IKK-β mediates hydrogen peroxide induced cell death through p85 S6K1

The I kappa B kinase (IKK)/NF-kappa B 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-beta contributed to hydrogen peroxide (H2O2)induced cell death independent of the NF-kappa B pathway. Our results demonstrated that the pro-death function of IKK-beta 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-beta associated with p85, but not p70 S6K1, which was required for H2O2-induced activation of p85 S6K1. IKK-beta and p85 S6K1 contributed to H2O2-induced phosphorylation of Mdm2 (S166) and p53 accumulation. p85 S6K1 is critical for IKK-beta-mediated cell death. Thus, these findings established a novel oxidative stress-responsive pathway that involves IKK-beta, p85 S6K1 and Mdm2, which is response for H2O2-induced cell death. Our results have important implications for IKK-beta and p85 S6K1 as potential targets for the prevention of diseases involved in oxidative stress-induced aberrant cell death. Cell Death and Differentiation (2013) 20, 248-258; doi:10.1038/cdd.2012.115; published online 7 September 2012