Evaluation of Zinc (II) chelators for inhibiting p53-mediated apoptosis
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Akinori Morita1,2, Shinya Ariyasu3, Soichiro Ohya4, Ippei Takahashi2, Bing Wang5, Kaoru Tanaka5, Takatoshi Uchida4, Haruna Okazaki4, Kengo Hanaya6, Atsushi Enomoto7, Mitsuru Nenoi5, Masahiko Ikekita4, Shin Aoki3,6, Yoshio Hosoi2
1 Department of Radiological Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
2 Department of Radiation Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
3 Center for Technologies against Cancer, Tokyo University of Science, Chiba, Japan
4 Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan
5 Radiation Risk Reduction Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan
6 Department of Medicinal and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan
7 Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Akinori Morita, email:
Keywords: p53, zinc chelator, zinc binding site, radiation, apoptosis
Received: October 23, 2013 Accepted: November 22, 2013 Published: November 24, 2013
In a previous study, we reported that sodium orthovanadate (vanadate) is the first known inhibitor that is capable of protecting mice from death from the radiation-induced gastrointestinal syndrome via its ability to block both transcription-dependent and transcription-independent p53 apoptotic pathways. In this paper, we report that vanadate has a unique activity for inducing the denaturation of p53 relative to other known radioprotective p53 inhibitors, pifithrin-α (PFTα) and pifithrin-µ (PFTµ). This potent radioprotective effect of vanadate prompted us to undertake a more extensive search for p53 inhibitors that can induce p53 denaturation. Based on the fact that p53 denaturation can be induced by the dissociation of a zinc ion, which is used as a structural factor of p53, we screened some zinc (II) chelators for the suppression of the DNA binding activity of p53 in vitro and the inhibition of radiation-induced p53-dependent apoptosis in MOLT-4 cells. The findings indicate that two of five zinc (II) chelators also suppressed apoptosis. Among the inhibitors tested, Bispicen (N,N’-Bis(2-pyridylmethyl)-1,2-ethanediamine) had the highest inhibition activity. A mechanistic study using cells bearing different p53 status or functions (i.e., p53-knockdown MOLT-4 transformant and its revertants, p53 mutant cells, p53-null cells), and p53-independent apoptotic stimuli revealed that the suppressive effect of Bispicen on apoptosis is specifically mediated through p53. Moreover, Bispicen, similar to vanadate, induces the denaturation of p53 as well as the blocking of both transcription-dependent and -independent apoptotic pathways. Our findings indicate that the use of zinc (II) chelators represent a new approach for protecting against radiation-induced p53-dependent apoptosis through the inhibition of p53-dependent apoptotic pathways.
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