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ID 36312
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title alternative
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
creator
NDC
Medical sciences
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.

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.
date of created
2014-11-21
language
eng
nii type
Thesis or Dissertation
HU type
Doctoral Theses
DCMI type
text
format
application/pdf
text version
ETD
rights
Copyright(c) by Author
relation references
Hidetaka Miyagi, Soshi Kanemoto, Atsushi Saito, Rie Asada, Hideo Iwamoto, Soutarou Izumi, Miori Kido, Fumi Gomi, Kohji Nishida, Yoshiaki Kiuchi and Kazunori Imaizumi; Transcriptional Regulation of VEGFA by the Endoplasmic Reticulum Stress Transducer OASIS in ARPE-19 Cells; PLoS ONE 8(1): e55155. (doi: 10.1371/journal.pone.0055155)
relation references URL
http://dx.doi.org/10.1371/journal.pone.0055155
grantid
甲第6399号
degreeGrantor
広島大学(Hiroshima University)
degreename Ja
博士(医学)
degreename En
Philosophy in Medical Science
degreelevel
doctoral
date of granted
2014-03-23
department
Graduate School of Biomedical Science