p85  mediates NFAT3-dependent VEGF induction in the cellular UVB response

Abstract

SummaryExposure to solar ultraviolet B (UVB) radiation is known to induce several pathological reactions in the skin. In these processes, upregulation of VEGF expression has been demonstrated to be important in 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 phosphoinositide 3-kinase (PI3K), p85a, plays a role in mediating UVB-induced VEGF expression in mouse embryonic fibroblasts (MEFs) and mouse epithermal cells, the effect of which is unrelated to the PI3K activity. The transcriptional factor NFAT3 functions as a downstream target of p85a to mediate the induction of VEGF expression in the UVB response. Although lacking NFAT3-binding ability, p85a is required for the recruitment of NFAT3 to the NFAT-response element within the vegf promoter. Furthermore, by identifying the adjacent NFAT-and AP-1-binding sites within the vegf promoter, we also found an 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 reveal a novel PI3K-independent role for p85a in controlling VEGF induction during the cellular UVB response by regulating NFAT3 activity. Targeting p85a might be helpful for preventing UVBinduced angiogenesis and the associated photodamage.

Nuclear Factor of Activated T Cells Is Activated in the Endothelium of Retinal Microvessels in Diabetic Mice

“…However, recent in vivo kinetic data show that the retinal barrier function is compromised before VEGF levels are increased and use of a neutralizing anti-VEGF antibody is not effective at reducing permeability at early stages of diabetes (8 weeks) [ 15 ]. In the context of angiogenesis [ 16 , 17 ], VEGF appears to be an upstream activator of NFAT, but both VEGF and its receptor VEGFR2 are also downstream targets of NFAT in endothelial cells [ 18 , 19 ]. Hence, a role of NFAT in the early changes of DR cannot be ruled out.…”