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KMID : 0620920220540081277
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Experimental & Molecular Medicine
2022 Volume.54 No. 8 p.1277 ~ p.1289
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Hepatocyte-specific Prominin-1 protects against liver injury-induced fibrosis by stabilizing SMAD7
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Lee Hyun
Yu Dong-Min
Bahn Myeong-Suk
Kwon Young-Jae
Um Min-Jee
Yoon Seo-Yeon
Kim Ki-Tae
Lee Myoung-Woo
Jo Sung-Je
Lee Sung-Soo
Koo Seung-Hoi
Jung Ki-Hoon
Lee Jae-Seon
Ko Young-Gyu
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Abstract
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Prominin-1 (PROM1), also known as CD133, is expressed in hepatic progenitor cells (HPCs) and cholangiocytes of the fibrotic liver. In this study, we show that PROM1 is upregulated in the plasma membrane of fibrotic hepatocytes. Hepatocellular expression of PROM1 was also demonstrated in mice (Prom1CreER; R26TdTom) in which cells expressed TdTom under control of the Prom1 promoter. To understand the role of hepatocellular PROM1 in liver fibrosis, global and liver-specific Prom1-deficient mice were analyzed after bile duct ligation (BDL). BDL-induced liver fibrosis was aggravated with increased phosphorylation of SMAD2/3 and decreased levels of SMAD7 by global or liver-specific Prom1 deficiency but not by cholangiocyte-specific Prom1 deficiency. Indeed, PROM1 prevented SMURF2-induced SMAD7 ubiquitination and degradation by interfering with the molecular association of SMAD7 with SMURF2. We also demonstrated that hepatocyte-specific overexpression of SMAD7 ameliorated BDL-induced liver fibrosis in liver-specific Prom1-deficient mice. Thus, we conclude that PROM1 is necessary for the negative regulation of TGFβ signaling during liver fibrosis.
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KEYWORD
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Apoptosis, Cell signalling, Mechanisms of disease, Post-translational modifications
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