ToxSci Advance Access published online on November 3, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi027
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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1 School of Pharmacy, University of Wisconsin at Madison, Madison, WI 53705
* To whom correspondence should be addressed. Recent studies indicate that Nrf2 is a substrate for the ubiquitin-proteasome pathway. The present study is aimed to determine whether increased protein stability is a mechanism by which quinone compounds, like tert-butylhydroquinone (tBHQ), may enhance Nrf2-mediated transcriptional activation and subsequent antioxidant protection. H2O2-induced necrotic cell death, evidenced by TEM imaging with no caspase 3 activation and PARP cleavage, was significantly attenuated by pretreatment with tBHQ or overexpression of Nrf2 through advenovirus-mediated infection in human neural stem cells (hNSCs). Microarray analysis showed that those identified antioxidant genes, responsible for antiapoptotic action in IMR-32 cells (Li et al. 2002), were also coordinately upregulated through Nrf2-dependent ARE activation in hNSC. The stabilization of Nrf2 by tBHQ in IMR-32 cells was evidenced by a pulse-chase assay showing no significant increase in Nrf2 protein synthesis after tBHQ treatment, and by ubiquitin immunoprecipitation showing that tBHQ stabilized ubiquitinated Nrf2. An in vitro proteasomal activity assay showed that tBHQ did not act as a 20S/26S proteasome inhibitor. Nrf2 stabilization by tBHQ also was observed in hNSCs. Taken together, this study suggests that identified antioxidant genes, which were upregulated through tBHQ induced Nrf2 stabilization, confer protection on target cells against H2O2-induced apoptotic cell death in neuroblastoma cells as well as the necrotic cell death in the hNSC. Nrf2 stabilization by pharmacological modulation or adenovirus-mediated Nrf2 overexpression, therefore, might be viable strategies to prevent a wide-spectrum of oxidative stress-related neuronal cell injuries.
Accepted October 30, 2004
Neurotoxicology
Stabilization of Nrf2 by tBHQ Confers Protection against Oxidative Stress-Induced Cell Death in Human Neural Stem Cells
2 School of Pharmacy, University of Wisconsin at Madison, Madison, WI 53705; Environmental Toxicology Center, University of Wisconsin at Madison, Madison, WI 53705
3 Waisman Center, University of Wisconsin at Madison, Madison, WI 53705
4 School of Pharmacy, University of Wisconsin at Madison, Madison, WI 53705; Environmental Toxicology Center, University of Wisconsin at Madison, Madison, WI 53705; Waisman Center, University of Wisconsin at Madison, Madison, WI 53705
Jeffrey Johnson, E-mail: jajohnson{at}pharmacy.wisc.edu
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