title: p85α mediates NFAT3-dependent VEGF induction in the cellular UVB response.
abstract: Exposure 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), p85α, 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 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-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 p85α in controlling VEGF induction during the cellular UVB response by regulating NFAT3 activity. Targeting p85α might be helpful for preventing UVB-induced angiogenesis and the associated photodamage.
authors: Department of Pathophysiology, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors: Wen
authors: W
authors: Dong
authors: Yi
authors: Y
authors: Li
authors: Xiaoguang
authors: X
authors: Li
authors: Meiru
authors: M
authors: Hu
authors: Aodengqimuge
authors: Li
authors: L
authors: Sun
authors: Ning
authors: N
authors: Guo
authors: Shengtao
authors: S
authors: Yuan
authors: Lun
authors: L
authors: Song
mesh_terms: D000818:Animals; D002460:Cell Line; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000235:genetics / Q000528:radiation effects; D055786:Gene Knockout Techniques; D051379:Mice; D058990:Molecular Targeted Therapy; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D012871:Skin Diseases / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D050778:NFATC Transcription Factors; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D058543:Class Ia Phosphatidylinositol 3-Kinase
keywords: NFAT3; UVB; VEGF; c-Fos; p85α