METALLOTHIONE EXPRESSION REGULATED BY OXIDATIVE STRESS

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DESCRIPTION Using mouse lung epithelial and macrophage cell lines, the applicant proposes three specific aims: 1) characterize the levels of Cd-induced MT protein, MT mRNA, and MT gene transcription (via transient transfection), in lung epithelial vs. macrophage cell lines; 2) identify the cis regulatory elements responsible for Cd-induced transcription, focussing on the role of both metal response elements (MREs) and antioxidant response elements (AREs); and 3) characterize the phosphorylaton state of the MRE transcription factor (MTF) isolated from Cd- or H2O2-treated, 32P-labelled cells. The research will seek to answer two basic questions: 1) Does the antioxidant response element play an important role in Cd induced MT gene expression? and 2) Might both Cd and H2O2 activate metallothionein transcription through a common pathway -- by altering the phosphorylation state of MTF? The proposed research is designed to establish mechanistic linkages between the environmental toxin Cd, metal-induced ROS production, metallothionein gene expression, and the exacerbation of lung related diseases.