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

Citation
Kw. Kang et al., Activation of phosphatidylinositol 3-kinase and Akt by tert-butylhydroquinone is responsible for antioxidant response element-mediated rGSTA2 induction in H4IIE cells, MOLEC PHARM, 59(5), 2001, pp. 1147-1156
Citations number
38
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
MOLECULAR PHARMACOLOGY
ISSN journal
0026-895X → ACNP
Volume
59
Issue
5
Year of publication
2001
Pages
1147 - 1156
Database
ISI
SICI code
0026-895X(200105)59:5<1147:AOP3AA>2.0.ZU;2-7
Abstract
The protective adaptive response to electrophiles and reactive oxygen speci es is mediated by enhanced expression of phase II detoxifying genes, includ ing glutathione S-transferases, through activation of antioxidant response element (ARE). The current study was designed to investigate the role of ph osphatidylinositol 3-kinase (PI3-kinase)-Akt and mitogen-activated protein (MAP) kinase signaling pathways in the induction of rGSTA2 by tert-butylhyd roquinone (t-BHQ). Nuclear ARE complex was activated 1 to 6 h after treatme nt 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, wh ereas wortmannin or LY294002, PI3-kinase inhibitors, completely abolished A RE 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 inhibito r, however, increased rGSTA2 mRNA and further enhanced t-BHQ-induced expres sion of rGSTA2. Neither SB203580 nor overexpression of JNK1 dominant negati ve mutant altered t-BHQ-inducible rGSTA2 expression. These results demonstr ated that t-BHQ activated PI3-kinase and Akt, which was responsible for ARE -mediated rGSTA2 induction, and that ERK might negatively regulate rGSTA2 e xpression, whereas activation of p38 MAP kinase or of JNK by t-BHQ was not associated with the enzyme induction.