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J. Biol. Chem., Vol. 279, Issue 18, 18717-18726, April 30, 2004

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Control of the Vascular Endothelial Growth Factor Internal Ribosome Entry Site (IRES) Activity and Translation Initiation by Alternatively Spliced Coding Sequences^*

Stéphanie Bornes, Mathieu Boulard, Corinne Hieblot, Catherine Zanibellato, Jason S. Iacovoni, Hervé Prats, and Christian Touriol

From the Institut National de la Santé et de la Recherche Médicale INSERM U589, Hormones, Facteurs de Croissance et Physiopathologie Vasculaire, Institut Fédératif de Recherche Louis Bugnard, C. H. U. Rangueil, 31403 Toulouse Cedex 04, France

The vascular endothelial growth factor-A (VEGF) gene locus contains eight exons that span 14 kb. Alternative splicing generates multiple, different mRNAs that in turn translate into at least five protein isoforms. While the canonical AUG start codon is located at position 1039 in exon 1, there also exists an upstream, in-frame CUG initiation codon that drives expression of L-VEGF, containing an additional 180 amino acids. Two separate internal ribosome entry sites (IRES) regulate the activity of each initiation codon. Thus the 5'-UTR of VEGF, which comprises the majority of exon 1, consists of IRES B, the CUG, IRES A, and the AUG, from 5' to 3'. Previously, it has been shown that IRES B regulates initiation at the CUG and IRES A regulates AUG usage. In this study, we have found evidence that the exon content of the VEGF mRNA, determined through alternative splicing, controls IRES A activity. While the CUG is most efficient at initiating translation, transcripts that lack both exons 6 and 7 and therefore contain an exon 5/8 junction lack AUG-initiated translation. The process of splicing is not responsible for this start codon selection since transfection of genomic and cDNA VEGF sequences give the same expression pattern. We hypothesize that long range tertiary interactions in the VEGF mRNA regulate IRES activity and thus control start codon selection. This is the first report describing the influence of alternatively spliced coding sequences on codon selection by modulating IRES activity.

Received for publication, July 31, 2003 , and in revised form, January 22, 2004.

^* Supported by a grant from the Ligue Nationale Contre le Cancer as an Equipe Labellisée. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 33-561-32-21-44; Fax: 33-561-32-21-41; E-mail: pratsh{at}toulouse.inserm.fr.

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