期刊
BIOCHEMICAL JOURNAL
卷 473, 期 -, 页码 1455-1469出版社
PORTLAND PRESS LTD
DOI: 10.1042/BCJ20160128
关键词
alpha B-crystallin; epithelial to mesenchymal transition; lens epithelial cells; TGF-beta 2
资金
- National Institutes of Health [EY022061, EY023286, P30EY-11373]
Transforming growth factor (TGF)-beta 2-mediated pathways play a major role in the epithelial to mesenchymal transition (EMT) of lens epithelial cells (LECs) during secondary cataract formation, which is also known as posterior capsule opacification (PCO). Although alpha B-crystallin is a major protein in LEC, its role in the EMT remains unknown. In a human LEC line (FHL124), TGF-beta 2 treatment resulted in changes in the EMT-associated proteins at the mRNA and protein levels. This was associated with nuclear localization of alpha B-crystallin, phosphorylated Smad2 (pSmad2) (S245/250/255), pSmad3 (S423/425), Smad4 and Snail and the binding of alpha B-crystallin to these transcription factors, all of which were reduced by the down-regulation of alpha B-crystallin. Expression of the functionally defective R120G mutant of alpha B-crystallin reduced TGF-beta 2-induced EMT in LECs of alpha B-crystallin knockout (KO) mice. Treatment of bovine lens epithelial explants and mouse LEC with TGF-beta 2 resulted in changes in the EMT-associated proteins at the mRNA and protein levels. This was accompanied by increase in phosphorylation of p44/42 mitogen-activated protein kinases (MAPK) (T202/Y204), p38 MAPK (T180/Y182), protein kinase B (Akt) (S473) and Smad2 when compared with untreated cells. These changes were significantly reduced in alpha B-crystallin depleted or knocked out LEC. The removal of the fibre cell mass from the lens of wild-type (WT) mice resulted in the up-regulation of EMT-associated genes in the capsule-adherent epithelial cells, which was reduced in the alpha B-crystallin KO mice. Together, our data show that aB-crystallin plays a central role in the TGF-beta 2-induced EMT of LEC. alpha B-Crystallin could be targeted to prevent PCO and pathological fibrosis in other tissues.
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