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Molecular Pharmacology

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Research ArticleArticle

The Essential Role of Phosphatidylinositol 3-Kinase and of p38 Mitogen-Activated Protein Kinase Activation in the Antioxidant Response Element-Mediated rGSTA2 Induction by Decreased Glutathione in H4IIE Hepatoma Cells

Keon Wook Kang, Ji Hwa Ryu and Sang Geon Kim
Molecular Pharmacology November 2000, 58 (5) 1017-1025; DOI: https://doi.org/10.1124/mol.58.5.1017
Keon Wook Kang
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
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Ji Hwa Ryu
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
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Sang Geon Kim
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
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Abstract

The protective adaptive response to electrophiles and reactive oxygen species is mediated by the enhanced expression of the phase II detoxifying genes through antioxidant response elements (AREs). The current study was designed to identify the signaling pathways responsible for the expression of rGSTA2 in response to cellular oxidative stress and to establish the molecular mechanistic basis. Deprivation of cystine and methionine caused oxidative stress in H4IIE hepatoma cells as evidenced by a marked decrease in the reduced glutathione (first order rate constant = 0.056 h−1;t 1/2 = 12.6 h) and an increase in pro-oxidant production. Electrophoretic mobility shift assay revealed that the ARE complex, consisting of Nrf-1/2 and Maf proteins, was activated 12 to 48 h after sulfur amino acid deprivation (SAAD). The rGSTA2 mRNA level was elevated by SAAD beginning at 24 h, whereas the rGSTA2 subunit was maximally induced at 48 h. Nuclear ARE activation and rGSTA2 mRNA increase were both completely inhibited by wortmannin or LY294002, the phosphatidylinositol 3-kinase (PI3-kinase) inhibitors. The p38 mitogen-activated protein (MAP) kinase was activated at 0.5 to 3 h after SAAD, followed by sustained diminished activation up to 12 h. Inhibition of p38 MAP kinase by SB203580 prevented the ARE-mediated rGSTA2 induction. The activation of p38 MAP kinase, however, failed to be inhibited by wortmannin or LY294002, showing that PI3-kinase is not involved in the activation of p38 MAP kinase. Data showed that PI3-kinase plays an essential role in the ARE-mediated rGSTA2 induction by oxidative stress after SAAD, which activates the p38 MAP kinase and leads to rGSTA2 induction.

Footnotes

    • Received January 24, 2000.
    • Accepted August 1, 2000.
  • Send reprint requests to: Sang Geon Kim, Ph.D., College of Pharmacy, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, South Korea. E-mail: sgk{at}snu.ac.kr

  • This work was supported by Grant No. 2000-2-21700-002-5 from the Basic Research Program of the Korea Science and Engineering Foundation (KOSEF), Republic of Korea.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 58 (5)
Molecular Pharmacology
Vol. 58, Issue 5
1 Nov 2000
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Research ArticleArticle

The Essential Role of Phosphatidylinositol 3-Kinase and of p38 Mitogen-Activated Protein Kinase Activation in the Antioxidant Response Element-Mediated rGSTA2 Induction by Decreased Glutathione in H4IIE Hepatoma Cells

Keon Wook Kang, Ji Hwa Ryu and Sang Geon Kim
Molecular Pharmacology November 1, 2000, 58 (5) 1017-1025; DOI: https://doi.org/10.1124/mol.58.5.1017

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Research ArticleArticle

The Essential Role of Phosphatidylinositol 3-Kinase and of p38 Mitogen-Activated Protein Kinase Activation in the Antioxidant Response Element-Mediated rGSTA2 Induction by Decreased Glutathione in H4IIE Hepatoma Cells

Keon Wook Kang, Ji Hwa Ryu and Sang Geon Kim
Molecular Pharmacology November 1, 2000, 58 (5) 1017-1025; DOI: https://doi.org/10.1124/mol.58.5.1017
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