IKK-ß mediates hydrogen peroxide induced cell death through p85 S6K1.

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-ß 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-ß 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-ß associated with p85, but not p70 S6K1, which was required for H(2)O(2)-induced activation of p85 S6K1. IKK-ß and p85 S6K1 contributed to H(2)O(2)-induced phosphorylation of Mdm2 (S166) and p53 accumulation. p85 S6K1 is critical for IKK-ß-mediated cell death. Thus, these findings established a novel oxidative stress-responsive pathway that involves IKK-ß, p85 S6K1 and Mdm2, which is response for H(2)O(2)-induced cell death. Our results have important implications for IKK-ß and p85 S6K1 as potential targets for the prevention of diseases involved in oxidative stress-induced aberrant cell death.