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J Biol Chem, Vol. 275, Issue 20, 15466-15473, May 19, 2000
From the Schering-Plough Research Institute, Kenilworth,
New Jersey 07033
The antioxidant response element (ARE) mediates
the transcriptional activation of many genes encoding phase II
drug-metabolizing enzymes in response to oxidative stress. Recent
studies using knockout mice suggest that NF-E2-related factor 2 (Nrf2), along with small Maf proteins, binds and activates the
ARE. In this study, using in vitro binding assays,
Nrf2/MafK heterodimers were found to interact with high affinity
to the ARE. However, distinct differences were observed when this
interaction was compared with that formed with nuclear proteins from
H4II EC3 or HepG2 cells. Overexpression of Nrf2 activated
ARE-mediated transcription in HepG2 cells, and this activation was
further increased by tert-butylhydroquinone. In HeLa cells,
overexpression of Nrf2 resulted in activation of the ARE, but
this activation was no longer induced by
tert-butylhydroquinone. Using ARE constructs with point
mutations in the core sequence, we found that only mutations at the T
or G nucleotides within the core (TGAC) render the ARE unresponsive to
Nrf2. Overexpression of MafK led to dose-dependent
repression of ARE activity. Activation of the ARE by Nrf2 was
similarly antagonized by MafK. These data suggest that Nrf2
plays an important role mediating basal activity of the ARE but that
small Maf proteins are repressors and not activators of ARE-mediated transcription.
To whom correspondence should be addressed: Schering-Plough
Research Inst., 2015 Galloping Hill Rd., Kenilworth, NJ 07033. Tel.:
908-740-7300; Fax: 908-740-7514; E-mail:
cecil.pickett@spcorp.com.
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