Transcriptional Regulation of VEGFA by the Endoplasmic Reticulum Stress Transducer OASIS in ARPE-19 Cells

• Material Type: 博士論文
• Title: Transcriptional Regulation of VEGFA by the Endoplasmic Reticulum Stress Transducer OASIS in ARPE-19 Cells
• Author/Editor: Miyagi, Hidetaka
• Author Heading: Miyagi, Hidetaka
• Alternative Title: ヒト網膜色素上皮細胞ARPE-19における、小胞体ストレス変換分子OASISによる血管内皮増殖因子VEGFAの転写制御
• Degree grantor/type: 広島大学(Hiroshima University)
• Date Granted: 2014-03-23
• Dissertation Number: 甲第6399号
• Degree Type: 博士(医学)
• Text Language Code: eng
• NDC: 490
• Target Audience: 一般
• Note (General): type:text; 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. Principal Findings: 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 59-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 and Significance: 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.
• Format (IMT): application/pdf
• Source: fulltext; http://ir.lib.hiroshima-u.ac.jp/files/public/3/36312/20141121020317693384/k6399_3.pdf; http://ir.lib.hiroshima-u.ac.jp/files/public/3/36312/20181127112154878646/k6399_1.pdf; http://ir.lib.hiroshima-u.ac.jp/files/public/3/36312/20181127112155548268/K6399_2.pdf
• Access Restrictions: インターネット公開
• Rights (production): Copyright(c) by Author
• References (URI): URI; http://dx.doi.org/10.1371/journal.pone.0055155
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 広島大学 : 広島大学学術情報リポジトリ