in mammalian
in mammalian
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2012
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相关的转录增强因子-1亚型TEAD 4（216）可抑制血管内皮生长因子表达细胞。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生血管疾病的发生和进展的原因，靶向VEGF翻译后产物的治疗用于治疗这些疾病。开发控制和修饰VEGF基因转录的方法是可能具有治疗潜力的替代方法。我们以前已经表明，转录增强因子1相关（TEAD 4）蛋白的亚型可以增强VEGF的产生。在这项研究中，我们描述了一个新的TEAD 4亚型，TEAD 4 216，它抑制VEGF启动子活性。TEAD 4 216同种型抑制人VEGF启动子活性，并且不需要缺氧反应元件（HRE）的存在，缺氧反应元件（HRE）是缺氧诱导因子（HIF）介导的效应的关键序列。TEAD 4 216蛋白定位于细胞质，而增强子同种型在细胞核内发现。TEAD 4 216同种型可竞争性抑制TEAD 4 434和TEAD 4 148增强子的刺激活性。天然VEGF 165蛋白的合成和细胞增殖被TEAD 4 216同种型抑制。突变分析表明，核或细胞质定位的任何亚型决定了它是否作为一个增强子或阻遏物，分别。TEAD 4 216同种型似乎独立于HRE所需的HIF活性而抑制VEGF的产生，这表明TEAD 4的这种可变剪接同种型可能提供治疗VEGF依赖性疾病的新方法。
The related transcriptional enhancer factor-1 isoform, TEAD4(216), can repress vascular endothelial growth factor expression cells. 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.