The redox active components H2O2 and N-acetyl-L-cysteine regulate expression of c-jun and c-fos in lens systems.
Hydrogen peroxide (H2O2) is implicated in human cataract development. At the molecular level H2O2 has been observed to cause damage to DNA, protein and lipid. It is now demonstrated, for the first time in a lens system, that H2O2 at concentrations found in cataract patients induces expression of both c-jun and c-fos. At optimal concentrations of H2O2, mRNA accumulation of c-jun and c-fos in the rat lenses is induced 20- and 18-fold above normal levels respectively, but with distinct kinetics. This induction occurs at the transcriptional level. H2O2 also induces transactivation by activating protein-1 (AP-1) in rabbit lens epithelial cells. The antioxidant N-acetyl-cysteine (NAC) has a dual effect on the induction of c-jun and c-fos. Preincubation of rat lenses with 5 mM NAC inhibits the induction by H2O2, while 30 mM and 50 mM NAC induce expression of these genes and mask the H2O2 effect. H7 (50 microM), genistein (2 microM) and okadaic acid (20 nM), all block the induction of c-jun and c-fos mRNA accumulation in the H2O2-treated rat lenses. These results suggest that H2O2 activates protein kinase and phosphatase dependent signal transduction pathways to induce c-jun and c-fos expression which may regulate lens crystallin genes and other genes containing AP-1 binding sites.
Department of Ophthalmology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
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D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D002386:Cataract / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005786:Gene Expression Regulation; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007908:Lens, Crystalline / Q000378:metabolism*; D010084:Oxidation-Reduction; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000096:biosynthesis; D015533:Transcriptional Activation
D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D006861:Hydrogen Peroxide; D010749:Phosphoprotein Phosphatases; D000111:Acetylcysteine