Cell Signaling by Oxidants:Pathways Leading to Activation ofMitogen-activated Protein Kinases(MAPK) and Activator Protein-1 (AP-1)

摘要

Agents inducing oxidative stress activate one or more pathways of the Mitogen-Activated Protein Kinases (MAPK), a family of signaling proteins leading to acti-vation of the Fos/Jun protooncogene family that comprise the Activator Protein-1(AP-1) transcription factor. Redox sensitive molecular targets usually containhighly conserved cysteine residues, and their oxidation, nitration and formationof disulfide links are crucial events in oxidant/redox signaling. Oxidation of sul-fide groups in signaling proteins causes structural modifications, resulting in theexposure of active sites and protein activation. Thiol proteins such as intracellularglutathione (GSH) and thioredoxin (Trx) are of central importance in the regulated control of redox signaling pathways by reducing disulfide bridges or oxidized cys-teine residues. We review here how oxidants interact with membrane receptors,other proteins, and Mitogen-Activated Protein Kinase Phosphatases (MKPs) toactivate MAPK and AP-1 regulated gene expression critical to cell differentiation,proliferation, death/apoptosis, and disease. These pathways have been studied ex-tensively in cells in culture after exposure to H_2O_2, generating systems of reactiveoxygen or nitrogen species (ROS/NOS), and a number of naturally occurring oxi-dant stresses such as chemotherapeutic drugs or airborne pollutants. The epithelialcell of the respiratory tract and inhalation models of lung injury, inflammation,carcinogenesis, and fibrogenesis have been employed by us and others to studyMAPK and AP-1 activation by soluble oxidants and insoluble particulates (as-bestos, silica, particulate matter or PM) inducing oxidative stress. Responses ofcells to these oxidant stresses are critical to injury or repair, inflammation, andcritical outcomes of disease.