title: Transcriptional regulation of VEGFA by the endoplasmic reticulum stress transducer OASIS in ARPE-19 cells.
abstract: BACKGROUND
  Vascular endothelial growth factor-A (VEGFA) is the main mediator of angiogenesis. Angiogenesis plays important roles not only in many physiological processes, but also in the pathophysiology of many diseases. VEGFA is one of the therapeutic targets of treatment for ocular diseases with neovascularization. Therefore, elucidation of the regulatory mechanisms for VEGFA expression is important for the development of pharmaceutical drugs. Recent studies have demonstrated that the unfolded protein response is involved in the transcriptional regulation of VEGFA. However, the precise regulation of VEGFA in the human retina is not fully understood.
  
  
  RESULTS
  When human retinal pigment epithelial cells, ARPE-19, were exposed to endoplasmic reticulum stressors, VEGFA mRNA was significantly upregulated. The unfolded protein response-related transcription factors XBP1, ATF4, ATF6, and OASIS were expressed in ARPE-19 cells. To determine which transcription factors preferentially contribute to the induction of VEGFA expression after endoplasmic reticulum stress, we carried out reporter assays using an approximately 6-kbp 5'-upstream region of the human VEGFA gene. Among these transcription factors, OASIS acted most effectively on the VEGFA promoter in ARPE-19 cells. Based on data obtained for certain deleted and mutated reporter constructs, we determined that OASIS promoted VEGFA expression by acting on a cyclic AMP-responsive element-like site located at around -500 bp relative to the VEGFA transcription start site. Furthermore, we confirmed that OASIS directly bound to the promoter region containing this site by chromatin immunoprecipitation assays.
  
  
  CONCLUSIONS
  We have demonstrated a novel regulatory mechanism for VEGFA transcription by OASIS in human retinal pigment epithelial cells. Chemical compounds that regulate the binding of OASIS to the promoter region of the VEGFA gene may have potential as therapeutic agents for ocular diseases with neovascularization.
authors: Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors: Hidetaka
authors: H
authors: Miyagi
authors: Soshi
authors: S
authors: Kanemoto
authors: Atsushi
authors: A
authors: Saito
authors: Rie
authors: R
authors: Asada
authors: Hideo
authors: H
authors: Iwamoto
authors: Soutarou
authors: S
authors: Izumi
authors: Miori
authors: M
authors: Kido
authors: Fumi
authors: F
authors: Gomi
authors: Kohji
authors: K
authors: Nishida
authors: Yoshiaki
authors: Y
authors: Kiuchi
authors: Kazunori
authors: K
authors: Imaizumi
mesh_terms: D002460:Cell Line; D000242:Cyclic AMP / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D055213:Retinal Pigment Epithelium / Q000166:cytology*; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: C485618:CREB3L1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000242:Cyclic AMP
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