Induction of CHOP and apoptosis by nitric oxide in p53‐deficient microglial cells

FEBS Letters

Kawahara, Kohichi³  Oyadomari, Seiichi³  Gotoh, Tomomi³  Kohsaka, Shinichi¹  Nakayama, Hitoshi²  Mori, Masataka³ 

[1] Department of Neurochemistry, National Institute of Neuroscience, 4-4-1 Ogawahigashi, Kodaira, Tokyo 187-8851, Japan;Department of Biofunctional Chemistry, Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Ohe-Honmachi, Kumamoto 862-0973, Japan;Department of Molecular Genetics, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 860-0811, Japan

关键词: Nitric oxide;    Apoptosis;    CHOP;    Endoplasmic reticulum stress;    p53;    Microglia;    Lipopolysaccharide;    ER;    endoplasmic reticulum;    LPS;    lipopolysaccharide;    IFN-γ;    interferon-γ;    NO;    nitric oxide;    iNOS;    inducible NO synthase;    SIN-1;    3-(4-morpholinyl)-sydnonimine hydrochloride;    SNAP;    S-nitroso-N-acetyl-DL-penicillamine;   

DOI  :  10.1016/S0014-5793(01)02898-8

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown