Tristetraprolin inhibits Ras-dependent tumor vascularization by inducing vascular endothelial growth factor mRNA degradation.
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.
Essafi-Benkhadir
Khadija
K
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.
Onesto
Cercina
C
Stebe
Emmanuelle
E
Moroni
Christoph
C
Pagès
Gilles
G
D000818:Animals; D004789:Enzyme Activation; D017930:Genes, Reporter / Q000235:genetics; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000378:metabolism*
D006454:Hemoglobins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051816:Tristetraprolin; D042461:Vascular Endothelial Growth Factor A; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins