| Project/Area Number |
17390097
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Kumamoto University |
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Principal Investigator |
AKAIKE Takaaki Kumamoto University, Grad. Sch. of Med. Sci., Professor (20231798)
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| Co-Investigator(Kenkyū-buntansha) |
ARIMOTO Hirokazu Tohoku University, Grad. Sch. of Life Sci., Professor (60262789)
SAWA Tomohiro Kumamoto University, Grad. Sch. of Med. Sci, Associate Professor (30284756)
芥 照夫 熊本大学, 大学院・医学薬学研究部, 助手 (00346975)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥14,870,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2007: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2006: ¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 2005: ¥4,200,000 (Direct Cost: ¥4,200,000)
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| Keywords | Nitric oxide / 8-nitroguanosine / 8-nitro-cGMP / signal transduction / S-guanylation / post-translational modification / genome mutation / oxidative stress / NO / 炎症 / 発がん / ニトロ化ストレス / DNA損傷 / ゲノム / 8-ニトログアニン / 変異原性 / 修復システム / デナイトラーゼ / 核酸損傷 / 脱プリン反応 |
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| Research Abstract |
Excess production of free radical species including superoxide and nitric oxide (NO) has been implicated in pathophysiology of infectious and inflammatory diseases, by causing chemical modifications of biological molecules. In the present study, we investigated the roles of genome modifications and regulation by NO, with particular focus on the formation and biological effects of 8-nitroguanosine, a unique product of NO-mediated nucleic acid modification. Followings are summary of the present study.
1. 8-Nitroguanosine was found to be mutagenic to mammalian cultured cells. CHO cells treated with 8-nitroguanosine exhibited remarkably higher mutation frequency of the marker gene gpt, with G to T transversion as a dominant form of mutation, compared with control cells. Furthermore, 8-nitroguanosine treatment induced enhanced formation of abasic sites in genome DNA of CHO cells.
2. Formation of 8-nitroguanosine was significantly stimulated in the regenerative epithelium of the lung tissues of idiopathic pulmonary fibrosis. Importantly, lung squamous cell carcinoma cells were also strongly stained with 8-nitroguanosine immunohistochemistry. It was found that 8-nitroguanine was excreted in human urine, that was associated with cigarette smoking.
3. 8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) was identified, for the first time, in mammalian cells as a novel nitrated derivative of cGMP. 8-Nitro-cGMP was found to be highlyl reactive with cysteine sulfhydryls to form cGMP adduct (S-guanylation), that can be involved in cellular signaling, especially in oxidative stress response, as a unique post-translational modification.
These data suggest that guanine nitration may be a novel signaling mechanism mediated by NO. that can regulate genome stability as well as stress responses. Better understanding of the mechanisms how 8-nitro-cGMP regulates cellular signaling will give insights into the molecular pathogenesis of infectious and inflammatory diseases.
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