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Induction of CHOP and apoptosis by nitric oxide in p53‐deficient microglial cells
Author(s) -
Kawahara Kohichi,
Oyadomari Seiichi,
Gotoh Tomomi,
Kohsaka Shinichi,
Nakayama Hitoshi,
Mori Masataka
Publication year - 2001
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(01)02898-8
Subject(s) - chop , unfolded protein response , endoplasmic reticulum , apoptosis , nitric oxide synthase , neurotoxicity , nitric oxide , chemistry , microbiology and biotechnology , toxicity , biology , endocrinology , medicine , biochemistry
Excessive nitric oxide (NO) has been implicated in neurotoxicity after stresses such as ischemia. NO toxicity is generally thought to be mediated by the DNA damage–p53 pathway or mitochondrial dysfunction. We investigated the mechanism of NO toxicity by using murine microglial MG5 cells established from p53‐deficient mice. When MG5 cells were exposed to bacterial lipopolysaccharide plus interferon‐γ, mRNA and protein for inducible NO synthase (iNOS) were markedly induced, and apoptosis occurred. Under these conditions, we found that mRNA and protein for CHOP/GADD153, a C/EBP family transcription factor which is involved in endoplasmic reticulum (ER) stress‐induced apoptosis, are induced. iNOS mRNA was induced 2 h after treatment, whereas CHOP mRNA began to increase at 6 h with a time lag. CHOP mRNA was also induced by NO donors S ‐nitroso‐ N ‐acetyl‐ DL ‐penicillamine (SNAP) or NOC18, or a peroxynitrite generator 3‐(4‐morpholinyl)‐sydnonimine hydrochloride (SIN‐1). Bip/GRP78, an ER chaperone which is known to be induced by ER stress, was also induced by SNAP or SIN‐1, indicating that NO causes ER stress. These results suggest that NO‐induced apoptosis in MG5 cells occurs through the ER stress pathway involving CHOP, but is independent of p53.