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

Cell Death Differ. 2013 Feb;20(2):248-58. doi: 10.1038/cdd.2012.115. Epub 2012 Sep 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Humans
  • Hydrogen Peroxide / pharmacology*
  • I-kappa B Kinase / antagonists & inhibitors
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • MCF-7 Cells
  • Oxidative Stress / drug effects
  • Phosphorylation
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • Hydrogen Peroxide
  • Proto-Oncogene Proteins c-mdm2
  • TOR Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • I-kappa B Kinase