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

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N-acetylcysteine induces cell cycle arrest in hepatic stellate cells through its reducing activity
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
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.
Amer Soc Biochemistry Molecular Biology Inc
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Division of Biomedical Research > Immunotherapy Research Center > 1. Journal Articles
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