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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Nrf2 Possesses a Redox-sensitive Nuclear Exporting Signal in the Neh5 Transactivation Domain.

NF-E2-related factor 2 ( Nrf2) is the key transcription factor regulating the antioxidant response. Previous studies identified a nuclear localization signal (NLS) in the basic region and a nuclear exporting signal (NES) in the leucine zipper domain of Nrf2. In this study, we characterize a new functional NES ((175)LLSIPELQCLNI(186)) in the transactivation (TA) domain of Nrf2. A green fluorescence protein (GFP)-tagged Nrf2 segment (amino acids162-295) called GFP-NES(TA) exhibited a cytosolic distribution that could be disrupted by L184A mutation or leptomycin B treatment. Chimeric expression of this NES(TA) with a nuclear protein GAL4DBD could expel GAL4DBD into the cytoplasm. A variety of oxidants, including sulforaphane, tert-butylhydroquinone, and H(2)O(2), could effectively induce nuclear translocation of GFP-NES(TA). Mutational studies showed that cysteine 183 may mediate the redox response of NES(TA). The discovery of multiple NLS/NES motifs in Nrf2 and the redox sensitivity of NES(TA) imply Nrf2 may be self-sufficient to sense and transduce oxidative signals into the nucleus, consequently initiating antioxidant gene transcription.[1]


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