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

Abstract

The IjB kinase (IKK)/NF-jB 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-b contributed to hydrogen peroxide (H 2 O 2 )-induced cell death independent of the NF-jB pathway. Our results demonstrated that the pro-death function of IKK-b 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-b associated with p85, but not p70 S6K1, which was required for H 2 O 2 -induced activation of p85 S6K1. IKK-b and p85 S6K1 contributed to H 2 O 2 -induced phosphorylation of Mdm2 (S166) and p53 accumulation. p85 S6K1 is critical for IKK-b-mediated cell death. Thus, these findings established a novel oxidative stress-responsive pathway that involves IKK-b, p85 S6K1 and Mdm2, which is response for H 2 O 2 -induced cell death. Our results have important implications for IKK-b and p85 S6K1 as potential targets for the prevention of diseases involved in oxidative stress-induced aberrant cell death. Reactive oxygen species (ROS), such as hydrogen peroxide (H 2 O 2 ), are generated in cells as a consequence of oxidative metabolism. Although low levels of ROS are usually detoxified quickly by antioxidant enzymes, an excessive accumulation of ROS may result in oxidative stress. High and/or persistent levels of oxidative stress represent a major cause of cellular damage and aberrant death in a plethora of pathological conditions during the initiation and progression of a plethora of pathological conditions, including neurodegenerative diseases, cancer, autoimmune and the ageing process.1 While ROS may trigger cell death through multiple mechanisms, 2 recent studies have established the nuclear factor-kB (NF-kB) pathway as a critical signaling pathway in mediating the action of ROS in cell survival/cell death.

Loss of IKKβ but Not NF-κB p65 Skews Differentiation towards Myeloid over Erythroid Commitment and Increases Myeloid Progenitor Self-Renewal and Functional Long-Term Hematopoietic Stem Cells

“…Protection from apoptosis is explained in part by the increased levels of Mcl1, whose expression in hematopoietic stem cells is critical [ 54 , 55 ], and increased Bcl-xL. IKKβ may partly regulate apoptosis in an NF-κB independent manner, for example, it mediates oxidative stress induced apoptosis through association with p85 S6K1, phosphorylation of Mdm2, and accumulation of p53 [ 56 ]. Absence of these pathways may explain the different antiapoptotic phenotype in IKKβ Δ/Δ versus p65 deficient marrow cells and may contribute to their different HSC phenotypes, Interestingly, IKKβ-deletion is also associated with decreased apoptosis in MEPs suggesting that resistance to apoptosis plays only a limited role in IKKβ Δ/Δ - associated erythroid defect.…”

mTORC1 regulates PTHrP to coordinate chondrocyte growth, proliferation and differentiation

“…Immunoblotting was performed as described in our previous studies 50 . To lyse cartilage, tissue was frozen and ground into a powder using liquid nitrogen in a mortar.…”

The IκB kinase complex in NF ‐κB regulation and beyond

“…IKKβ phosphorylates the BH3‐only protein BAD at serine‐26 (Ser26), which primes it for inactivation and suppresses TNFα‐induced apoptosis . In response to oxidative stress, however, IKKβ mediates pro‐apoptotic functions through the activation of p85 S6K1 . The IKK complex also has a direct role in the induction of autophagy .…”