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Regulation of fibronectin splicing in sinusoidal endothelial cells from normal or injured liver
journal contribution
posted on 2023-06-08, 00:19 authored by Ming-Ling Chang, Jeng-Chang Chen, Claudio AlonsoClaudio Alonso, Alberto R Kornblihtt, D Montgomery BissellFn containing an extra type III domain (EIIIA in the rat, ED1 or EDA in humans) is commonly termed "fetal" fibronectin, but it is prominent during the injury response of adult tissues and mediates important early events in the response. This form is particularly apparent in acute liver injury, where it has been shown that sinusoidal endothelial cells produce EIIIA-fibronectin. This fibronectin isoform arises by alternative splicing of the primary transcript. In the present experiments, we have studied the regulation of fibronectin splicing in primary sinusoidal endothelial cells by transfecting a minigene containing the EIIIA exon and its flanking introns, driven by various promoters. The results indicate that fibronectin splicing in endothelial cells from normal liver is in part promoter-dependent. However, in cells from injured liver in which expression of both total and EIIIA-fibronectin is strikingly increased, promoter effects disappear. Because fibronectin splicing is known to be regulated in part by TGF, we also examined the effect of a soluble inhibitor of the TGF type 2 receptor. This agent had no effect on splicing by normal endothelial cells. By contrast, for endothelial cells from the injured liver, the splicing pattern reverted to that of normal cells, i.e., it became promoter-dependent. We conclude that, in the setting of injury in vivo, TGF overrides the promoter dependence of fibronectin splicing in normal cells. The data suggest that TGF modifies the spliceosome, if not through its known signaling intermediates, then through the products of genes regulated by this cytokine.
History
Publication status
- Published
Journal
Proceedings of the National Academy of SciencesISSN
0027-8424Publisher
National Academy of SciencesExternal DOI
Issue
52Volume
101Page range
18093-18098Department affiliated with
- Evolution, Behaviour and Environment Publications
Notes
My initial studies identified the factors that operate a CRE-CCAAT composite site located in the proximal regions of the fibronectin promoter, and revealed the molecular interactions among them via in vitro protein-protein interaction assays. I then moved on to demonstrate that the functional roles of the individual DNA-binding elements within the CRE-CCAAT composite site are distinct in different mammalian cell lines and primary culturesFull text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2012-02-06Usage metrics
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