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

The I κ B kinase (IKK)/NF- κ 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- β contributed to hydrogen peroxide (H 2 O 2 )-induced cell death independent of the NF- κ B 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.