S. Dhakshinamoorthy⁽¹⁾, D. Bloom⁽²⁾, Anil Jaiswal^(3)
(1)(2)Department of Pharmacology. Baylor College of Medicine. - Houston. United States
⁽³⁾Baylor College of Medicine - Houston. United States

Antioxidant Response Element

Deletion mutagenesis studies of the human NQO1 gene promoter identified several cis-elements that are essential for the expression and induction of the NQO1 gene ^(46-50,17). One of these elements was 24 base pairs of the antioxidant response element (ARE) that are required for basal expression as well as induction of NQO1 gene in response to b-naphthoflavone (b-NF), 2⁽³⁾-tert-butyl-4-hydroxy-anisole (BHA), tert-butylhydroquinone (tBHQ) and hydrogen peroxide. Other elements include a DNA fragment (between -780 to -365) that is required for TCDD induction of NQO1 gene expression; a basal element (region between -130 to -47) and an AP2 element (at nucleotide position -157) essential for cAMP induced expression of the NQO1 gene. ARE-like elements have also been found in the promoter regions of the rat NQO1 gene ⁽⁵¹⁾; the human NQO2 gene ⁽⁴¹⁾; the rat and mouse glutathione S-transferase Ya (GST Ya) subunit genes ^(52-55), the rat glutathione S-transferase P gene ⁽⁵⁶⁾ and g-glutamyl cysteinyl synthetase gene ⁽⁵⁷⁾ (Fig. 3). The conservation of the ARE in the genes of many detoxifying enzymes indicated that these genes may be coordinately regulated by a single mechanism involving ARE (58; Fig. 3). The NQO1 gene ARE contains one perfect and one imperfect TRE (TPA response element) arranged as inverse repeats separated by three base pairs followed by a ´GC´ box (58, Fig.3). The nucleotide sequence analysis of the other gene AREs also revealed that they contain TRE/TRE-like elements arranged as inverse or direct repeats. These repeats are separated by three or eight nucleotides, followed by a GC box ⁽⁵⁸⁾. The seven base pairs TRE was characterized previously in the promoter regions of the collagenase and metallothionein genes, and is required to activate expression of these genes in response to TPA ⁽⁵⁹⁾. The human NQO1 gene ARE and other detoxifying enzyme gene AREs are unique cis-elements even though they contain TRE and TRE-like elements. This is because it is ARE, rather than TRE, that is responsive to antioxidants and xenobiotics ⁽⁵⁸⁾. Mutational analysis of the ARE identified GTGAC***GC as the core of the ARE sequence ^(49,53) (Fig. 3). Additional cis-element and nucleotide sequences flanking the core sequence have been shown to contribute to the ARE-mediated expression and induction ^(49,60-62).

Discussion Board

Any Comment to this presentation?

[ABSTRACT] [Antioxidants and their Mode of Action] [Induction of Genes Encoding Enzymes that Detoxify Xenobiotics and Carcinogens.] [Antioxidant Response Element] [Figures] [Figures-2] [Antioxidant Response Element-Binding Proteins] [Summary and Conclusions] [Acknowledgements] [References] [Discussion Board]

---

S. Dhakshinamoorthy, D. Bloom, Anil Jaiswal
Copyright © 1999-2000. All rights reserved.

Last update: 24/01/00