Abstract
Lead compounds are potent human carcinogens. Lead exposure has been highly associated with kidney, brain and lung cancers. Moreover, Pb(II) can induce reactive oxygen species (ROS) formation causing DNA strand breakage and damaging cells. Pb(II) persistently activates ERK1/2 signaling pathway that enhances nucleotide excision repair synthesis and confers anti-cytotoxicity and anti-mutagenicity in human non-small cell lung adenocarcinoma CL3 cells. Several reports have indicated that alteration of cellular ROS levels can affect numerous signal transduction pathways and gene expressions; also, modulating the expression of antioxidant enzymes may antagonize cellular ROS levels. However, little is known about how the expression of antioxidant enzymes is regulated by specific signaling molecules. In this thesis, we investigate the role of ERK1/2 activated persistently by Pb(II) in regulating the expression of SOD2, CAT and GPX1 in CL3 cells. By inhibition of MKK1/2-ERK1/2 signal pathway, we discover that ERK1/2 signal can increase SOD2, decrease CAT protein expression, and induce ubiqutin-directed 26S proteolysis pathway to degrade GPX1 protein. Furthermore, over-expressing MKK1-ERK1/2 in H293 cells can increase SOD2 and decrease GPX1 protein levels. Taken together, the present study demonstrates for the first time that ERK1/2 can regulate the expression of antioxidant enzymes that may modulate cellular ROS levels. This may provide a novel concept for future researches.