Sodium orthovanadate is a bifunctional inhibitor of transcription-dependent and -independent p53-mediated apoptosis
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- MORITA Akinori
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science
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- YAMAMOTO Shinichi
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science
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- WANG Bing
- Research Center for Radiation Protection, National Institute of Radiological Sciences
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- TANAKA Kaoru
- Research Center for Radiation Protection, National Institute of Radiological Sciences
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- SUZUKI Norio
- Emeritus Professor, University of Tokyo
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- AOKI Shin
- Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo
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- ITO Azusa
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science
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- NANAO Tomohisa
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science
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- OHYA Soichiro
- 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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- ENOMOTO Atsushi
- Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo
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- MATSUMOTO Yoshihisa
- Research Laboratory for Nuclear Reactors, Tokyo Institute of Technology
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- FUNATSU Osamu
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science
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- HOSOI Yoshio
- Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo
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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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- オルトバナジン酸ナトリウムによるp53転写非依存性アポトーシス抑制機構および放射線防護効果
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Abstract
We recently reported a novel suppressive effect of sodium orthovanadate (vanadate) on the DNA-binding activity of p53. In this study, we initially showed that vanadate had a more potent antiapoptotic activity than three other chemical p53 inhibitors, including pifithrin-α (PFTα), a well-known inhibitor of p53. Although the other agents inhibited the p53 transcriptional activity, they did not suppress p53-dependent apoptosis in irradiated MOLT-4 cells. Further investigations using cells with defective or impaired p53 function indicated vanadate’s specificity for p53 in suppressing DNA damage-induced apoptosis. To investigate the cause for the different effects of vanadate and the other inhibitors, we chose PFTα and PFTµ (an inhibitor of p53-mediated transcription-independent apoptotic pathway), as references, and determined the effect of them and vanadate on p53-mediated apoptosis, with a particular focus on the transcription-independent pathway. We found that vanadate suppressed the p53-associated apoptotic events at the mitochondria, such as the loss of the mitochondrial membrane potential, the conformational change of Bax and Bak, the mitochondrial translocation of p53, and its interaction with Bcl-2. Vanadate also suppressed the apoptosis-inducing activity of mitochondrially-targeted temperature-sensitive p53 in stable transfectants of the SaOS-2 cell line. Finally, we tested vanadate’s potential use as a radioprotector. Vanadate completely protected mice from a sublethal dose of 8 Gy and partially from a lethal dose of 12 Gy. Our data demonstrate that vanadate can suppress both the transcription-dependent and the transcription-independent pathways, and suggest that both pathways must be inhibited to completely block p53-mediated apoptosis.
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 2009 (0), 140-140, 2009
The Japanese Radiation Research Society
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Details 詳細情報について
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- CRID
- 1390282680618205824
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- NII Article ID
- 130007000976
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- Data Source
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- JaLC
- CiNii Articles
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- Abstract License Flag
- Disallowed