An upstream open reading frame within an IRES controls expression of a specific VEGF-A isoform.
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.
Bastide
Amandine
A
Institut National de la Santé et de la Recherche Médicale (INSERM), U858, CHU Rangueil, BP 84225, 31432 Toulouse cedex 4, France.
Karaa
Zeineb
Z
Bornes
Stéphanie
S
Hieblot
Corinne
C
Lacazette
Eric
E
Prats
Hervé
H
Touriol
Christian
C
D020121:5' Untranslated Regions / Q000737:chemistry*; D017398:Alternative Splicing; D001483:Base Sequence; D018387:Codon, Initiator; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D010442:Peptide Chain Initiation, Translational; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D012315:RNA Caps / Q000378:metabolism; D012333:RNA, Messenger / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics*
D020121:5' Untranslated Regions; D018387:Codon, Initiator; D020033:Protein Isoforms; D012315:RNA Caps; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A