| Co-Investigator(Kenkyū-buntansha) |
GOTOH Tomomi Kumamoto University, Grad.Sch.Med.Sci., Lecture, 大学院・医学薬学研究部, 講師 (20264286)
TERADA Kazutoyo Kumamoto University, Grad.Sch.Med.Sci., Associate Professor, 大学院・医学薬学研究部, 助教授 (00253724)
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| Research Abstract |
Endoplasmic reticulum (ER) is the site of synthesis and folding of secretory proteins. Purturbations of ER homrostasis affect protein folding and cause ER stress. Nitric oxide (NO) is a messenger molecule functioning in vascular regulation, immunity, neurotransmission and others, and has been implicated in many diseases. NO is synthesized from arginine by NO synthase (NOS), and the availability of arginine has been shown to be a rate-limiting factor in NO production. Citrulline formed as a by-product of the NOS reaction can be recycled to arginine by argininosuccinate synthetase and argininosuccinate lyase, forming the "citrulline-NO cycle". On the other hand, arginase isoforms have been shown to downregulate NO production by depleting arginine. Excessive NO leads to apoptosis in various cells. When macrophages were immunostimulated or treated with NO, apoptosis occurred. Under these conditions, p53 accumulation was not observed, indicating that DNA damage is not the main trigger of NO-mediated apoptosis. Furthermore, apoptosis was induced in p53-deficient microglial cells by NO. We found that CHOP/GADD153, a C/EBP family transcription factor which is involved in ER stress-mediated apoptosis, is induced. The induction of CHOP was followed by the mitochondrial apoptotic pathway involving cytochrome c release and activation of caspase cascade. Excessive NO production in cytokine-activated β-cells has been implicated in β-cell distruption in type 1 diabetes. NO depleted ER Ca^<2+>, and overexpression of calreticulin, a major Ca^<2+> binding protein in ER, increased ER Ca^<2+> and protected cells against NO-mediated apoptosis. Furthermore, pancreatic islets from CHOP-deficient mice showed resistance to NO. We conclude that NO depletes ER Ca^<2+>, causes ER stress, and leads to apoptosis.
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