NAD(P)H:quinone oxidoreductase1 (DT-diaphorase): expression, regulation, and role in cancer.
NAD(P)H:quinone oxidoreductase1 (DT-diaphorase or NQO1) is a flavoprotein that promotes obligatory two-electron reduction of quinones, preventing their participation in redox cycling, oxidative stress, and neoplasia. NQO1 is ubiquitously expressed. However, a large amount of variation in NQO1 gene expression was noticed among various human tissues. NQO1 gene is upregulated in livers of hepatocarcinoma patients, and its expression is induced in response to a variety of compounds, including planar aromatic hydrocarbons, phenolic antioxidants/chemoprotectors, tumor promoters, and hydrogen peroxide. Deletion mutagenesis in the NQO1 gene promoter identified several cis-elements including antioxidant response element (ARE), xenobiotic response element, and AP2 element, which regulate the expression and induction of the NQO1 gene. Among these DNA elements, ARE is the most important cis-element required for high basal expression of the NQO1 gene in tumor tissues, as compared to the normal tissues of the same origin, and for its induction in response to xenobiotics and antioxidants. Nucleotide sequence analysis of the ARE indicated presence of three AP1/AP1-like elements and a GCA box. Mutational analysis indicated a requirement of two AP1/AP1-like elements arranged as inverse repeats at the interval of three base pairs for the ARE activity. The GCA box in the ARE was required for optimum basal and induced expression. ARE is a novel cis-element because a single AP1/AP1-like element did not stimulate gene expression in response to xenobiotics and antioxidants. Band shift and supershift assays identified Jun, Fos, and novel proteins in the hARE-nuclear protein complexes that mediate regulation of the NQO1 gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)
Joseph
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Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Xie
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Xu
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Jaiswal
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AK
D000818:Animals; D001483:Base Sequence; D001580:Benzopyrenes / Q000378:metabolism / Q000493:pharmacokinetics; D001711:Biotransformation; D003579:Cytochrome Reductases / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009369:Neoplasms / Q000201:enzymology*; D014407:Tumor Cells, Cultured
D001580:Benzopyrenes; D004273:DNA, Neoplasm; C018003:benzo(a)pyrene-3,6-quinone; D003579:Cytochrome Reductases; D016660:NAD(P)H Dehydrogenase (Quinone)