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Exposure to ultraviolet B (UVB) irradiation from sunlight induces the upregulation of VEGF, a potent angiogenic factor that is critical for mediating angiogenesis-associated photodamage. However, the molecular mechanisms related to UVB-induced VEGF expression have not been fully defined. Here, we demonstrate that one of the catalytic subunits of the IκB kinase complex (IKK), IKKα, plays a critical role in mediating UVB-induced VEGF expression in mouse embryonic fibroblasts (MEFs), which requires IKKα kinase activity but is independent of IKKβ, IKKγ and the transactivation of NF-κB. We further show that the transcriptional factor AP-1 functions as the downstream target of IKKα that is responsible for VEGF induction under UVB exposure. Both the accumulation of AP-1 component, c-Fos and the transactivation of AP-1 by UVB require the activated IKKα located within the nucleus. Moreover, nuclear IKKα can associate with c-Fos and recruit to the vegf promoter regions containing AP-1-responsive element and then trigger phosphorylation of the promoter-bound histone H3. Thus, our results have revealed a novel independent role for IKKα in controlling VEGF expression during the cellular UVB response by regulating the induction of the AP-1 component and phosphorylating histone H3 to facilitate AP-1 transactivation. Targeting IKKα shows promise for the prevention of UVB-induced angiogenesis and the associated photodamage.

No abstract

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Arsenite is a cytotoxic reagent that has been used clinically to treat certain cancers. Although the cytotoxic mechanisms of arsenite have been investigated, the cellular mechanisms that act against arsenite damage are poorly understood. Heme oxygenase 1 (HO-1) has been implicated in cellular survival under other multiple stress conditions. Here, we show that a significant induction of HO-1 expression is present in human bronchial epithelial cells (Beas-2B) treated with lethal doses of arsenite treatment. This induction depends on the known ERK/AP1 signaling pathway. As expected, HO-1 RNAi knockdown, or ERK/AP1 inhibition, renders the Beas-2B cells more sensitive to arsenite damage. Our data thus suggest that transcriptional upregulation of HO-1 expression via a putative ERK/AP-1 pathway constitutes an inherent mechanism by which arsenite-induced apoptosis is attenuated.