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Molecular Pharmacology

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Research ArticleArticle

Synthetic Metallochaperone ZMC1 Rescues Mutant p53 Conformation by Transporting Zinc into Cells as an Ionophore

Adam R. Blanden, Xin Yu, Aaron J. Wolfe, John A. Gilleran, David J. Augeri, Ryan S. O’Dell, Eric C. Olson, S. David Kimball, Thomas J. Emge, Liviu Movileanu, Darren R. Carpizo and Stewart N. Loh
Molecular Pharmacology May 2015, 87 (5) 825-831; DOI: https://doi.org/10.1124/mol.114.097550
Adam R. Blanden
Department of Biochemistry and Molecular Biology (A.R.B.,S.N.L.) and Department of Neuroscience and Physiology (R.S.O., E.C.O.), State University of New York Upstate Medical University, Syracuse, New York; Rutgers Cancer Institute of New Jersey (X.Y., D.R.C.), Department of Surgery, Rutgers Robert Wood Johnson Medical School (X.Y., D.R.C.), Office of Translational Sciences (J.A.G., D.J.A., S.D.K.), and Department of Chemistry and Chemical Biology (T.J.E.), Rutgers University, New Brunswick, New Jersey; and Department of Physics, Syracuse University, Syracuse, New York (A.J.W., L.M.)
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Xin Yu
Department of Biochemistry and Molecular Biology (A.R.B.,S.N.L.) and Department of Neuroscience and Physiology (R.S.O., E.C.O.), State University of New York Upstate Medical University, Syracuse, New York; Rutgers Cancer Institute of New Jersey (X.Y., D.R.C.), Department of Surgery, Rutgers Robert Wood Johnson Medical School (X.Y., D.R.C.), Office of Translational Sciences (J.A.G., D.J.A., S.D.K.), and Department of Chemistry and Chemical Biology (T.J.E.), Rutgers University, New Brunswick, New Jersey; and Department of Physics, Syracuse University, Syracuse, New York (A.J.W., L.M.)
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Aaron J. Wolfe
Department of Biochemistry and Molecular Biology (A.R.B.,S.N.L.) and Department of Neuroscience and Physiology (R.S.O., E.C.O.), State University of New York Upstate Medical University, Syracuse, New York; Rutgers Cancer Institute of New Jersey (X.Y., D.R.C.), Department of Surgery, Rutgers Robert Wood Johnson Medical School (X.Y., D.R.C.), Office of Translational Sciences (J.A.G., D.J.A., S.D.K.), and Department of Chemistry and Chemical Biology (T.J.E.), Rutgers University, New Brunswick, New Jersey; and Department of Physics, Syracuse University, Syracuse, New York (A.J.W., L.M.)
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John A. Gilleran
Department of Biochemistry and Molecular Biology (A.R.B.,S.N.L.) and Department of Neuroscience and Physiology (R.S.O., E.C.O.), State University of New York Upstate Medical University, Syracuse, New York; Rutgers Cancer Institute of New Jersey (X.Y., D.R.C.), Department of Surgery, Rutgers Robert Wood Johnson Medical School (X.Y., D.R.C.), Office of Translational Sciences (J.A.G., D.J.A., S.D.K.), and Department of Chemistry and Chemical Biology (T.J.E.), Rutgers University, New Brunswick, New Jersey; and Department of Physics, Syracuse University, Syracuse, New York (A.J.W., L.M.)
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David J. Augeri
Department of Biochemistry and Molecular Biology (A.R.B.,S.N.L.) and Department of Neuroscience and Physiology (R.S.O., E.C.O.), State University of New York Upstate Medical University, Syracuse, New York; Rutgers Cancer Institute of New Jersey (X.Y., D.R.C.), Department of Surgery, Rutgers Robert Wood Johnson Medical School (X.Y., D.R.C.), Office of Translational Sciences (J.A.G., D.J.A., S.D.K.), and Department of Chemistry and Chemical Biology (T.J.E.), Rutgers University, New Brunswick, New Jersey; and Department of Physics, Syracuse University, Syracuse, New York (A.J.W., L.M.)
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Ryan S. O’Dell
Department of Biochemistry and Molecular Biology (A.R.B.,S.N.L.) and Department of Neuroscience and Physiology (R.S.O., E.C.O.), State University of New York Upstate Medical University, Syracuse, New York; Rutgers Cancer Institute of New Jersey (X.Y., D.R.C.), Department of Surgery, Rutgers Robert Wood Johnson Medical School (X.Y., D.R.C.), Office of Translational Sciences (J.A.G., D.J.A., S.D.K.), and Department of Chemistry and Chemical Biology (T.J.E.), Rutgers University, New Brunswick, New Jersey; and Department of Physics, Syracuse University, Syracuse, New York (A.J.W., L.M.)
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Eric C. Olson
Department of Biochemistry and Molecular Biology (A.R.B.,S.N.L.) and Department of Neuroscience and Physiology (R.S.O., E.C.O.), State University of New York Upstate Medical University, Syracuse, New York; Rutgers Cancer Institute of New Jersey (X.Y., D.R.C.), Department of Surgery, Rutgers Robert Wood Johnson Medical School (X.Y., D.R.C.), Office of Translational Sciences (J.A.G., D.J.A., S.D.K.), and Department of Chemistry and Chemical Biology (T.J.E.), Rutgers University, New Brunswick, New Jersey; and Department of Physics, Syracuse University, Syracuse, New York (A.J.W., L.M.)
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S. David Kimball
Department of Biochemistry and Molecular Biology (A.R.B.,S.N.L.) and Department of Neuroscience and Physiology (R.S.O., E.C.O.), State University of New York Upstate Medical University, Syracuse, New York; Rutgers Cancer Institute of New Jersey (X.Y., D.R.C.), Department of Surgery, Rutgers Robert Wood Johnson Medical School (X.Y., D.R.C.), Office of Translational Sciences (J.A.G., D.J.A., S.D.K.), and Department of Chemistry and Chemical Biology (T.J.E.), Rutgers University, New Brunswick, New Jersey; and Department of Physics, Syracuse University, Syracuse, New York (A.J.W., L.M.)
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Thomas J. Emge
Department of Biochemistry and Molecular Biology (A.R.B.,S.N.L.) and Department of Neuroscience and Physiology (R.S.O., E.C.O.), State University of New York Upstate Medical University, Syracuse, New York; Rutgers Cancer Institute of New Jersey (X.Y., D.R.C.), Department of Surgery, Rutgers Robert Wood Johnson Medical School (X.Y., D.R.C.), Office of Translational Sciences (J.A.G., D.J.A., S.D.K.), and Department of Chemistry and Chemical Biology (T.J.E.), Rutgers University, New Brunswick, New Jersey; and Department of Physics, Syracuse University, Syracuse, New York (A.J.W., L.M.)
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Liviu Movileanu
Department of Biochemistry and Molecular Biology (A.R.B.,S.N.L.) and Department of Neuroscience and Physiology (R.S.O., E.C.O.), State University of New York Upstate Medical University, Syracuse, New York; Rutgers Cancer Institute of New Jersey (X.Y., D.R.C.), Department of Surgery, Rutgers Robert Wood Johnson Medical School (X.Y., D.R.C.), Office of Translational Sciences (J.A.G., D.J.A., S.D.K.), and Department of Chemistry and Chemical Biology (T.J.E.), Rutgers University, New Brunswick, New Jersey; and Department of Physics, Syracuse University, Syracuse, New York (A.J.W., L.M.)
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Darren R. Carpizo
Department of Biochemistry and Molecular Biology (A.R.B.,S.N.L.) and Department of Neuroscience and Physiology (R.S.O., E.C.O.), State University of New York Upstate Medical University, Syracuse, New York; Rutgers Cancer Institute of New Jersey (X.Y., D.R.C.), Department of Surgery, Rutgers Robert Wood Johnson Medical School (X.Y., D.R.C.), Office of Translational Sciences (J.A.G., D.J.A., S.D.K.), and Department of Chemistry and Chemical Biology (T.J.E.), Rutgers University, New Brunswick, New Jersey; and Department of Physics, Syracuse University, Syracuse, New York (A.J.W., L.M.)
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Stewart N. Loh
Department of Biochemistry and Molecular Biology (A.R.B.,S.N.L.) and Department of Neuroscience and Physiology (R.S.O., E.C.O.), State University of New York Upstate Medical University, Syracuse, New York; Rutgers Cancer Institute of New Jersey (X.Y., D.R.C.), Department of Surgery, Rutgers Robert Wood Johnson Medical School (X.Y., D.R.C.), Office of Translational Sciences (J.A.G., D.J.A., S.D.K.), and Department of Chemistry and Chemical Biology (T.J.E.), Rutgers University, New Brunswick, New Jersey; and Department of Physics, Syracuse University, Syracuse, New York (A.J.W., L.M.)
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This article has a correction. Please see:

  • Correction to “Synthetic metallochaperone ZMC1 rescues mutant p53 conformation by transporting zinc into cells as an ionophore” - December 01, 2015

Abstract

p53 is a Zn2+-dependent tumor suppressor inactivated in >50% of human cancers. The most common mutation, R175H, inactivates p53 by reducing its affinity for the essential zinc ion, leaving the mutant protein unable to bind the metal in the low [Zn2+]free environment of the cell. The exploratory cancer drug zinc metallochaperone-1 (ZMC1) was previously demonstrated to reactivate this and other Zn2+-binding mutants by binding Zn2+ and buffering it to a level such that Zn2+ can repopulate the defective binding site, but how it accomplishes this in the context of living cells and organisms is unclear. In this study, we demonstrated that ZMC1 increases intracellular [Zn2+]free by functioning as a Zn2+ ionophore, binding Zn2+ in the extracellular environment, diffusing across the plasma membrane, and releasing it intracellularly. It raises intracellular [Zn2+]free in cancer (TOV112D) and noncancer human embryonic kidney cell line 293 to 15.8 and 18.1 nM, respectively, with half-times of 2–3 minutes. These [Zn2+]free levels are predicted to result in ∼90% saturation of p53-R175H, thus accounting for its observed reactivation. This mechanism is supported by the X-ray crystal structure of the [Zn(ZMC1)2] complex, which demonstrates structural and chemical features consistent with those of known metal ionophores. These findings provide a physical mechanism linking zinc metallochaperone-1 in both in vitro and in vivo activities and define the remaining critical parameter necessary for developing synthetic metallochaperones for clinical use.

Footnotes

    • Received December 22, 2014.
    • Accepted February 20, 2015.
  • This work was supported by grants from the National Institutes of Health National Cancer Institute [Grant K08-CA172676-02], the Breast Cancer Research Foundation, the Harrington Discovery Institute, and the Sidney Kimmel Foundation for Cancer Research to D.R.C., the Carol M. Baldwin Breast Cancer Research Award to S.N.L., and the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM088403] to L.M.

  • dx.doi.org/10.1124/mol.114.097550.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.asetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 87 (5)
Molecular Pharmacology
Vol. 87, Issue 5
1 May 2015
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Research ArticleArticle

ZMC1 Reactivates Mutant p53 by Transporting Zn2+

Adam R. Blanden, Xin Yu, Aaron J. Wolfe, John A. Gilleran, David J. Augeri, Ryan S. O’Dell, Eric C. Olson, S. David Kimball, Thomas J. Emge, Liviu Movileanu, Darren R. Carpizo and Stewart N. Loh
Molecular Pharmacology May 1, 2015, 87 (5) 825-831; DOI: https://doi.org/10.1124/mol.114.097550

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Research ArticleArticle

ZMC1 Reactivates Mutant p53 by Transporting Zn2+

Adam R. Blanden, Xin Yu, Aaron J. Wolfe, John A. Gilleran, David J. Augeri, Ryan S. O’Dell, Eric C. Olson, S. David Kimball, Thomas J. Emge, Liviu Movileanu, Darren R. Carpizo and Stewart N. Loh
Molecular Pharmacology May 1, 2015, 87 (5) 825-831; DOI: https://doi.org/10.1124/mol.114.097550
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