Involvement of glutathione in induction of c-jun proto-oncogene by methylmethanesulfonate in NIH 3T3 cells.
The c-jun proto-oncogene plays a vital role in the carcinogenic process. Although numerous works have extensively investigated the induction mechanisms of c-jun by UV, hydrogen peroxide or 12-O-tetradecanoylphorbol-13-acetate, the mechanism induced by alkylating agents has received little attention. In this study, NIH 3T3 cells were exposed to methylmethanesulfonate (MMS), revealing that the agent clearly induced c-jun expression with a peak at 2 h. Pretreatment of cells with various kinase inhibitors, e.g. H7, genistein, herbimycin A and tyrphostin, did not show any significant effects on the MMS-induced c-jun expression. Benzamide, an inhibitor of poly(ADP)-ribosylation, enhanced the MMS-induced DNA breakages, but did not potentiate that agent which elicited c-jun expression. Another experiment showed that this agent transfected and overexpressed an activated v-H-ras gene in NIH 3T3 cells, which became more resistant to MMS-induced DNA damage but expressed the same level of c-jun transcript as compared with NIH 3T3 cells in response to MMS. If intracellular glutathione (GSH) was completely depleted by buthionine sulfoximine (BSO), the MMS-elicited c-jun expression was blocked. Subsequently, re-elevating intracellular GSH by washing off BSO caused the expression of c-jun by MMS to increase proportionately. Based on these findings, we can conclude that the mechanism by which MMS induced c-jun expression does not occur through activation of protein tyrosine kinases or initiation of DNA damage, but is closely related to the intracellular GSH.
Kuo
M L
ML
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei.
Meng
T C
TC
Lin
J K
JK
D016475:3T3 Cells; D000818:Animals; D004249:DNA Damage / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007700:Kinetics; D008741:Methyl Methanesulfonate / Q000494:pharmacology*; D051379:Mice; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D008741:Methyl Methanesulfonate; D006861:Hydrogen Peroxide; D005978:Glutathione; D013755:Tetradecanoylphorbol Acetate