2007 Fiscal Year Final Research Report Summary
Molecular mechanisms of nitric oxide-dependent modification and regulation of genome functions
| 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)
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| Project Period (FY) |
2005 – 2007
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| Keywords | Nitric oxide / 8-nitroguanosine / 8-nitro-cGMP / signal transduction / S-guanylation / post-translational modification / genome mutation / oxidative stress |
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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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Research Products
(63 results)
