Hypersensitive site 2 located in the f-globin locus control region confers high levels of expression to the genes of the 1-globin cluster. A tandem repeat of the consensus sequence for the transcription factors AP1 and NF-E2 (acti-

No abstract

The antioxidant responsive element (ARE) mediates transcriptional regulation of phase II detoxification enzymes and antioxidant proteins such as NAD(P)H:quinone oxidoreductase (NQO1), glutathione S-transferases, and glutamate-cysteine ligase. In this study, we demonstrate that NF-E2-related factor-2 (Nrf2) plays a major role in transcriptional activation of ARE-driven genes and identify Nrf2-dependent genes by oligonucleotide microarray analysis using primary cortical astrocytes from Nrf2 ؉/؉ and Nrf2 ؊/؊ mice. Nrf2 ؊/؊ astrocytes had decreased basal NQO1 activity and no induction by tert-butylhydroquinone compared with Nrf2 ؉/؉ astrocytes. Similarly, both basal and induced levels of human NQO1-ARE-luciferase expression in Nrf2 ؊/؊ astrocytes were significantly lower than in Nrf2 ؉/؉ astrocytes. Furthermore, human NQO1-ARE-luciferase expression in Nrf2 ؊/؊ astrocytes was restored by overexpression of Nrf2, whereas ARE activation in Nrf2 ؉/؉ astrocytes was completely blocked by dominantnegative Nrf2. In addition, we observed that Nrf2-dependent genes protected primary astrocytes from H 2 O 2 -or platelet-activating factor-induced apoptosis. In support of these observations, we identified Nrf2-dependent genes encoding detoxification enzymes, glutathione-related proteins, antioxidant proteins, NADPHproducing enzymes, and anti-inflammatory genes using oligonucleotide microarrays. Proteins within these functional categories are vital to the maintenance and responsiveness of a cell defense system, suggesting that an orchestrated change in gene expression via Nrf2 and the ARE gives a synergistic protective effect against oxidative stress.