title: IKK-β mediates hydrogen peroxide induced cell death through p85 S6K1.
abstract: The IκB kinase (IKK)/NF-κB pathway has been shown to be a major regulator in cell survival. However, the mechanisms through which IKK mediates cell death are not clear. In this study, we showed that IKK-β contributed to hydrogen peroxide (H(2)O(2))-induced cell death independent of the NF-κB pathway. Our results demonstrated that the pro-death function of IKK-β under oxidative stress was mediated by p85 S6K1 (S6 kinase 1), but not p70 S6K1 through a rapamycin-insensitive and mammalian target of rapamycin complex 1 kinase-independent mechanism. We found that IKK-β associated with p85, but not p70 S6K1, which was required for H(2)O(2)-induced activation of p85 S6K1. IKK-β and p85 S6K1 contributed to H(2)O(2)-induced phosphorylation of Mdm2 (S166) and p53 accumulation. p85 S6K1 is critical for IKK-β-mediated cell death. Thus, these findings established a novel oxidative stress-responsive pathway that involves IKK-β, p85 S6K1 and Mdm2, which is response for H(2)O(2)-induced cell death. Our results have important implications for IKK-β and p85 S6K1 as potential targets for the prevention of diseases involved in oxidative stress-induced aberrant cell death.
authors.affiliation: Department of Cell Biology, Southern Medical University, Guangzhou 510515, China.
authors.forename: C-H
authors.initials: CH
authors.lastname: Jia
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: L
authors.initials: L
authors.lastname: Zhao
authors.forename: J
authors.initials: J
authors.lastname: Lin
authors.forename: P-L
authors.initials: PL
authors.lastname: Lai
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: Z-G
authors.initials: ZG
authors.lastname: Chen
authors.forename: H-Y
authors.initials: HY
authors.lastname: Li
authors.forename: A-L
authors.initials: AL
authors.lastname: Liu
authors.forename: C-L
authors.initials: CL
authors.lastname: Yang
authors.forename: T-M
authors.initials: TM
authors.lastname: Gao
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.forename: X-C
authors.initials: XC
authors.lastname: Bai
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; D051736:Proto-Oncogene Proteins c-mdm2; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D051550:I-kappa B Kinase