Abstract
The protective adaptive response to electrophiles and reactive oxygen species is mediated by the induction of phase II detoxifying genes including glutathione S-transferases (GSTs). NF-E2-related factor-2 (Nrf2) phosphorylation by protein kinase C (PKC) is a critical event for its nuclear translocation in response to oxidative stress. Previously, we have shown that peroxynitrite plays a role in activation of Nrf2 and Nrf2 binding to the antioxidant response element (ARE) via the pathway of phosphatidylinositol 3-kinase (PI3-kinase) and that nitric oxide synthase in hepatocytes is required for GSTA2 induction. In view of the importance of PKC and PI3-kinase in Nrf2-mediated GST induction, we investigated the role of these kinases in peroxynitrite formation for GSTA2 induction by oxidative stress and determined the relationship between PKC and PI3-kinase. Although PKC activation by phorbol 12-myristate-13-acetate (PMA) did not increase the extents of constitutive and inducible GSTA2 expression, either PKC depletion by PMA or PKC inhibition by staurosporine significantly inhibited GSTA2 induction bytert-butylhydroquinone (t-BHQ) a prooxidant chemical. Therefore, the basal PKC activity is requisite for GSTA2 induction. 3-Morpholinosydnonimine (SIN-1), which decomposes and yields peroxynitrite, induced GSTA2, which was not inhibited by PKC depletion, but slightly enhanced by PKC activation, suggesting that PKC promotes peroxynitrite formation for Nrf2-mediated GSTA2 induction. Treatment of cells withS-nitroso-N-acetyl-penicillamine (SNAP), an exogenous NO donor, in combination witht-BHQ may produce peroxynitrite. GSTA2 induction by SNAP +t-BHQ was not decreased by PKC depletion, but rather enhanced by PKC activation, showing that the activity of PKC might be required for peroxynitrite formation. LY294002 a PI3-kinase inhibitor blocked GSTA2 induction byt-BHQ, which was reversed by PMA-induced PKC activation. These results provide evidence that PKC may play a role in formation of peroxynitrite that activates Nrf2 for GSTA2 induction and that PKC may serve an activator for GSTA2 induction downstream of PI3-kinase.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Cho, M. K., Kim, Y. G., Lee, M. G., and Kim, S. G., The effect of cysteine on the altered expression of class alpha and mu glutathioneS-transferase genes in the rat liver during proteincalorie malnutrition.Biochim. Biophys. Acta, 1502, 235–246 (2000).
Huang, H. C., Nguyen T., and Pickett, C. B., Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor-2.Proc. Natl. Acad. Sci. U.S.A., 97, 12475–12480 (2000).
Huang, H. C., Nguyen, T., and Pickett, C. B., Phosphorylation ofv Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription.J. Biol. Chem., 277, 42769–42774 (2002).
Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., O’Connor, T., and Yamamoto, M., Keapl regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles.Genes Cells, 8, 379–391 (2003).
Kang, K. W., Ryu, J. H., and Kim, S. G., The essential role of phosphatidylinositol 3-kinase and of p38 mitogen-activated protein kinase activation in the antioxidant response elementmediated rGSTA2 induction by decreased glutathione in H4IIE hepatoma cells.Mol. Pharmacol., 58, 1017–1025 (2000).
Kang, K. W., Cho, M. K., Lee, C. H., and Kim, S. G., Activation of phosphatidylinositol 3-kinase and Akt bytert-butyl-hydroquinone is responsible for antioxidant response element-mediated rGSTA2 induction in H4IIE cells.Mol. Pharmacol., 59, 1147–1156 (2001).
Kang, K. W., Choi, S. H., and Kim, S. G., Peroxynitrite activates NF-E2-related factor 2/antioxidant response element through the pathway of phosphatidylinositol 3-kinase: the role of nitric oxide synthase in rat glutathione S-transferase A2 induction.Nitric Oxide, 7, 244–253 (2002).
Kang, K. W., Choi, S. Y., Cho, M. K., Lee, C. H., and Kim, S. G., Thrombin induces nitric-oxide synthasevia G alpha 12/13-coupled protein kinase C-dependent l-kapa B alpha phosphorylation and JNK-mediated l-kappa B alpha degradation.J. Biol. Chem., 278, 17368–17378 (2003).
Kang, K. W., Cho, I. J., Lee, C. H., and Kim, S. G., Essential role of phosphatidylinositol 3-kinase-dependent CCAAT/enhancer binding protein beta activation in the induction of glutathione S-transferase by oltipraz.J. Natl. Cancer. Inst., 95, 53–66 (2003).
Kim, S. G., Nam, S. Y., Kim, J. H., Cho, C. K., and Yoo, S. Y., Enhancement of radiation-inducible hepatic glutathioneS-transferase Ya1, Yb1, Yb2, Yc1, and Yc2 expression by oltipraz: Possible role in radioprotection.Mol. Pharmacol., 51, 225–233 (1997).
Klotz, L. O., Schieke, S. M., Sies, H., and Holbrook, N. J., Peroxynitrite activates the phosphoinositide 3-kinase/Akt pathway in human skin primary fibroblasts.Biochem. J., 352, 219–225 (2000).
Liu, S. and Pickett, C. B., The rat liver glutathioneS-transferase Ya subunit gene: Characterization of the binding properties of a nuclear protein from HepG2 cells that has high affinity for the antioxidant response element.Biochemistry, 35, 11517–11521 (1996).
Marshall, H. E., Merchant, K., and Stamler, J. S., Nitrosation and oxidation in the regulation of gene expression.FASEB J., 14, 1889–1900 (2000).
McMahon, M., Itoh, K., Yamamoto, M., Chanas, S. A., Henderson, C. J., McLellan, L. I., Wolf, C. R., Cavin, C., and Hayes, J. D., The Cap’n’Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes.Cancer Res., 61, 3299–3307 (2001).
Nguyen, T. and Pickett, C. B., Regulation of rat glutathioneS-transferase Ya subunit gene expression. DNA-protein interaction at the antioxidant responsive element.J. Biol. Chem., 267, 13535–13539 (1992).
Numazawa, S., Ishikawa, M., Yoshida, A., Tanaka, S., and Yoshida, T., Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress.Am. J. Physiol. Cell Physiol., 285, C334–342 (2003).
Park, H. S., Huh, S. H., Kim, M. S., Lee S. H., and Choi, E. J., Nitric oxide negatively regulatesc-JunN-terminal kinase/ stress-activated protein kinase by means ofS-nitrosylation.Proc. Natl. Acad. Sci. U.S.A.., 97, 14382–14387 (2000).
Shah, B. H. and Catt, K. J., Calcium-independent activation of extracellularly regulated kinases 1 and 2 by angiotensin II in hepatic C9 cells: Role of protein kinase Cδ, Src/proline-rich tyrosine kinase 2, and epidermal growth factor receptortrans-activation.Mol. Pharmacol., 61, 343–351 (2002).
Vaughan, R. A., Huff, R. A., Uhi, G. R., and Kuhar, M. J., Protein kinase C-mediated phosphorylation and functional regulation of dopamine transporters in striatal synaptosomes.J. Biol. Chem., 272, 15541–15546 (1997).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kim, S.G., Kim, S.O. Pkc downstream of pi3-kinase regulates peroxynitrite formation for nrf2-mediated gsta2 induction. Arch Pharm Res 27, 757–762 (2004). https://doi.org/10.1007/BF02980145
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF02980145