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(Circulation Research. 2007;100:305.)
© 2007 American Heart Association, Inc.

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Translational Induction of VEGF Internal Ribosome Entry Site Elements During the Early Response to Ischemic Stress

Stéphanie Bornes^*, Leonel Prado-Lourenco^*, Amandine Bastide, Catherine Zanibellato, Jason S. Iacovoni, Eric Lacazette, Anne-Catherine Prats, Christian Touriol, Hervé Prats

From INSERM U858 (S.B., L.P.-L., A.B., C.Z., J.S.I., E.L., A.-C.P., C.T., H.P.), Université Paul Sabatier, Toulouse; and MilleGen (L.P.-L.), Prologue Biotech, Labège, France.

Correspondence to Hervé Prats, INSERM U858, Université Paul Sabatier, IFR31, BP 84225, 31432 Toulouse Cedex 04, France. E-mail pratsh{at}toulouse.inserm.fr

Vascular endothelial growth factor-A (VEGF), a powerful factor involved in vasculogenesis and angiogenesis, is translationally regulated through 2 independent internal ribosome entry sites (IRESs A and B). IRESs enable an mRNA to be translated under conditions in which 5'-cap–dependent translation is inhibited, such as low oxygen stress. In the VEGF mRNA, IRES A influences translation at the canonical AUG codon, whereas the 5' IRES B element regulates initiation at an upstream, in frame CUG. In this study, we have developed transgenic mice expressing reporter genes under the control of these 2 IRESs. We reveal that although these IRESs display low activity in embryos and adult tissues, they permit efficient translation at early time points in ischemic muscle, a stress under which cap-dependent translation is inhibited. These results demonstrate the in vivo efficacy of the VEGF IRESs in response to a local environmental stress such as hypoxia.

Key Words: VEGF • translation • internal ribosome entry site • transgenic mice • ischemia

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