Nucleic Acids Research Advance Access published online on February 26, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn093
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Molecular Biology |
An upstream open reading frame within an IRES controls expression of a specific VEGF-A isoform
1Institut National de la Santé et de la Recherche Médicale (INSERM), U858, CHU Rangueil, BP 84225, 31432 Toulouse cedex 4, France and 2Université Toulouse III Paul-Sabatier, Institut de Médecine Moléculaire de Rangueil, Equipe n°15, IFR31, Toulouse, France
*To whom correspondence should be addressed. Tel: +33 561 32 21 44; Fax: +33 561 32 21 41; Email: pratsh{at}toulouse.inserm.fr; touriol{at}toulouse.inserm.fr
Received November 28, 2007. Revised February 12, 2008. Accepted February 13, 2008.
Vascular endothelial growth factor A (VEGF-A) is a potent secreted mitogen critical for physiological and pathological angiogenesis. Regulation of VEGF-A occurs at multiple levels, including transcription, mRNA stabilization, splicing, translation and differential cellular localization of various isoforms. Recent advances in our understanding of the posttranscriptional regulation of VEGF-A are comprised of the identification of stabilizing mRNA-binding proteins and the discovery of two internal ribosomal entry sites (IRES) as well as two alternative initiation codons in the 5'UTR of the VEGF-A mRNA. We have previously reported that VEGF-A translation initiation at both the AUG and CUG codons is dependent on the exon content of the coding region. In this report, we show that the expression of different VEGF-A isoforms is regulated by a small upstream open reading frame (uORF) located within an internal ribosome entry site, which is translated through a cap-independent mechanism. This uORF acts as a cis-regulatory element that regulates negatively the expression of the VEGF 121 isoform. Our data provide a framework for understanding how VEGF-A mRNAs are translated, and how the production of the VEGF 121 isoform is secured under non-hypoxic environmental conditions.
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