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X-Irradiation, Phorbol Esters, and H₂O₂ Stimulate Mitogen-activated Protein Kinase Activity in NIH-3T3 Cells through the Formation of Reactive Oxygen Intermediates

Dana Farber Cancer Institute and Joint Center for Radiation Therapy, Harvard Medical School, Boston, Massachusetts 02115

¹ To whom requests for reprints should be addressed, at Joint Center for Radiation Therapy, Harvard Medical School, 50 Binney St., Boston, MA 02115.

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 H₂O₂. Both radiation and H₂O₂, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/ 8/93. Accepted 11/12/93.

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