Essential role of protein kinase C in silica-induced map kinase and AP-1 activation.
Ding-M; Lu-Y; Bowman-L; Castranova-V; Vallyathan-V
Toxicologist 2006 Mar; 90(1):208
Crystalline silica has long been well established as a fibrogenic agent and recent evidence has implicated it as a potential human carcinogen. However, the mechanisms of silica-induced disease development and progression are not well understood. Our previous studies demonstrated that crystalline silica is able to activate activator protein-1 (AP-1) through mitogen-activated protein kinase (MAPK) pathways. The present study investigates the possible involvement of protein kinase C (PKC) in silica-induced activation of the MAPK-AP-1 signal transduction pathway. Treatment of mouse epidermal cells (JB6 cell line) with freshly fractured silica stimulated translocation of PKCa and PKCe from the cytosol to the membrane and activated AP-1 transcription activity. Pretreatment of cells with PKC inhibitors, including RO-32-0432, calphostin C, and bisindolylmaleimide I, inhibited silica-induced AP-1 activation and phosphorylation of ERKs and p38 kinase. These inhibitory effects by PKC inhibitors were dose dependent. Furthermore, over-expression of a dominant negative mutant of PKCa or PKCe markedly blocked AP-1 activation as well as phosphorylation of ERKs and p38 kinase induced by freshly fractured silica. These results demonstrate that PKCa and PKCe are essential in silica-induced AP-1 activation through the MAP kinase (ERKs and p38 kinases) pathway.
Silica-dusts; Silicates; Silicosis; Proteins; Quartz-dust; Fibrogenicity; Fibrogenesis; Carcinogens; Carcinogenicity; Carcinogenesis
Research Tools and Approaches: Cancer Research Methods
The Toxicologist. Society of Toxicology 45th Annual Meeting and ToxExpo, March 5-9, 2006, San Diego, California