title: Methionine restriction up-regulates the expression of the pi class of glutathione S-transferase partially via the extracellular signal-regulated kinase-activator protein-1 signaling pathway initiated by glutathione depletion.
abstract: Understanding the molecular events underlying gene regulation by amino acids has attracted increasing attention. Here, we explored whether the mechanism by which methionine restriction affects the expression of the pi class of glutathione S-transferase (GSTP) is related to oxidative stress initiated by glutathione (GSH) depletion. Rat primary hepatocytes were cultured in an L-15-based medium in the absence or presence of 200 muM L-buthionine sulfoximine (BSO) or in a methionine-restricted L-15 medium supplemented with 20 muM L-methionine up to 72 h. BSO and methionine restriction time-dependently induced GSTP mRNA and protein expression in a similar pattern accompanied by a decrease in the cellular GSH level. The phosphorylation of extracellular signal-regulated kinase (ERK), but not of c-Jun NH(2)-terminal kinase and p38, was stimulated by methionine restriction and BSO. Electromobility gel shift assay showed that the DNA-binding activity of nuclear activator protein-1 (AP-1) increased in cells exposed to methionine restriction or BSO. With the ERK inhibitor FR180204, AP-1 activation and GSTP expression were abolished. Moreover, the induction of GSTP by methionine restriction and BSO was reversed by GSH monoethyl ester and N-acetylcysteine. Our results suggest that methionine restriction up-regulates GSTP gene expression, which appears to be initiated by the ERK-AP-1 signaling pathway through GSH depletion in rat hepatocytes.
authors.affiliation: Department of Nutrition, China Medical University, Taichung, Taiwan.
authors.forename: Chia-Wen
authors.initials: CW
authors.lastname: Tsai
authors.forename: Ai-Hsuan
authors.initials: AH
authors.lastname: Lin
authors.forename: Tsung-Shing
authors.initials: TS
authors.lastname: Wang
authors.forename: Kai-Li
authors.initials: KL
authors.lastname: Liu
authors.forename: Haw-Wen
authors.initials: HW
authors.lastname: Chen
authors.forename: Chong-Kuei
authors.initials: CK
authors.lastname: Lii
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005978:Glutathione / Q000032:analysis / Q000378:metabolism*; D051549:Glutathione S-Transferase pi / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D008297:Male; D008715:Methionine / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D019328:Buthionine Sulfoximine; D008715:Methionine; D051549:Glutathione S-Transferase pi; D048049:Extracellular Signal-Regulated MAP Kinases; D005978:Glutathione