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1 Department of Biochemical Toxicology, Showa University School of Pharmaceutical Sciences, 1-5-8 Hatanodai, Shinagawa, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: numazawa{at}pharm.showa-u.ac.jp.
Transcription factor NF-E2 related factor 2 (Nrf2) regulates the induction of anti-oxidative proteins, including heme oxygenase-1 (HO-1). Nrf2 is sequestered in the cytoplasm by Keap1 under unstimulated conditions, but translocates into the nucleus and transactivates the anti-oxidant responsive element (ARE) upon exposure to oxidative insults. It has recently been demonstrated that in vitro phosphorylation of Nrf2 on Ser40 by protein kinase C (PKC) facilitates the dissociation of Nrf2 from the Keap1 complex (Huang et al., J Biol Chem 277: 42769-42774, 2002). The present study was designed to examine whether PKC is involved in oxidative stress-mediated nuclear translocation of Nrf2 in vivo and, if so, which PKC isoforms are involved. Induction of HO-1 gene expression by phorone, a glutathione depletor, and 4-hydoroxy-2,3-nonenal (4-HNE), an end product of lipid peroxidation, was suppressed by a specific PKC inhibitor, Ro-31-8220, at concentrations that inhibit all isoforms in WI-38 cells. The induction of HO-1 was not affected by prolonged exposure of the cells to 12-O-tetradecanoyl phorbol-13 acetate (TPA), suggesting that TPA-insensitive atypical PKC (aPKC) isoforms are involved. An immunocomplex kinase assay revealed that phorone and 4-HNE increased aPKC
activity. In COS-7 cells, 4-HNE induced nuclear translocation of the Nrf2-GFP fusion protein, but not the Nrf2(S40A)-GFP mutant. In the absence of oxidative insults, the Nrf2(S40E)-GFP mutant was distributed in the nucleus. The Nrf2-GFP accumulation in the nucleus was induced by co-expression of aPKC, but not by a kinase inactive mutant aPKC(K274W). The activity of an ARE-driven reporter was increased by co-expression of aPKC and this effect was eliminated by Ro-31-8220 in HepG2 cells. The reporter activity induced by 4-HNE was inhibited by co-expression of aPKC(K274W). These results suggest that phosphorylation of Nrf2 Ser40 by aPKC(s) is involved in the nuclear translocation and ARE transactivation of Nrf2 by oxidative stress.
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