Activation of phosphatidylinositol 3-kinase and Akt by tert-butylhydroquinone is responsible for antioxidant response element-mediated rGSTA2 induction in H4IIE cells

• Published in: Molecular pharmacology 2001-05, Vol.59 (5), p.1147-1156
• Main Authors: Kang, K W, Cho, M K, Lee, C H, Kim, S G
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - pharmacology; Enzyme Activation - drug effects; Enzyme Induction; Gene Expression Regulation, Enzymologic - drug effects; Glutathione Transferase - biosynthesis; Glutathione Transferase - genetics; Hydroquinones - pharmacology; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinases - metabolism; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol 3-Kinases - physiology; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Rats; Response Elements - drug effects; RNA, Messenger - biosynthesis; RNA, Messenger - drug effects; Tumor Cells, Cultured
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.59.5.1147

The protective adaptive response to electrophiles and reactive oxygen species is mediated by enhanced expression of phase II detoxifying genes, including glutathione S-transferases, through activation of antioxidant response element (ARE). The current study was designed to investigate the role of phosphatidylinositol 3-kinase (PI3-kinase)-Akt and mitogen-activated protein (MAP) kinase signaling pathways in the induction of rGSTA2 by tert-butylhydroquinone (t-BHQ). Nuclear ARE complex was activated 1 to 6 h after treatment of H4IIE cells with t-BHQ. The rGSTA2 mRNA level was elevated 6 to 24 h after t-BHQ treatment, which led to the enzyme induction. Activities of PI3-kinase and Akt were increased 10 min through 6 h after t-BHQ treatment, whereas wortmannin or LY294002, PI3-kinase inhibitors, completely abolished ARE binding activity and increases in rGSTA2 mRNA and protein. Extracellular signal-regulated kinase (ERK), p38 MAP kinase, and c-Jun N-terminal kinase (JNK) were all activated by t-BHQ. Treatment with PD98059, an ERK inhibitor, however, increased rGSTA2 mRNA and further enhanced t-BHQ-induced expression of rGSTA2. Neither SB203580 nor overexpression of JNK1 dominant negative mutant altered t-BHQ-inducible rGSTA2 expression. These results demonstrated that t-BHQ activated PI3-kinase and Akt, which was responsible for ARE-mediated rGSTA2 induction, and that ERK might negatively regulate rGSTA2 expression, whereas activation of p38 MAP kinase or of JNK by t-BHQ was not associated with the enzyme induction.