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J Biol Chem, Vol. 274, Issue 46, 32596-32602, November 12, 1999

Hydrogen Peroxide Activates p70^S6k Signaling Pathway

Gyu-Un Bae, Dong-Wan Seo, Hyoung-Keun Kwon, Hoi Young Lee^§, Sungyoul Hong^¶, Zee-Won Lee, Kwon-Soo Ha, Hyang-Woo Lee, and Jeung-Whan Han

From the  Department of Biochemistry, College of Pharmacy, and the ^¶ Department of Genetic Engineering, College of Life Science and Natural Resources, Sungkyunkwan University, Suwon 440-746, Korea, the ^§ Department of Pharmacology, College of Medicine, Konyang University, Nonsan 320-711, Korea, and the  Biomolecule Research Group, Korea Basic Science Institute, Taejon 305-333, Korea

We investigated a possible role of reactive oxygen species (ROS) in p70^S6k activation, which plays an important role in the progression of cells from G₀/G₁ to S phase of the cell cycle by translational up-regulation of a family of mRNA transcripts that encode for components of the protein synthetic machinery. Treatment of mouse epidermal cell JB6 with H₂O₂ generated extracellularly by glucose/glucose oxidase led to the activation of p70^S6k and p90^Rsk and to phosphorylation of p42^MAPK/p44^MAPK. The activation of p70^S6k and p90^Rsk was dose-dependent and transient, maximal activities being in extracts treated for 15 and 30 min, respectively. Further characterization of ROS-induced activation of p70^S6k using specific inhibitors for p70^S6k signaling pathway, rapamycin, and wortmannin revealed that ROS acted upstream of the rapamycin-sensitive component FRAP/RAFT and wortmannin-sensitive component phosphatidylinositol 3-kinase, because both inhibitors caused the inhibition of ROS-induced p70^S6k activity. In addition, Ca²⁺ chelation also inhibited ROS-induced activation of p70^S6k, indicating that Ca²⁺ is a mediator of p70^S6k activation by ROS. However, down-regulation of 12-O-tetradecanoylphorbol-13-acetate (TPA)-responsive protein kinase C (PKC) by chronic pretreatment with TPA or a specific PKC inhibitor Ro-31-8220 did not block the activation of p70^S6k by ROS, indicating that the activation of TPA-responsive PKC was not required for stimulation of p70^S6k activity by H₂O₂ in JB6 cells. Exposure of JB6 cells to platelet-derived growth factor or epidermal growth factor led to a rapid increase in H₂O₂, phosphorylation, and activation of p70^S6k, which were antagonized by the pretreatment of catalase. Taken together, the results suggest that ROS act as a messenger in growth factor-induced p70^S6k signaling pathway.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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