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Biochem Biophys Res Commun. 2017 Mar 18;484(4):753-761. doi: 10.1016/j.bbrc.2017.01.148. Epub 2017 Jan 30.

Positive feedback loop of YB-1 interacting with Smad2 promotes liver fibrosis.

Author information

1
Department of Digestive Diseases, Shanghai East Hospital, Tongji University, Shanghai 200120, PR China.
2
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, PR China.
3
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, PR China. Electronic address: jieliu@fudan.edu.cn.
4
Department of Digestive Diseases, Shanghai East Hospital, Tongji University, Shanghai 200120, PR China. Electronic address: liufeiguo2010@163.com.

Abstract

Y-box binding protein (YB-1), known as a multifunctional cellular protein in various biological processes, was recently reported to be associated with liver fibrosis. The critical role of TGF-β/Smad signaling pathway in stimulating the transcription of fibrotic genes in fibroblasts have already been identified, however, whether and how YB-1 modulated liver fibrosis via TGF-β/Smad signaling pathway remains largely unknown. In our previous study, we proved that ectopic TGF-β was associated with YB-1 expression. Herein, by combining in vitro experiments in LX2 human hepatic stellate cells and in vivo studies by building CCl4 based mice liver fibrosis model, we showed that YB-1 and p-YB-1 were upregulated in liver fibrosis tissue, and YB-1 promoted the deposition of excess extracellular matrix. Mechanistically, Smad2, a key member in TGF-β signaling pathway, acted as a transcription factor that triggered YB-1 promoter, while on the other hand, p-YB-1 stabilized Smad2 by attenuating its ubiquitination. Knockdown of Smad2 could reduce YB-1 expression, which in turn shorter the half time of Smad2. Furthermore, the serine102 residue of YB-1 both affected its binding and stabilizing activity to Smad2. These finding demonstrated that YB-1 and Smad2 played as a positive feedback loop in promoting liver fibrosis. In conclusion, TGF-β signaling pathway may influence liver fibrosis by incorporating with YB-1, indicating that YB-1 could be a potential target for therapies against liver fibrosis.

KEYWORDS:

Positive feedback loop; Smad2; TGF-β; Y-box binding protein (YB-1)

PMID:
28153731
DOI:
10.1016/j.bbrc.2017.01.148
[Indexed for MEDLINE]

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