title: IKKα contributes to UVB-induced VEGF expression by regulating AP-1 transactivation.
abstract: 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.
authors.affiliation: Department of Pathophysiology, Beijing Institute of Basic Medical Sciences, Beijing 100850, P R China.
authors.forename: Wen
authors.initials: W
authors.lastname: Dong
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.forename: Meiru
authors.initials: M
authors.lastname: Hu
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Li
authors.forename: Sanyue
authors.initials: S
authors.lastname: Mai
authors.forename: Ning
authors.initials: N
authors.lastname: Guo
authors.forename: Shengtao
authors.initials: S
authors.lastname: Yuan
authors.forename: Lun
authors.initials: L
authors.lastname: Song
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D006657:Histones / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051550:I-kappa B Kinase / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D014466:Ultraviolet Rays; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D051550:I-kappa B Kinase