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Inhibition of apoptosis signal-regulating kinase 1 by nitric oxide through a thiol redox mechanism

Authors
 Hee-Sae Park  ;  Je-Wook Yu  ;  Eui-Ju Choi  ;  Kanghyun Ryoo  ;  Sung-Ho Huh  ;  Mi-Sung Kim  ;  Jun-Ho Cho 
Citation
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.279(9) : 7584-7590, 2004 
Journal Title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN
 0021-9258 
Issue Date
2004
MeSH
Animals ; Cell Line ; Cysteine ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology* ; Fibrosarcoma ; Humans ; Hydrogen Peroxide/pharmacology ; Interferon-gamma/pharmacology ; MAP Kinase Kinase Kinase 5 ; MAP Kinase Kinase Kinases/antagonists & inhibitors* ; MAP Kinase Kinase Kinases/chemistry ; MAP Kinase Kinase Kinases/genetics ; Mice ; Mutagenesis, Site-Directed ; Nitric Oxide/pharmacology* ; Nitric Oxide Donors/pharmacology ; Nitric Oxide Synthase/antagonists & inhibitors ; Nitroarginine/pharmacology ; Oxidation-Reduction ; Penicillamine/analogs & derivatives* ; Penicillamine/pharmacology ; Structure-Activity Relationship ; Sulfhydryl Compounds/metabolism* ; Transfection ; Tumor Cells, Cultured
Abstract
Nitric oxide is an endogenous thiol-reactive molecule that modulates the functions of many regulatory proteins by a thiol-redox mechanism. NO has now been shown to inhibit the activation of apoptosis signal-regulating kinase 1 (ASK1) in murine fibrosarcoma L929 cells through such a mechanism. Exposure of L929 cells to interferon-gamma resulted in the endogenous production of NO and in inhibition of the activation of ASK1 by hydrogen peroxide. The interferon-gamma-induced inhibition of ASK1 activity was blocked by N(G)-nitro-l-arginine, an inhibitor of NO synthase. Furthermore, the NO donor S-nitro-N-acetyl-dl-penicillamine (SNAP) inhibited ASK1 activity in vitro, and this inhibition was reversed by thiol-reducing agents such as dithiothreitol and beta-mercaptoethanol. SNAP did not inhibit the kinase activities of MKK3, MKK6, or p38 in vitro. The inhibition of ASK1 by interferon-gamma was not changed by 1H- (1,2,4)oxadiazolo[4,3-alpha]quinoxalin-1-one, an inhibitor of guanylyl cyclase nor was it mimicked by 8-bromo-cyclic GMP. Site-directed mutagenesis revealed that replacement of cysteine 869 of ASK1 by serine rendered this protein resistant to the inhibitory effects both of interferon-gamma in intact cells and of SNAP in vitro. Co-immunoprecipitation data showed that NO production inhibited a binding of ASK1, but not ASK1(C869S), to MKK3 or MKK6. Moreover, interferon-gamma induced the S-nitrosylation of endogenous ASK1 in L929 cells. Together, these results suggest that NO mediates the interferon-gamma-induced inhibition of ASK1 in L929 cells through a thiolredox mechanism.
Files in This Item:
T200404831.pdf Download
DOI
10.1074/jbc.M304183200
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Yu, Je Wook(유제욱) ORCID logo https://orcid.org/0000-0001-5943-4071
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/113006
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