Activation of phosphatidylinositol 3-kinase and Akt by tert-butylhydroquinone is responsible for antioxidant response element-mediated rGSTA2 induction in H4IIE cells.
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.
Kang
K W
KW
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
Cho
M K
MK
Lee
C H
CH
Kim
S G
SG
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000235:genetics; D006873:Hydroquinones / Q000494:pharmacology*; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D020218:Response Elements / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D000975:Antioxidants; D005982:Glutathione Transferase; D006873:Hydroquinones; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases; C018855:2-tert-butylhydroquinone; C494920:Akt1 protein, rat