The Redox Active Components H₂0₂ and N-AcetyI-L-Cysteine Regulate Expression of c-jun and c-fos in Lens Systems

Abstract

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 μM), genistein (2 μM) 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.