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アイテム
A Chemical Modulator of p53 Transactivation that Acts as a Radioprotective Agonist
https://repo.qst.go.jp/records/48555
https://repo.qst.go.jp/records/48555b7e61324-7552-4cff-a57c-28c75304ec7f
| Item type | 学術雑誌論文 / Journal Article(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2018-03-05 | |||||
| タイトル | ||||||
| タイトル | A Chemical Modulator of p53 Transactivation that Acts as a Radioprotective Agonist | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
| 資源タイプ | journal article | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Morita, Akinori
× Morita, Akinori× Takahashi, Ippei× Sasatani, Megumi× Aoki, Shin× Wang, Bing× Ariyasu, Shinya× Tanaka, Kaoru× Yamaguchi, Tetsuji× Sawa, Akiko× Nishi, Yurie× Teraoka, Tatsuro× Ujita, Shohei× Kawate, Yosuke× Yanagawa, Chihiro× Tanimoto, Keiji× Enomoto, Atsushi× Nenoi, Mitsuru× Kamiya, Kenji× Nagata, Yasushi× Hosoi, Yoshio× Inaba, Toshiya× 王 冰× 田中 薫× 根井 充 |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Inhibiting p53-dependent apoptosis by inhibitors of p53 is an effective strategy for preventing radiation-induced damage in hematopoietic lineages, while p53 and p21 also play radioprotective roles in the gastrointestinal epithelium. We previously identified some zinc(II) chelators, including 8-quinolinol derivatives, that suppress apoptosis in attempts to discover compounds that target the zinc-binding site in p53. We found that 5-chloro-8-quinolinol (5CHQ) has a unique p53-modulating activity that shifts its transactivation from proapoptotic to protective responses, including enhancing p21 induction and suppressing PUMA induction. This p53-modulating activity also influenced p53 and p53-target gene expression in unirradiated cells without inducing DNA damage. The specificity of 5CHQ for p53 and p21 was demonstrated by silencing the expression of each protein. These effects seem to be attributable to the sequence-specific alteration of p53 DNA-binding, as evaluated by chromatin immunoprecipitation and electrophoretic mobility shift assays. In addition, 5-chloro-8-methoxyquinoline itself had no antiapoptotic activity, indicating that the hydroxyl group at the 8-position is required for its antiapoptotic activity. We applied this remarkable agonistic activity to protecting the hematopoietic and gastrointestinal system in mouse irradiation models. The dose reduction factors of 5CHQ in total-body and abdominally irradiated mice were about 1.2 and 1.3, respectively. 5CHQ effectively protected mouse epithelial stem cells from a lethal dose of abdominal irradiation. Furthermore, the specificity of 5CHQ for p53 in reducing the lethality induced by abdominal irradiation was revealed in Trp53-KO mice. These results indicate that the pharmacologic upregulation of radioprotective p53 target genes is an effective strategy for addressing the gastrointestinal syndrome. | |||||
| 書誌情報 |
Molecular Cancer Therapeutics 巻 17, 号 2, p. 432-442, 発行日 2017-09 |
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| 出版者 | ||||||
| 出版者 | American Association for Cancer Research | |||||
| ISSN | ||||||
| 収録物識別子タイプ | ISSN | |||||
| 収録物識別子 | 1535-7163 | |||||
| DOI | ||||||
| 識別子タイプ | DOI | |||||
| 関連識別子 | 10.1158/1535-7163 | |||||
| 関連サイト | ||||||
| 識別子タイプ | URI | |||||
| 関連識別子 | http://mct.aacrjournals.org/content/17/2/432 | |||||
| 関連名称 | http://mct.aacrjournals.org/content/17/2/432 | |||||
