Department of Pathophysiology, Beijing Institute of Basic Medical Sciences, Beijing 100850, P R China.
Nucleic Acids Res. 2012 Apr;40(7):2940-55. doi: 10.1093/nar/gkr1216. Epub 2011 Dec 14.
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.
暴露于阳光中的紫外线 B（UVB）辐射会诱导 VEGF 的上调，VEGF 是一种有效的血管生成因子，对于介导与血管生成相关的光损伤至关重要。然而，与 UVB 诱导的 VEGF 表达相关的分子机制尚未完全确定。在这里，我们证明 IκB 激酶复合物（IKK）的一个催化亚基 IKKα 在介导 UVB 诱导的小鼠胚胎成纤维细胞（MEFs）中的 VEGF 表达中起着关键作用，这需要 IKKα 激酶活性，但不依赖于 IKKβ、IKKγ 和 NF-κB 的转录激活。我们进一步表明，转录因子 AP-1 是 IKKα 的下游靶标，负责在 UVB 暴露下诱导 VEGF。AP-1 成分 c-Fos 的积累和 UVB 对 AP-1 的转录激活都需要位于核内的激活的 IKKα。此外，核 IKKα 可以与 c-Fos 结合，并募集到含有 AP-1 反应元件的 vegf 启动子区域，然后触发结合在启动子上的组蛋白 H3 的磷酸化。因此，我们的研究结果揭示了 IKKα 在通过调节 AP-1 成分的诱导和组蛋白 H3 的磷酸化来促进 AP-1 转录激活来控制细胞对 UVB 反应中的 VEGF 表达方面的新的独立作用。靶向 IKKα 有望预防 UVB 诱导的血管生成和相关的光损伤。
