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相关转录增强因子-1 同工型 TEAD4(216) 可在哺乳动物细胞中抑制血管内皮生长因子的表达。

The related transcriptional enhancer factor-1 isoform, TEAD4(216), can repress vascular endothelial growth factor expression in mammalian cells.

机构信息

Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, United States of America.

出版信息

PLoS One. 2012;7(6):e31260. doi: 10.1371/journal.pone.0031260. Epub 2012 Jun 22.

DOI:10.1371/journal.pone.0031260
PMID:22761647
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3382240/
Abstract

Increased cellular production of vascular endothelial growth factor (VEGF) is responsible for the development and progression of multiple cancers and other neovascular conditions, and therapies targeting post-translational VEGF products are used in the treatment of these diseases. Development of methods to control and modify the transcription of the VEGF gene is an alternative approach that may have therapeutic potential. We have previously shown that isoforms of the transcriptional enhancer factor 1-related (TEAD4) protein can enhance the production of VEGF. In this study we describe a new TEAD4 isoform, TEAD4(216), which represses VEGF promoter activity. The TEAD4(216) isoform inhibits human VEGF promoter activity and does not require the presence of the hypoxia responsive element (HRE), which is the sequence critical to hypoxia inducible factor (HIF)-mediated effects. The TEAD4(216) protein is localized to the cytoplasm, whereas the enhancer isoforms are found within the nucleus. The TEAD4(216) isoform can competitively repress the stimulatory activity of the TEAD4(434) and TEAD4(148) enhancers. Synthesis of the native VEGF(165) protein and cellular proliferation is suppressed by the TEAD4(216) isoform. Mutational analysis indicates that nuclear or cytoplasmic localization of any isoform determines whether it acts as an enhancer or repressor, respectively. The TEAD4(216) isoform appears to inhibit VEGF production independently of the HRE required activity by HIF, suggesting that this alternatively spliced isoform of TEAD4 may provide a novel approach to treat VEGF-dependent diseases.

摘要

血管内皮生长因子（VEGF）的细胞产生增加是多种癌症和其他新血管条件发展和进展的原因，针对翻译后 VEGF 产物的治疗方法用于这些疾病的治疗。开发控制和修饰 VEGF 基因转录的方法是一种替代方法，可能具有治疗潜力。我们之前已经表明，转录增强因子 1 相关（TEAD4）蛋白的异构体可以增强 VEGF 的产生。在这项研究中，我们描述了一种新的 TEAD4 异构体，TEAD4(216)，它抑制 VEGF 启动子活性。TEAD4(216) 异构体抑制人 VEGF 启动子活性，并且不需要缺氧反应元件（HRE）的存在，HRE 是缺氧诱导因子（HIF）介导的作用的关键序列。TEAD4(216) 蛋白定位于细胞质，而增强子异构体存在于核内。TEAD4(216) 异构体可以竞争性地抑制 TEAD4(434)和 TEAD4(148)增强子的刺激活性。天然 VEGF(165)蛋白的合成和细胞增殖受到 TEAD4(216)异构体的抑制。突变分析表明，任何异构体的核或细胞质定位分别决定其是作为增强子还是抑制剂起作用。TEAD4(216) 异构体似乎独立于 HIF 所需的 HRE 抑制 VEGF 产生，这表明 TEAD4 的这种选择性剪接异构体可能为治疗 VEGF 依赖性疾病提供一种新方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/0ab718d07459/pone.0031260.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/a7a9106a19fc/pone.0031260.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/347ac1a1547d/pone.0031260.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/13e2bc32a141/pone.0031260.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/6cd327518401/pone.0031260.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/4f2e641f3890/pone.0031260.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/8dabf16ac28a/pone.0031260.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/7a36d78a944d/pone.0031260.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/b79094da00ad/pone.0031260.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/2f0a2930dc8a/pone.0031260.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/0ab718d07459/pone.0031260.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/a7a9106a19fc/pone.0031260.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/347ac1a1547d/pone.0031260.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/13e2bc32a141/pone.0031260.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/6cd327518401/pone.0031260.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/4f2e641f3890/pone.0031260.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/8dabf16ac28a/pone.0031260.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/7a36d78a944d/pone.0031260.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/b79094da00ad/pone.0031260.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/2f0a2930dc8a/pone.0031260.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/39a0/3382240/0ab718d07459/pone.0031260.g010.jpg

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