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がん治療効果改善を目指すDNA傷害センサーの解析
https://doi.org/10.24517/00063112
https://doi.org/10.24517/000631129ece4bf5-af37-4407-adf8-8ad5a610b1ab
名前 / ファイル | ライセンス | アクション |
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ME-PR-ISHIGAKI-Y-kaken 2007-2p.pdf (113.2 kB)
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Item type | 報告書 / Research Paper(1) | |||||
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公開日 | 2021-11-08 | |||||
タイトル | ||||||
タイトル | がん治療効果改善を目指すDNA傷害センサーの解析 | |||||
タイトル | ||||||
言語 | en | |||||
タイトル | Analysis of mouse DDB1 and human SMG1 | |||||
言語 | ||||||
言語 | jpn | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_18ws | |||||
資源タイプ | research report | |||||
ID登録 | ||||||
ID登録 | 10.24517/00063112 | |||||
ID登録タイプ | JaLC | |||||
著者 |
石垣, 靖人
× 石垣, 靖人 |
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著者別表示 |
Ishigaki, Yasuhito
× Ishigaki, Yasuhito |
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提供者所属 | ||||||
内容記述タイプ | Other | |||||
内容記述 | 金沢大学総合医学研究所 | |||||
書誌情報 |
平成17(2005)年度 科学研究費補助金 基盤研究(C) 研究成果報告書概要 en : 2005 Fiscal Year Final Research Report Summary 巻 2004 – 2005, p. 2p., 発行日 2007-12-12 |
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抄録 | ||||||
内容記述タイプ | Abstract | |||||
内容記述 | 放射線や薬剤等によって引き起こされるDNA傷害は、細胞内においてDNA傷害センサーと呼ばれる因子群によって感知される。センサー因子は傷害を感知した後、細胞周期の調節、修復、アポトーシスなどの機構へシグナルを送ることによって細胞応答を誘導している。がんの治療では、これらセンサー因子の機能抑制によって放射線や抗がん剤の効果を増強し治療効果を高めることが提案されている(Yazlovitskaya & Persons,2003、Collins et al.,2003、Zhou et al.,2003など)。しかし、これらの報告では予備的な結果や考察が示されているに過ぎず、未知のセンサー因子の同定や各センサー因子間の相互作用については解明されるべき点が多い。本研究では、がん治療の増感法開発を目的として、既に詳細に性格づけられてきたセンサー因子であるPI3型キナーゼファミリーのATM、ATRおよび、センサー因子の侯補として本研究で初めて解析を行うATX/SMG1およびDDB1/p127の発現抑制系(ノックアウト系)の開発と、その影響を解析することによって、DNA傷害センサー因子の機能と相互作用を明らかにすることを目指した。その結果、マウスES細胞においてDDB1ヘテロ細胞を確立した。さらにSMG1ノックダウン系では他のNMD関連因子の発現が上昇することを明らかにし、これらの代謝にユビキチン-プロテアソーム系が関与する可能性を明らかにできた。あわせて本研究遂行に必要な基盤術後のひとつとしてプラスミドベクターによるRNAi誘導法に工夫を行い良好な成果をあげた。 | |||||
抄録 | ||||||
内容記述タイプ | Abstract | |||||
内容記述 | To investigate the biological function of damaged DNA binding 1 (DDB1) and new DNA damage sensor SMG1, we tried knockout or knockdown system of them. At first, to improve the efficiency of shRNA knockdown, we constructed multiple shRNA expression sequences in single plasmid vector, which carries RNA polymerase III promoter. XPA gene was selected for target gene because it is not essential for cell viability and easy to check the functional knockdown by the measurement of repair efficiency or sensitivity. After establishment of stable clones, the efficiency of knockdown was compared among single and triple expression vectors. The single shRNA-expressing vector caused limited knockdown of target protein in stable transfectants, but the multiple expression vectors resulted in significantly increased the frequency of knockdown transfectants. There were significant correlations between knockdown level and EGFP expression in multiple-expressing transfectants, while poor correlations were observed in singe vector transfectants. Multiple-transfectants showed the reduced repair efficiency of UV-induced DNA damage and the increased sensitivity to UV-irradiation. We concluded that multiple shRNA expression might be useful strategy to establish knockdown cells with shRNA expression vectors. In addition to this, we established the DDB1 knockout heterozygous mouse ES cells by Cre-loxP conditional knockout method. Further work is required to develop the homozygous DDB1 knockout cells. SMG1 knockdown experiments were also carried to know its biological significance in DNA damage response. SMG1 is one of essential factors in nonsense mediated mRNA decay pathway (NMD), but recent reports show the second function of SMG1 as DNA damage sensor. We could not detect the significant role of SMG1 against DNA damaging agents. However we observed the accumulation of other NND components in SMG1 knockdown cells. Ubiquitin-proteasome inhibitors also had similar effect on the amount of NMD factors and we are going to continue the investigation of the mechanism. | |||||
内容記述 | ||||||
内容記述タイプ | Other | |||||
内容記述 | 研究課題/領域番号:16590045, 研究期間(年度):2004 – 2005 | |||||
内容記述 | ||||||
内容記述タイプ | Other | |||||
内容記述 | 出典:「がん治療効果改善を目指すDNA傷害センサーの解析」研究成果報告書 課題番号16590045 (KAKEN:科学研究費助成事業データベース(国立情報学研究所)) (https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-16590045/165900452005kenkyu_seika_hokoku_gaiyo/)を加工して作成 |
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著者版フラグ | ||||||
出版タイプ | AM | |||||
出版タイプResource | http://purl.org/coar/version/c_ab4af688f83e57aa | |||||
関連URI | ||||||
識別子タイプ | URI | |||||
関連識別子 | https://nrid.nii.ac.jp/ja/search/?kw=20232275 | |||||
関連名称 | https://nrid.nii.ac.jp/ja/search/?kw=20232275 | |||||
関連URI | ||||||
識別子タイプ | URI | |||||
関連識別子 | https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-16590045/ | |||||
関連名称 | https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-16590045/ | |||||
関連URI | ||||||
識別子タイプ | URI | |||||
関連識別子 | https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-16590045/165900452005kenkyu_seika_hokoku_gaiyo/ | |||||
関連名称 | https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-16590045/165900452005kenkyu_seika_hokoku_gaiyo/ |