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j.celrep.2021.108876.pdf | 6.41 MB | Adobe PDF | 見る/開く |
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dc.contributor.author | Higuchi, Makio | en |
dc.contributor.author | Ishiyama, Kenichi | en |
dc.contributor.author | Maruoka, Masahiro | en |
dc.contributor.author | Kanamori, Ryosuke | en |
dc.contributor.author | Takaori-Kondo, Akifumi | en |
dc.contributor.author | Watanabe, Naoki | en |
dc.contributor.alternative | 樋口, 牧郎 | ja |
dc.contributor.alternative | 石山, 賢一 | ja |
dc.contributor.alternative | 圓岡, 真宏 | ja |
dc.contributor.alternative | 高折, 晃史 | ja |
dc.contributor.alternative | 渡邊, 直樹 | ja |
dc.date.accessioned | 2021-03-25T01:50:21Z | - |
dc.date.available | 2021-03-25T01:50:21Z | - |
dc.date.issued | 2021-03-23 | - |
dc.identifier.issn | 2211-1247 | - |
dc.identifier.uri | http://hdl.handle.net/2433/262322 | - |
dc.description | 抗がん剤抵抗性の新規メカニズムの解明 --薬剤抵抗性がん細胞は抗がん剤により増殖する--. 京都大学プレスリリース. 2021-03-25. | ja |
dc.description.abstract | ATP-competitive inhibitors have been developed as promising anti-cancer agents. However, drug-resistance frequently occurs, and the underlying mechanisms are not fully understood. Here, we show that the activation of c-Src and its downstream phosphorylation cascade can be paradoxically induced by Src-targeted and RTK-targeted kinase inhibitors. We reveal that inhibitor binding induces a conformational change in c-Src, leading to the association of the active form c-Src with focal adhesion kinase (FAK). Reduction of the inhibitor concentration results in the dissociation of inhibitors from the c-Src-FAK complex, which allows c-Src to phosphorylate FAK and initiate FAK-Grb2-mediated Erk signaling. Furthermore, a drug-resistant mutation in c-Src, which reduces the affinity of inhibitors for c-Src, converts Src inhibitors into facilitators of cell proliferation by enhancing the phosphorylation of FAK and Erk in c-Src-mutated cells. Our data thus reveal paradoxical enhancement of cell growth evoked by target-based kinase inhibitors, providing potentially important clues for the future development of effective and safe cancer treatment. | en |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Elsevier BV | en |
dc.rights | © 2021 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). | en |
dc.subject | c-Src | en |
dc.subject | FAK | en |
dc.subject | kinase inhibitor | en |
dc.subject | drug resistance | en |
dc.subject | anchorage-dependent signaling | en |
dc.subject | paradoxical activation | en |
dc.subject | allosteric effects | en |
dc.title | Paradoxical activation of c-Src as a drug-resistant mechanism | en |
dc.type | journal article | - |
dc.type.niitype | Journal Article | - |
dc.identifier.jtitle | Cell Reports | en |
dc.identifier.volume | 34 | - |
dc.identifier.issue | 12 | - |
dc.relation.doi | 10.1016/j.celrep.2021.108876 | - |
dc.textversion | publisher | - |
dc.identifier.artnum | 108876 | - |
dc.identifier.pmid | 33761359 | - |
dc.identifier.kaken | 19H01020 | - |
dc.relation.url | https://www.kyoto-u.ac.jp/ja/research-news/2021-03-25 | - |
dcterms.accessRights | open access | - |
dc.identifier.eissn | 2211-1247 | - |
出現コレクション: | 学術雑誌掲載論文等 |
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