Role of mitogen-activated protein kinases, early response protooncogenes, and activator protein-1 in cell signaling by asbestos

Cell signaling by pathogenic minerals may initiate the transactivation of g enes that are critical to carcinogenesis and fibroproliferative diseases of the lung and pleura. We have shown previously that stimulation of the mito gen-activated protein kinase (MAPK) cascade hi: asbestos fibers leads to ph osphorylation events involved in transactivation of Jun and Fos proteins th at comprise the activator protein-1 (AP-1) transcription factor Recently we have also used AP-1 luciferase reporter transgenic mice and immunocytochem istry to show that transactivation of AP-1 occurs in bronchiolar and alveol ar epithelial cells after inhalation of asbestos fibers. After inhalation o f asbestos, epithelial cells of the lung also show increased immunoreactivi ty of phosphorylated extracellular signal regulated kinases (ERKs 1/2) at s ites of fibrogenesis. The availability of lung epithelial cell-specific pro moters has allowed the creation of transgenic mice with mutations in the tr ansactivation domains of kev receptors and protein intermediates that compr ise the MAPK signaling cascade. These rodent models may reveal whether cell signaling events initiated by mineral dusts in epithelial cells are critic al to the development of cell proliferation, apoptosis, and lung disease.