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2014 ; 157
(7
): 1605-18
Nephropedia Template TP
Eswarappa SM
; Potdar AA
; Koch WJ
; Fan Y
; Vasu K
; Lindner D
; Willard B
; Graham LM
; DiCorleto PE
; Fox PL
Cell
2014[Jun]; 157
(7
): 1605-18
PMID24949972
show ga
Translational readthrough, observed primarily in less complex organisms from
viruses to Drosophila, expands the proteome by translating select transcripts
beyond the canonical stop codon. Here, we show that vascular endothelial growth
factor A (VEGFA) mRNA in mammalian endothelial cells undergoes programmed
translational readthrough (PTR) generating VEGF-Ax, an isoform containing a
unique 22-amino-acid C terminus extension. A cis-acting element in the VEGFA 3'
UTR serves a dual function, not only encoding the appended peptide but also
directing the PTR by decoding the UGA stop codon as serine. Heterogeneous nuclear
ribonucleoprotein (hnRNP) A2/B1 binds this element and promotes readthrough.
Remarkably, VEGF-Ax exhibits antiangiogenic activity in contrast to the
proangiogenic activity of VEGF-A. Pathophysiological significance of VEGF-Ax is
indicated by robust expression in multiple human tissues but depletion in colon
adenocarcinoma. Furthermore, genome-wide analysis revealed AGO1 and MTCH2 as
authentic readthrough targets. Overall, our studies reveal a novel
protein-regulated PTR event in a vertebrate system.
|*Protein Biosynthesis
[MESH]
|3' Untranslated Regions
[MESH]
|Amino Acid Sequence
[MESH]
|Animals
[MESH]
|Aorta/cytology
[MESH]
|Base Sequence
[MESH]
|Cattle
[MESH]
|Cell Line
[MESH]
|Codon, Terminator
[MESH]
|Endothelial Cells/*metabolism
[MESH]
|HEK293 Cells
[MESH]
|Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism
[MESH]