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

International audienceVascular endothelial growth factor A (VEGF-A) is apotent secreted mitogen critical for physiologicaland pathological angiogenesis. Regulation of VEGF-A occurs at multiple levels, including transcription,mRNA stabilization, splicing, translation and differ-ential cellular localization of various isoforms.Recent advances in our understanding of the post-transcriptional regulation of VEGF-A are comprisedof the identification of stabilizing mRNA-bindingproteins and the discovery of two internal ribosomalentry sites (IRES) as well as two alternative initiationcodons in the 5’UTR of the VEGF-A mRNA. We havepreviously reported that VEGF-A translation initia-tion at both the AUG and CUG codons is dependenton the exon content of the coding region. In thisreport, we show that the expression of differentVEGF-A isoforms is regulated by a small upstreamopen reading frame (uORF) located within an inter-nal ribosome entry site, which is translated througha cap-independent mechanism. This uORF acts as acis-regulatory element that regulates negatively theexpression of the VEGF 121 isoform. Our dataprovide a framework for understanding how VEGF-A mRNAs are translated, and how the production ofthe VEGF 121 isoform is secured under non-hypoxic environmental conditions