/j.taap.2015.08.021
Open Access Status File (Author Post-print)
Volume 289
Issue 1
Start page 30
End page 39
Total pages 10
Place of publication Maryland Heights, MO, United States
Publisher Academic Press
Collection year 2016
Language eng
Formatted 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.
Keyword Bilirubin
Bilirubin oxidase
Oxidative stress
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
National Research Centre for Environmental Toxicology Publications
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