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

Toxicology and Applied Pharmacology
Hao HuA'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 3kb 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 -160bp from the TSS--showed p53 responsiveness in p53 overexpressed C3A cells. However, a further deletion from -160 to -74bp, 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 int...Continue Reading

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Citations

May 23, 2018·Basic & Clinical Pharmacology & Toxicology·A'edah Abu-BakarMatti A Lang
Jul 25, 2019·Journal of Biochemical and Molecular Toxicology·Mohammad S AkhterNektarios Barabutis
Apr 1, 2021·Seminars in Cancer Biology·Yanqing Liu, Wei Gu
Oct 11, 2021·Cell Death and Differentiation·Timothy J HumptonKaren H Vousden
Jan 30, 2020·Acta Pharmaceutica Sinica. B·Albert Braeuning, Michael Schwarz

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