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Ultraviolet-induced Phosphorylation of p70^S6K at Thr³⁸⁹ and Thr⁴²¹/Ser⁴²⁴ Involves Hydrogen Peroxide and Mammalian Target of Rapamycin but not Akt and Atypical Protein Kinase C¹

Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987 [C. H., J. L., Q. K., M. C.]; Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505 [S. S. L., V. C., X. S.]; and MBR Cancer Center, Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia 26506 [B-H. J., X-S. Z.]

The p70 S6 kinase (p70^S6k) is a Ser/Thr kinase that plays an important role in cell growth, transformation, and the transition of the cell cycle in mammalian cells. Because UV radiation has been reported to induce activation of p70^S6k, which is believed to play some role in the carcinogenic effects of sun exposure, the present study investigated the signaling pathways involved in this activation induced by UV radiation in mouse epidermal JB6 Cl41 cells. Exposure of cells to UV radiation led to marked increases in p70^S6k activity and phosphorylation at Thr³⁸⁹ and Thr⁴²¹/Ser⁴²⁴. UV radiation also generated reactive oxygen species as measured by electron spin resonance and by H₂O₂ and O₂ fluorescence staining assays in JB6 Cl 41 cells. The scavenging of UV-generated H₂O₂ by N-acety-L-cyteine (a general antioxidant) or catalase (a specific H₂O₂ scavenger) inhibited p70^S6k phosphorylation at Thr³⁸⁹ and Thr⁴²¹/Ser⁴²⁴, whereas pretreatment of cells with sodium formate (an ·OH radical scavenger) or superoxide dismutase (an O₂ radical scavenger) did not show any inhibitory effects. Importantly, UV-induced increases in p70^S6k phosphorylation at Thr³⁸⁹ and Thr⁴²¹/Ser⁴²⁴ were dramatically inhibited by pretreatment of cells with rapamycin, LY294002, or PD98059, whereas overexpression of dominant-negative mutants of PKC/ and Akt1 did not inhibit p70^S6k phosphorylation at Thr³⁸⁹ and Thr⁴²¹/Ser⁴²⁴. These results demonstrated that H₂O₂, phosphatidylinositol 3-kinase, and mammalian target of rapamycin were important players for UV-induced p70^S6k phosphorylation at Thr³⁸⁹ and Thr⁴²¹/Ser⁴²⁴, whereas Akt and atypical protein kinase C were not involved in this activation. The role of H₂O₂ in p70^S6k phosphorylation at Thr³⁸⁹ and Thr⁴²¹/Ser⁴²⁴ was further supported by the findings that treatment of cells with H₂O₂ also caused p70^S6k phosphorylation at Thr³⁸⁹ and Thr⁴²¹/Ser⁴²⁴.

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