Essafi-Benkhadir Khadija, Onesto Cercina, Stebe Emmanuelle, Moroni Christoph, Pagès Gilles
Unité Mixte de Recherche Centre National de la Recherche Scientifique 6543, University of Nice-Sophia Antipolis, Equipe Labellisée Ligue Nationale Contre le Cancer, 06189 Nice Cedex, France.
Mol Biol Cell. 2007 Nov;18(11):4648-58. doi: 10.1091/mbc.e07-06-0570. Epub 2007 Sep 12.
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.
血管内皮生长因子（VEGF）是生理和病理血管生成最重要的调节因子之一。细胞外信号调节激酶（ERK）通路的组成性激活和VEGF的过表达是不同起源肿瘤的共同特征。我们在VEGF mRNA稳定性这一共同基础上建立了这两个基本观察结果之间的新联系。在这一复杂现象中，富含腺苷酸和尿苷酸元件的结合蛋白锌指蛋白36（TTP）通过与VEGF mRNA的3'非翻译区结合，诱导VEGF mRNA降解，从而在正常细胞中维持基础VEGF mRNA水平，发挥关键作用。ERK的激活导致TTP mRNA的积累。然而，ERK降低了TTP对VEGF mRNA的去稳定作用，导致VEGF表达增加，有利于血管生成开关的开启。此外，TTP可降低RasVal12依赖性VEGF的表达以及裸鼠血管化肿瘤的生长。因此，TTP可能是一种新型的抗血管生成和抗肿瘤药物，通过其对VEGF mRNA的去稳定活性发挥作用。检测TTP和ERK的状态将为评估人类肿瘤的血管生成潜力提供有用信息。
