Induction of Quinone Reductase NQO1 by Resveratrol in Human K562 Cells Involves the Antioxidant Response Element ARE and is Accompanied by Nuclear Translocation of Transcription Factor Nrf2

Joseph   M.   Wu; Tze-chen      Hsieh; Xiaohua      Lu; Zhirong      Wang

Abstract

The phytochemical resveratrol has been reported to induce NQO1, an enzyme involved in detoxification reactions, by as yet undetermined mechanisms. Using K562 cells as a model, we showed that 25-50 μM resveratrol increased NQO1 that peaked at 24-48 h. A 2.5-fold rise in NQO1 protein levels was accompanied by a comparable elevation in mRNA copy number and a 3- to 5-fold increase in NQO1 enzymatic activity. Fluorescent microscopic analysis in combination with transfection experiments with plasmids harboring different segments of the 5-flanking region of NQO1 gene linked to a reporter provided evidence that the modulation of NQO1 gene expression by resveratrol involved the antioxidant response element ARE, accompanied by an increase in the state of phosphorylation of transcription factor Nrf2 and its re-distribution to the nucleus. This change in cellular localization of Nrf2 may be linked to resveratrol-elicited disruption of the Nrf2-Keap1 complex in the cytosol, followed by the translocation of Nrf2 to the nucleus where it locates the ARE-containing 5-promoter region of NQO1 leading to its transcriptional activation.

Keywords: response element ARE, antioxidant, transcriptional factor Nrf2, transcriptional control, K562 cells, quinone reductase 1, Resveratrol

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