p85α mediates NFAT3-dependent VEGF induction in the cellular UVB response.

Exposure to solar ultraviolet B (UVB) radiation is known to induce multiple pathological reactions in the skin. In these processes, up-regulation of VEGF expression has been demonstrated to be important for mediating the angiogenesis-associated photodamage and even skin cancers. However, the signaling events that are responsible for VEGF induction under UVB exposure have not been fully defined. Here, we demonstrate that the regulatory subunit of the PI-3K, p85α, plays a novel role in mediating UVB-induced VEGF expression in the mouse embryonic fibroblasts (MEFs) and the mouse epithermal cells, which effect is unrelated to the PI-3K activity. The transcriptional factor NFAT3 functions as a downstream target of p85α to mediate the induction of VEGF expression in the UVB response. Although lacking NFAT3-binding ability, p85α is required for the recruitment of NFAT3 to the NFAT-responsive element within the vegf promoter. Furthermore, by identifying the adjacent NFAT- and AP-1-binding sites within the vegf promoter, we also find a induced interaction between NFAT3 and one of the AP-1 components, c-Fos, after UVB irradiation. Without the aid of c-Fos, NFAT3 lost its vegf promoter-binding ability. Taken together, our results have revealed a novel PI-3K-independent role for p85α in controlling VEGF induction during the cellular UVB response by regulating NFAT3 activity. Targeting p85α might be helpful for preventing the UVB-induced angiogenesis and the associated photodamage.