Tristetraprolin inhibits ras-dependent tumor vascularization by inducing vascular endothelial growth factor mRNA degradation
Tristetraprolin inhibits ras-dependent tumor vascularization by inducing vascular endothelial growth factor mRNA degradation
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DOI：
10.1091/mbc.e07-06-0570
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发表时间：
2007-11-01
影响因子：
3.3
通讯作者：
Pages, Gilles
中科院分区：
文献类型：
--
作者：
Essafi-Benkhadir, Khadija;Onesto, Cercina;Pages, Gilles
血管内皮生长因子（VEGF）是生理和病理性血管生成的重要调节因子之一。细胞外信号调节激酶（ERK）通路的组成性激活和VEGF的过表达是不同来源肿瘤的共同促发因素。我们已经建立了一个新的联系，这两个基本的观察结果收敛于VEGF mRNA的稳定性。在这种复杂的现象中，三曲脯氨酸（TTP），一种与VEGF mRNA 3 '-非翻译区结合的富含腺苷酸和尿苷酸的元素相关蛋白，通过诱导VEGF mRNA降解，从而维持正常细胞中的基础VEGF mRNA量，发挥关键作用。ERK的激活导致TTP mRNA的积累。然而，ERK降低TTP的VEGF mRNA去稳定作用，导致VEGF表达增加，有利于血管生成开关。此外，TTP降低RasVal 12依赖性VEGF表达和裸鼠血管化肿瘤的发展。因此，TTP可能代表一种新的抗血管生成和抗肿瘤剂，通过其对VEGF mRNA的去稳定活性发挥作用。TTP和ERK的检测将为评价肿瘤血管生成潜能提供有用的信息。
Vascular endothelial growth factor (VEGF) is one of the most important regulators of physiological and pathological angiogenesis. Constitutive activation of the extracellular signal-regulated kinase (ERK) pathway and overexpression of VEGF are common denominators of tumors from different origins. We have established a new link between these two fundamental observations converging on VEGF mRNA stability. In this complex phenomenon, tristetraprolin (TTP), an adenylate and uridylate-rich element-associated protein that binds to VEGF mRNA 3'-untranslated region, plays a key role by inducing VEGF mRNA degradation, thus maintaining basal VEGF mRNA amounts in normal cells. ERKs activation results in the accumulation of TTP mRNA. However, ERKs reduce the VEGF mRNA-destabilizing effect of TTP, leading to an increase in VEGF expression that favors the angiogenic switch. Moreover, TTP decreases RasVal12-dependent VEGF expression and development of vascularized tumors in nude mice. As a consequence, TTP might represent a novel antiangiogenic and antitumor agent acting through its destabilizing activity on VEGF mRNA. Determination of TTP and ERKs status would provide useful information for the evaluation of the angiogenic potential in human tumors.