A novel kind of radioprotector that targets the zinc binding site of p53
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- OHYA Soichiro
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science
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- MORITA AKinori
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science Center for Technologies against Cancer, Tokyo University of Science Department of Radiation Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University
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- MOHD Zulkefeli
- Department of Medicinal and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science
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- ISEKI Ari
- Department of Medicinal and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science
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- WANG Bing
- Active Radiation Protection Research Team, Radiation Risk Reduction Research Program, National Institute of Radiological Sciences
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- TANAKA Kaoru
- Active Radiation Protection Research Team, Radiation Risk Reduction Research Program, National Institute of Radiological Sciences
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- OKAZAKI Haruna
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science
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- YOSHINO Minako
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science
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- HOSOI Yoshio
- Department of Radiation Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University
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- AOKI Shin
- Department of Medicinal and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science
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- IKEKITA Masahiko
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science
Bibliographic Information
- Other Title
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- p53分子内の亜鉛イオン結合部位を標的とする新規放射線防護剤の開発
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Abstract
We have demonstrated that sodium orthovanadate (vanadate) is the first inhibitor that can protect death from radiation-induced gastrointestinal syndrome in mice by blocking both transcription-dependent and transcription-independent p53 apoptotic pathways. In this study, we initially found that vanadate has a unique activity in inducing a denaturation of p53 relative to other known radioprotective p53 inhibitors, pifithrin-α and pifithrin-µ. We therefore postulated that the activity might be associated with the potent radioprotective activity of vanadate, and searched for a new p53 inhibitor that could induce p53 denaturation. On the other hand, it is known that p53 denaturation is induced by dissociation of a zinc ion, which is coordinated to metal ion binding site of p53, and hence we evaluated some zinc chelators for inhibition of p53-dependent apoptosis of irradiated MOLT-4 cells. As a result, two out of five zinc chelators suppressed the apoptosis. Especially, bispicen, having the highest efficacy in inhibition of the apoptosis, shows the effects on p53 denaturation as well as on inhibition of both transcription-dependent and -independent apoptotic pathways, the similar effects to vanadate. In addition, we revealed that the suppressive effect of bispicen on apoptosis is specifically mediated by p53 using p53-knockdown MOLT-4 transformants, p53 mutant cells, and p53-null cells. Our findings indicate that using zinc chelation would be a new approach to inhibition of p53-dependent apoptotic pathways. We are currently characterizing a new compound that is a hybrid compound that consists of bispicen and a p53-specific peptide, which is synthesized in order to provide the specificity for p53.
Journal
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- The Japan Radiation Research Society Annual Meeting Abstracts
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The Japan Radiation Research Society Annual Meeting Abstracts 2011 (0), 106-106, 2011
The Japanese Radiation Research Society
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Details 詳細情報について
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- CRID
- 1390001205640321792
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- NII Article ID
- 130007000107
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- Text Lang
- ja
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- Data Source
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- JaLC
- CiNii Articles
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- Abstract License Flag
- Disallowed