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AP-1 mediates β-amyloid-induced iNOS expression in PC12 cells via the ERK2 and p38 MAPK signaling pathways

Cited 43 time in Web of Science Cited 46 time in Scopus
Authors
Jang, Jung-Hee; Surh, Young-Joon
Issue Date
2005-06
Citation
Biochemical and Biophysical Research Communications, Vol.331 No.4, pp.1421-1428
Keywords
AP-1beta-amyloidERKiNOSnitrosative stressp38 MAPKPC12 cells
Abstract
Nitrosative stress with subsequent inflammatory cell death has been implicated in some neurodegenerative disorders such as Alzheimer's disease (AD). Expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO) have been frequently elevated in AD. In this study, we have investigated the molecular mechanisms underlying nitrosative stress induced by beta-amyloid (A beta), a neurotoxic peptide associated with senile plaques formed in the brains of patients with AD. Exposure of rat pheochromocytoma (PC12) cells to the A beta resulted in increased mRNA and protein expression of iNOS and generation of NO. NO can rapidly interact with superoxide anion, forming more reactive peroxynitrite. Treatment of PC12 cells with A beta led to increased peroxynitrite production and nitrotyrosine formation. A beta induced activation of redox sensitive transcription factor activator protein-1 (AP-1), and AP-1 antisense oligonucleotide abolished the A beta-induced iNOS expression. Moreover, A beta transiently activated extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) via phosphorylation. Pharmacologic inhibition of both enzymes or dominant-negative mutation of ERK2 or p38 MAPK effectively down-regulated DNA binding as well is transcriptional activity of AP-1 and subsequent iNOS expression and NO production. The above findings suggest that A beta induces iNOS expression in PC12 cells through activation of AP-1 which is regulated by upstream kinases. such as ERK and p38 MAPK. (c) 2005 Elsevier Inc. All rights reserved.
ISSN
0006-291X
URI
https://hdl.handle.net/10371/172737
DOI
https://doi.org/10.1016/j.bbrc.2005.04.057
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
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