Involvement of cellular stress-medicated NF-kB activation in inflammation and cancer

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Tumor necrosis factor α (TNFα) activates NF-κB using the IκB kinase (IKK) complex that phosphorylates inhibitory proteins (IκBs) at N-terminal sites resulting in their ubiquitination and degradation in the cytoplasm. Ultraviolet (UV) irradiation also activates NF-κB by IκBα degradation, but its mechanism was unknown. In this study, we have revealed that, although UV does not lead to IKK activity and N-terminal phosphorylation of IκBα, IKK acts as an adaptor protein and activates NF-κB. UV irradiation induces the nuclear translocation of IκBα and association with IKKβ, which constitutively interacts with β-TrCP through heterogeneous ribonucleoprotein-U (hnRNP-U) leading to IκBα ubiquitination and degradation. NF-κB activated by the nuclear IKKβ adaptor protein suppresses anti-apoptotic gene expression and promotes UV-induced cell death. Importantly, IκBα translocates into the nucleus and associates with IKKβ and then is degraded when cells are subjected not only to UV stress but also to other types of oxidative stress.