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 Endothelial FGFR1 (Fibroblast Growth Factor Receptor 1) Deficiency Contributes Differential Fibrogenic Effects in Kidney and Heart of Diabetic Mice

Hypertension ◽  
2020 ◽  
Vol 76 (6) ◽  
pp. 1935-1944 ◽  
Author(s):  
Jinpeng Li ◽  
Haijie Liu ◽  
Swayam Prakash Srivastava ◽  
Qiongying Hu ◽  
Rongfen Gao ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Epithelial To Mesenchymal Transition ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Severe Fibrosis

Endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to organ fibrogenesis. We have reported that N-acetyl-seryl-aspartyl- lysyl-proline (AcSDKP) restored levels of diabetes mellitus-suppressed FGFR1 (fibroblast growth factor receptor 1), the endothelial receptor essential for combating EndMT. However, the molecular regulation and biological/pathological significance of the AcSDKP-FGFR1 relationship has not been elucidated yet. Here, we demonstrated that endothelial FGFR1 deficiency led to AcSDKP-resistant EndMT and severe fibrosis associated with EndMT-stimulated fibrogenic programming in neighboring cells. Diabetes mellitus induced severe kidney fibrosis in endothelial FGFR1-deficient mice ( FGFR1 fl/fl ; VE-cadherin-Cre: FGFR1 EKO ) but not in control mice (FGFR1 fl/fl ); AcSDKP completely or partially suppressed kidney fibrosis in control or FGFR1 EKO mice. Severe fibrosis was also induced in hearts of diabetic FGFR1 EKO mice; however, AcSDKP had no effect on heart fibrosis in FGFR1 EKO mice. AcSDKP also had no effect on EndMT in either kidney or heart but partially suppressed epithelial-to-mesenchymal transition in kidneys of diabetic FGFR1 EKO mice. The medium from FGFR1-deficient endothelial cells stimulated TGFβ (transforming growth factor β)/Smad-dependent epithelial-to-mesenchymal transition in cultured human proximal tubule epithelial cell line, AcSDKP inhibited such epithelial-to-mesenchymal transition. These data demonstrated that endothelial FGFR1 is essential as an antifibrotic core molecule as the target of AcSDKP.

scholarly journals Distinct Roles of Fibroblast Growth Factor Receptor 1 and 2 in Regulating Cell Survival and Epithelial-Mesenchymal Transition

2007 ◽  
Vol 21 (4) ◽  
pp. 987-1000 ◽  
Author(s):  
Wa Xian ◽  
Kathryn L. Schwertfeger ◽  
Jeffrey M. Rosen
Keyword(s):  
Growth Factor ◽  
Cell Survival ◽  
Fibroblast Growth Factor ◽  
Epithelial To Mesenchymal Transition ◽  
Fibroblast Growth Factor Receptor ◽  
Three Dimensional ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Mesenchymal Transition ◽  
Downstream Signaling

Abstract Two related receptor tyrosine kinases (RTKs), fibroblast growth factor receptor 1 and 2 (FGFR1 and FGFR2), exert distinct effects during carcinogenesis. To examine FGFR1 and FGFR2 signaling in polarized epithelia, we have developed an in vitro three-dimensional HC11 mouse mammary epithelial cell culture model combined with a chemically inducible FGFR (iFGFR) dimerization system. Although activation of both RTKs led to reinitiation of cell proliferation and loss of cell polarity, only iFGFR1 activation induced cell survival and epithelial to mesenchymal transition. In contrast, iFGFR2 activation induced cell apoptosis even in the cells in direct contact with the extracellular matrix. Activation of iFGFR2, but not iFGFR1, led to rapid receptor down-regulation and transient activation of downstream signaling, which were partially rescued by Cbl small interfering RNA knockdown or the proteasome inhibitor lactacystin. Importantly, inhibition of proteasome activity in iFGFR2-activated structures led to epithelial to mesenchymal transition and invasive phenotypes resembling those observed after iFGFR1 activation. These studies demonstrate, for the first time, that the duration of downstream signaling determines the distinct phenotypes mediated by very homologous RTKs in three-dimensional cultures.

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.

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