Control of BEK and K-SAM splice sites in alternative splicing of the fibroblast growth factor receptor 2 pre-mRNA

1993 ◽  
Vol 13 (9) ◽  
pp. 5461-5468
Author(s):  
E Gilbert ◽  
F Del Gatto ◽  
P Champion-Arnaud ◽  
M C Gesnel ◽  
R Breathnach
Keyword(s):  
Alternative Splicing ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Splice Sites ◽  
Polypyrimidine Tract ◽  
Profound Influence ◽  
In Cells

The fibroblast growth factor receptor 2 gene pre-mRNA can be spliced by using either the K-SAM exon or the BEK exon. The exon chosen has a profound influence on the ligand-binding specificity of the receptor obtained. Cells make a choice between the two alternative exons by controlling use of both exons. Using fibroblast growth factor receptor 2 minigenes, we have shown that in cells normally using the K-SAM exon, the BEK exon is not used efficiently even in the absence of the K-SAM exon. This is because these cells apparently express a titratable repressor of BEK exon use. In cells normally using the BEK exon, the K-SAM exon is not used efficiently even in the absence of a functional BEK exon. Three purines in the K-SAM polypyrimidine tract are at least in part responsible for this, as their mutation to pyrimidines leads to efficient use of the K-SAM exon, while mutating the BEK polypyrimidine tract to include these purines stops BEK exon use.

scholarly journals Control of BEK and K-SAM splice sites in alternative splicing of the fibroblast growth factor receptor 2 pre-mRNA.

1993 ◽  
Vol 13 (9) ◽  
pp. 5461-5468 ◽  
Author(s):  
E Gilbert ◽  
F Del Gatto ◽  
P Champion-Arnaud ◽  
M C Gesnel ◽  
R Breathnach
Keyword(s):  
Alternative Splicing ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Splice Sites ◽  
Polypyrimidine Tract ◽  
Profound Influence ◽  
In Cells

The fibroblast growth factor receptor 2 gene pre-mRNA can be spliced by using either the K-SAM exon or the BEK exon. The exon chosen has a profound influence on the ligand-binding specificity of the receptor obtained. Cells make a choice between the two alternative exons by controlling use of both exons. Using fibroblast growth factor receptor 2 minigenes, we have shown that in cells normally using the K-SAM exon, the BEK exon is not used efficiently even in the absence of the K-SAM exon. This is because these cells apparently express a titratable repressor of BEK exon use. In cells normally using the BEK exon, the K-SAM exon is not used efficiently even in the absence of a functional BEK exon. Three purines in the K-SAM polypyrimidine tract are at least in part responsible for this, as their mutation to pyrimidines leads to efficient use of the K-SAM exon, while mutating the BEK polypyrimidine tract to include these purines stops BEK exon use.

scholarly journals Bleomycin-enhanced alternative splicing of fibroblast growth factor receptor 2 induces epithelial to mesenchymal transition in lung fibrosis

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Kui-Jun Chen ◽  
Qing Li ◽  
Chang-Mei Weng ◽  
Zhao-Xia Duan ◽  
Dong-Dong Zhang ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Lung Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Transgenic Mouse Models ◽  
Mesenchymal Transition

Idiopathic pulmonary fibrosis (IPF) is an important public health problem, and it has few treatment options given its poorly understood etiology; however, epithelial to mesenchymal transition (EMT) of pneumocytes has been implicated as a factor. Herein, we aimed to explore the underlying mechanisms of lung fibrosis mediated by EMT, with a focus on the alternative splicing of fibroblast growth factor receptor 2 (FGFR2), using bleomycin (BLM)-induced lung fibrotic and transgenic mouse models. We employed BLM-induced and surfactant protein C (SPC)-Cre and LacZ double transgenic mouse models. The results showed that EMT occurred during lung fibrosis. BLM inhibited the expression of epithelial splicing regulatory protein 1 (ESRP1), resulting in enhanced alternative splicing of FGFR2 to the mesenchymal isoform IIIc. BLM-induced lung fibrosis was also associated with the activation of TGF-β/Smad signaling. These findings have implications for rationally targetted strategies to therapeutically address IPF.

scholarly journals An Intronic Splicing Silencer Causes Skipping of the IIIb Exon of Fibroblast Growth Factor Receptor 2 through Involvement of Polypyrimidine Tract Binding Protein

2000 ◽  
Vol 20 (19) ◽  
pp. 7388-7400 ◽  
Author(s):  
Russ P. Carstens ◽  
Eric J. Wagner ◽  
Mariano A. Garcia-Blanco
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Polypyrimidine Tract ◽  
Splicing Silencer ◽  
Polypyrimidine Tract Binding Protein ◽  
Rat Prostate

ABSTRACT Alternative splicing of fibroblast growth factor receptor 2 (FGF-R2) transcripts involves the mutually exclusive usage of exons IIIb and IIIc to produce two different receptor isoforms. Appropriate splicing of exon IIIb in rat prostate cancer DT3 cells requires a previously described cis element (ISAR, for “intronic splicing activator and repressor”) which represses the splicing of exon IIIc and activates the splicing of exon IIIb. This element is nonfunctional in rat prostate AT3 cells, which repress exon IIIb inclusion and splice to exon IIIc. We have now identified an intronic element upstream of exon IIIb that causes repression of exon IIIb splicing. Deletion of this element abrogates the requirement for ISAR in order for exon IIIb to be spliced in DT3 cells and causes inappropriate inclusion of exon IIIb in AT3 cells. This element consists of two intronic splicing silencer (ISS) sequences, ISS1 and ISS2. The ISS1 sequence is pyrimidine rich, and in vitro cross-linking studies demonstrate binding of polypyrimidine tract binding protein (PTB) to this element. Competition studies demonstrate that mutations within ISS1 that abolish PTB binding in vitro alleviate splicing repression in vivo. Cotransfection of a PTB-1 expression vector with a minigene containing exon IIIb and the intronic splicing silencer element demonstrate PTB-mediated repression of exon IIIb splicing. Furthermore, all described PTB isoforms were equally capable of mediating this effect. Our results support a model of splicing regulation in which exon IIIc splicing does not represent a default splicing pathway but rather one in which active repression of exon IIIb splicing occurs in both cells and in which DT3 cells are able to overcome this repression in order to splice exon IIIb.

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