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

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Title
N-acetylcysteine induces cell cycle arrest in hepatic stellate cells through its reducing activity
Author(s)
Ki Yong Kim; Tai Youn Rhim; In Pyo Choi; Soung Soo Kim
Bibliographic Citation
Journal of Biological Chemistry, vol. 276, no. 44, pp. 40591-40598
Publication Year
2001
Abstract
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 G1 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 p21Cip1/WAF1, a cell cycle-dependent kinase inhibitor, and mediated cell growth arrest through the Sp1 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.
ISSN
0021-9258
Publisher
Amer Soc Biochemistry Molecular Biology Inc
DOI
http://dx.doi.org/10.1074/jbc.M100975200
Type
Article
Appears in Collections:
Division of Biomedical Research > Immunotherapy Research Center > 1. Journal Articles
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