Protein kinase C δ activates IκB-kinase α to induce the p53 tumor suppressor in response to oxidative stress

Protein kinase C δ (PKCδ) functions as a redox-sensitive kinase in various cell types. Upon exposure to reactive oxygen species (ROS), it is activated by tyrosine phosphorylation, nuclear translocation and caspase-3-mediated cleavage. Activated PKCδ is associated with cell cycle arrest or apoptosis, although its precise mechanism of action is unclear. Previous studies have demonstrated that the transcription factor, nuclear factor κB (NF-κB), functions as a redox-sensitive factor. ROS induce NF-κB signaling pathways including upstream IκB kinases (IKKs), although the mechanisms of ROS-induced activation of IKKs are unknown. Here we show that both PKCδ and IKKα, but not IKKβ, translocate to the nucleus in response to oxidative stress. The results also demonstrate that PKCδ interacts with and activates IKKα. Importantly, our data suggest that, upon exposure to oxidative stress, PKCδ-mediated IKKα activation does not contribute to NF-κB activation; instead, nuclear IKKα regulates the transcription activity of the p53 tumor suppressor by phosphorylation at Ser20. These findings collectively support a novel mechanism in which the PKCδ → IKKα signaling pathway contributes to ROS-induced activation of the p53 tumor suppressor.