X-IRRADIATION, PHORBOL ESTERS, AND H2O2 STIMULATE MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVITY IN NIH-3T3 CELLS THROUGH THE FORMATION OF REACTIVE OXYGEN INTERMEDIATES

Extracellular signal-regulated kinases (ERKs), also known as mitogen-a ctivated protein (MAP) kinases, are rapidly phosphorylated and activat ed in response to a number of external factors which promote growth an d differentiation (T. G. Boulton, S. H. Nye, D. J. Robbins, N. Y. Ip, E. Radziejewska, S. D. Morgenbesser, R. A. DePinho, N. Panayotatos, M. H. Cobb, and G. D. Yancopoulos, Cell, 65: 663-675,1991; S. L. Pelech and S. S. Jasbinder, Science (Washington DC), 257: 1355-1356, 1992; G. Thomas, Cell, 68: 3-6, 1992). We have identified two novel stimulator s of MAP kinase activity, ionizing radiation and H2O2. Both radiation and H2O2, as well as the known agonist 12-O-tetradecanoylphorbol 13-ac etate activate MAP kinase through the production of reactive oxygen in termediates. Our results demonstrate a direct link between the MAP kin ase signal transduction pathway and reactive oxygen species and provid e a unifying mechanism for activation of early- and late-response gene s by inducers of oxidative stress.