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Vol. 18, Issue 11, 4648-4658, November 2007
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*Institute of Signalling, Developmental Biology, and Cancer Research, 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; and Institute for Medical Microbiology, Department of Clinical-Biological Sciences, University of Basel, CH-4003 Basel, Switzerland
Submitted June 15, 2007;
Revised August 29, 2007;
Accepted August 30, 2007
Monitoring Editor: Martin A. Schwartz
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.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
Present address: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB 7295, 102 Mason Farm Rd., Chapel Hill, NC 27599-7295.
Address correspondence to: Gilles Pagès (gpages{at}unice.fr)
Abbreviations used: ARE, AU-rich element; DRB, 5,6-dichlorobenzimidazole riboside; ELISA, enzyme-linked immunosorbent assay; ERK, extracellular signal-regulated kinase; GST, glutathione transferase; PBS, phosphate-buffered saline; REMSA, RNA electrophoretic mobility shift assay; RNP, ribonucleoprotein; siRNA, small interfering RNA; UTR, untranslated region; VEGF, vascular endothelial growth factor.
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