Activation of Protein Serine/Threonine Phosphatase PP2C alpha Efficiently Prevents Liver Fibrosis

doi:10.1371/journal.pone.0014230

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第三研究室

	Activation of Protein Serine/Threonine Phosphatase PP2C alpha Efficiently Prevents Liver Fibrosis
	Wang, Lirui 1; Wang, Xu 1; Chen, Jing1 ; Yang, Zhengyi 1; Yu, Liang1 ; Hu, Lihong 1; Shen, Xu1,2
刊名	PLOS ONE
	2010-12-06
卷号	5 期号:12
ISSN号	1932-6203
DOI	10.1371/journal.pone.0014230
文献子类	Article
英文摘要	Background: Over-activation of TGF beta signaling pathway and uncontrolled cell proliferation of hepatic stellate cells (HSCs) play pivotal roles in liver fibrogenesis, while the protein serine/threonine phosphatase PP2C alpha was reported to negatively regulate TGF beta signaling pathway and cell cycle. Our study aimed to investigate the role of PP2C alpha in liver fibrogenesis. Methodology/Principal Findings: The effects of PP2C alpha activation on liver fibrosis were investigated in human HSCs and primary rat HSCs in vitro using western blotting, real-time PCR, nuclear translocation, cell viability and cell cycle analyses. The antifibrogenic effects in carbon tetrachloride (CCl4)-and bile duct ligation (BDL)-induced mice in vivo were assessed using biochemical, histological and immunohistochemical analyses. The results demonstrated that activation of PP2C alpha by overexpression or the new discovered small molecular activator NPLC0393 terminated TGF beta-Smad3 and TGF beta-p38 signaling pathways, induced cell cycle arrest in HSCs and decreased alpha-smooth muscle actin (alpha-SMA) expression, collagen deposition and hepatic hydroxyproline (HYP) level in CCl4- and BDL-induced mice. Conclusions/Significance: Our findings suggested that PP2C alpha activation might be an attractive new strategy for treating liver fibrosis while the small molecular activator NPLC0393 might represent a lead compound for antifibrogenic drug development. Moreover, our study might provide the first evidence for the role of PP2C family members in the fibrotic disease.
资助项目	State Key Program of Basic Research of China[2010CB912501] ; State Key Program of Basic Research of China[2007CB914304] ; State Key Program of Basic Research of China[2009CB918502] ; National Natural Science Foundation of China[30925040] ; National Natural Science Foundation of China[30890044] ; National Natural Science Foundation of China[10979072] ; Key New Drug Creation and Manufacturing Program[2009ZX09301-001] ; Science Foundation of Shanghai[08431902900] ; E-Institutes of Shanghai Municipal Education Commission[E09013] ; Foundation of Chinese Academy of Sciences[KSCX2-YW-R-168] ; Foundation of Chinese Academy of Sciences[SCX1-YW-02-2]
WOS关键词	GROWTH-FACTOR-BETA ; HEPATIC STELLATE CELLS ; I RECEPTOR KINASE ; APOPTOSIS ; INHIBITOR ; 2C-ALPHA ; RATS ; 2C ; PROLIFERATION ; AMPLIFICATION
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
WOS记录号	WOS:000284995300002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278692]
专题	药理学第三研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Wang, Lirui
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 200031, Peoples R China; 2.Shanghai Jiao Tong Univ, Sch Med, E Inst Shanghai Municipal Educ Commiss, Shanghai 200030, Peoples R China
推荐引用方式 GB/T 7714	Wang, Lirui,Wang, Xu,Chen, Jing,et al. Activation of Protein Serine/Threonine Phosphatase PP2C alpha Efficiently Prevents Liver Fibrosis[J]. PLOS ONE,2010,5(12).
APA	Wang, Lirui.,Wang, Xu.,Chen, Jing.,Yang, Zhengyi.,Yu, Liang.,...&Shen, Xu.(2010).Activation of Protein Serine/Threonine Phosphatase PP2C alpha Efficiently Prevents Liver Fibrosis.PLOS ONE,5(12).
MLA	Wang, Lirui,et al."Activation of Protein Serine/Threonine Phosphatase PP2C alpha Efficiently Prevents Liver Fibrosis".PLOS ONE 5.12(2010).