Alternative Translation Initiation of Human Fibroblast Growth Factor 2 mRNA Controlled by Its 3′-Untranslated Region Involves a Poly(A) Switch and a Translational Enhancer

Abstract

Five fibroblast growth factor 2 (FGF-2) isoforms are synthesized from human FGF-2 mRNA by a process of alternative initiation of translation. The regulation of FGF-2 isoform expression by the mRNA 5823-nucleotidelong 3-untranslated region containing eight alternative polyadenylation sites was examined. Because previous studies had shown that FGF-2 expression was regulated in primary cells but not in transformed cells, primary human skin fibroblasts were used in this study. Using an approach of cell transfection with synthetic reporter mRNAs, a novel translational enhancer (3-TE) was identified in the 1370-nucleotide mRNA segment located upstream from the eighth poly(A) site. Deletion mutagenesis showed that the 3-TE was composed of two domains with additive effects. The 3-TE exhibited the unique feature of modulating the use of FGF-2 alternative initiation codons, which favored the relative expression of CUG-initiated isoforms. Interestingly, the use of an alternative polydenylation site removing the 3-TE was detected in skin fibroblasts in response to heat shock and cell density variations. At high cell densities, 3-TE removal was correlated with a loss of CUG-initiated FGF-2 expression. These data show that the FGF-2 mRNA 3-untranslated region is able to modulate FGF-2 isoform expression by the coupled processes of translation activation and alternative polyadenylation.

Generation of protein isoform diversity by alternative initiation of translation at non‐AUG codons

“…A translational enhancer (3'TE) has been identified in this 3' UTR, the presence of which is conditioned by the use of alternative polyadenylation sites (Touriol et al, 2000). The 3'TE is shown to activate the expression of CUG-initiated forms in low density human skin fibroblasts.…”

“…The density-dependent regulation of alternative initiation of translation is also influenced by sequences located in the FGF2 3' UTR (Touriol et al, 2000). A translational enhancer (3'TE) has been identified in this 3' UTR, the presence of which is conditioned by the use of alternative polyadenylation sites (Touriol et al, 2000).…”

“…The 3'TE is shown to activate the expression of CUG-initiated forms in low density human skin fibroblasts. A switch of polyadenylation site related to cell density variations leads to the loss of the 3'TE in high density cells, in correlation with the decrease of CUG-initiated FGF2 synthesis (Bost et al, 1993;Touriol et al, 2000).…”

Essential Role of Bone Marrow Fibroblast Growth Factor-2 in the Effect of Estradiol on Reendothelialization and Endothelial Progenitor Cell Mobilization

“…34 Furthermore, we have previously identified a translational enhancer located at the end of the 3Ј-untranslated region of the Fgf2 gene, the activation of which promotes a preferential increase of the FGF2 hmw forms. 35 These two phenomena involving the role of the 3Ј-untranslated region of Fgf2 mRNA could explain the effect observed here after stimulation by E 2 . Interestingly, the systematic analysis of gene expression in yeast clearly showed the lack of correlation between mRNA and protein levels, showing that this discrepancy between mRNA and protein abundance could be the rule rather than the exception in genes expressed at a low level.…”

The Minor MHC Class I Gene UDA of Ducks Is Regulated by Let-7 MicroRNA

“…Alternatively, miRNA can stimulate the transcription by binding to the 39UTR (55)(56)(57). There are also RNA-binding proteins that can bind to mRNA to increase mRNA stability or enhance translation (58)(59)(60)(61).…”