N-acetylcysteine induces cell cycle arrest in hepatic stellate cells through its reducing activity

被引:120
作者
Kim, KY
Rhim, T
Choi, I
Kim, SS [1 ]
机构
[1] Yonsei Univ, Coll Sci, Dept Biochem, Seoul 120749, South Korea
[2] Dobeel Corp, Seoul 135961, South Korea
[3] Korea Res Inst Biosci & Biotechnol, Immunol Lab, Taejon 305333, South Korea
关键词
D O I
10.1074/jbc.M100975200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Activation of hepatic stellate cells (HSC) has been identified as a critical step in hepatic fibrogenesis and is regulated by several factors including cytokines and oxidative stress. However, the molecular mechanism for HSC inactivation is not well understood. We investigated an N-acetyl-L-cysteine (NAC)-mediated signaling pathway involved in HSC inactivation. NAC, which acting through its reducing activity, induced cell arrest at Gl via the mitogen-activated protein kinase (MAPK) kinase (MEK)/ MAPK pathway in a Ras-independent manner. The sustained activation of this extracellular signal-regulated kinase induced the expression of p21(Cip/WAF1), a cell cycle-dependent kinase inhibitor, and mediated cell growth arrest through the Spl transcription activator-dependent mechanism. These effects of NAC were all reversed by treatment of HSC with MEK inhibitor PD98059 followed by culturing HSC on type I collagen-coated flasks. The collagen-mediated suppression of NAC-induced arrest may be due to an overriding of the cell cycle arrest through an acceleration of integrin-induced cell growth. NAC action is actually dependent on modulating the redox states of cysteine residues of target proteins such as Raf-1, MEK, and ERK. In conclusion, an understanding of the NAC signaling pathway in HSC should provide the theoretical basis for clinical approaches using antioxidant therapies in liver fibrosis.
引用
收藏
页码:40591 / 40598
页数:8
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