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-activated protein (MAP) kinases, are rapidly phosphorylated and activated in response to a number of external factors which promote growth and 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 stimulators of MAP kinase activity, ionizing radiation and H202. Both radiation and H202, as well as the known agonist 12-O-tetradecanoylphorbol 13-acetate activate MAP kinase through the production of reactive oxygen intermediates. Our results demonstrate a direct link between the MAP kinase signal transduction pathway and reactive oxygen species and provide a unifying mechanism for activation of early- and late-response genes by inducers of oxidative stress.