A novel kind of p53 inhibitor that targets the zinc binding site of p53

DOI
  • OHYA Soichiro
    Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science
  • MORITA Akinori
    Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science
  • AOKI Shin
    Department of Medicinal and Life Science, Faculty of Pharmaceutical Science, Tokyo University of Science
  • MOHD Zulkefeli
    Department of Medicinal and Life Science, Faculty of Pharmaceutical Science, Tokyo University of Science
  • ITAKURA Yasunari
    Department of Medicinal and Life Science, Faculty of Pharmaceutical Science, Tokyo University of Science
  • WANG Bing
    Research Center for Radiation Protection, National Institute of Radiological Sciences
  • TANAKA Kaoru
    Research Center for Radiation Protection, National Institute of Radiological Sciences
  • OKAZAKI Haruna
    Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science
  • YOSHINO Minako
    Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science
  • IKEKITA Masahiko
    Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science

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Other Title
  • p53分子内の亜鉛イオン結合部位を標的とする新規阻害剤の開発

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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. Our findings indicate that using zinc chelation would be a new approach to inhibition of p53-dependent apoptotic pathways.

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