Mechanism of UV-Induced IκBα-Independent Activation of NF-κB

Nuclear factor-kappa B (NF-kappa B) plays an important role in UV-induced skin tumorigenesis. Activation of NF-kappa B by UV-irradiation is composed of two phases. The early phase culminates with maximal levels of DNA binding ability at 4 h postirradiation and is dependent on translational inhibition. The late-phase activation of NF-kappa B occurs between 16 and 48 h post-irradiation and the mechanism is not clear due to the fact that NF-kappa B was activated in the presence of high level of I kappa B alpha. In this report, we provide evidence that without translational inhibition, the transcription of I kappa B alpha was induced by UV-irradiation. In the late-phase of UV-induced NF-kappa B activation, the I kappa B alpha depletion is the combined result of regulation at both transcriptional and translational levels. Neither ubiquitination nor proteasomal degradation have detectable attributions to I kappa B alpha breakdown. We also demonstrate that UV only induced phosphorylation of p65(S276), while tumor necrosis factor-alpha induced phosphorylation at both Ser276 and 536 sites of p65. Based upon our results, we propose a novel mechanism for translation-regulated I kappa B alpha depletion and MSK-mediated NF-kappa B activation at 24 h post-UV-irradiation.