Transcriptional regulation of VEGFA by the endoplasmic reticulum stress transducer OASIS in ARPE-19 cells.
Transcriptional regulation of VEGFA by the endoplasmic reticulum stress transducer OASIS in ARPE-19 cells.
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ARPE-19细胞中内质网应激透射剂绿洲对VEGFA的转录调节。
DOI：
10.1371/journal.pone.0055155
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Imaizumi K
中科院分区：
文献类型：
--
作者：
Miyagi H;Kanemoto S;Saito A;Asada R;Iwamoto H;Izumi S;Kido M;Gomi F;Nishida K;Kiuchi Y;Imaizumi K
血管内皮生长因子- a （VEGFA）是血管生成的主要介质。血管生成不仅在许多生理过程中起着重要作用，而且在许多疾病的病理生理中也起着重要作用。vegf是眼部新生血管疾病的治疗靶点之一。因此，阐明VEGFA表达的调控机制对药物的开发具有重要意义。最近的研究表明，未折叠蛋白反应参与了VEGFA的转录调控。然而，VEGFA在人类视网膜中的精确调控尚不完全清楚。当人视网膜色素上皮细胞ARPE-19暴露于内质网应激源时，VEGFA mRNA显著上调。未折叠蛋白应答相关转录因子XBP1、ATF4、ATF6和OASIS在ARPE-19细胞中表达。为了确定哪些转录因子优先促进内质网应激后VEGFA表达的诱导，我们使用人类VEGFA基因约6 kbp的5 '上游区域进行了报告基因检测。在这些转录因子中，OASIS对ARPE-19细胞中VEGFA启动子的作用最为有效。基于某些缺失和突变的报告基因结构获得的数据，我们确定OASIS通过作用于相对于VEGFA转录起始位点- 500bp左右的环状amp响应元件样位点来促进VEGFA的表达。此外，我们通过染色质免疫沉淀试验证实了OASIS直接结合到含有该位点的启动子区域。我们已经证明了OASIS在人视网膜色素上皮细胞中对VEGFA转录的一种新的调控机制。调节OASIS与VEGFA基因启动子区域结合的化合物可能有潜力作为伴有新生血管形成的眼部疾病的治疗剂。
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. 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. 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.
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