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An upstream open reading frame within an IRES controls expression of a specific VEGF-A isoform.

Abstract : 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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Submitted on : Thursday, August 20, 2009 - 2:18:33 PM
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Amandine Bastide, Zeineb Karaa, Stéphanie Bornes, Corinne Hieblot, Eric Lacazette, et al.. An upstream open reading frame within an IRES controls expression of a specific VEGF-A isoform.. Nucleic Acids Research, Oxford University Press, 2008, 36 (7), pp.2434-45. ⟨10.1093/nar/gkn093⟩. ⟨inserm-00408822⟩



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