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 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.
Stevenson
M A
MA
Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Pollock
S S
SS
Coleman
C N
CN
Calderwood
S K
SK
D016475:3T3 Cells; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013755:Tetradecanoylphorbol Acetate; D000111:Acetylcysteine