IKKα contributes to UVB-induced VEGF expression by regulating AP-1 transactivation

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 I kappa B kinase complex (IKK), IKK alpha, plays a critical role in mediating UVB-induced VEGF expression in mouse embryonic fibroblasts (MEFs), which requires IKK alpha kinase activity but is independent of IKK beta, IKK gamma and the transactivation of NF-kappa B. We further show that the transcriptional factor AP-1 functions as the downstream target of IKK alpha 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 IKK alpha located within the nucleus. Moreover, nuclear IKK alpha 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 IKK alpha 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 IKK alpha shows promise for the prevention of UVB-induced angiogenesis and the associated photodamage.