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Zinc is a potent inhibitor of the apoptotic protease, caspase-3. a novel target for zinc in the inhibition of apoptosis

Record type: Article

The prevention of apoptosis by Zn2+ has generally been attributed to its inhibition of an endonuclease acting in the late phase of apoptosis. In this study we investigated the effect of Zn2+ on an earlier event in the apoptotic process, the proteolysis of the "death substrate" poly(ADP-ribose) polymerase (PARP). Pretreatment of intact Molt4 leukemia cells with micromolar concentrations of Zn2+ caused an inhibition of PARP proteolysis induced by the chemotherapeutic agent etoposide. Using a cell-free system consisting of purified bovine PARP as a substrate and an apoptotic extract or recombinant caspase-3 as the PARP protease, Zn2+ inhibited PARP proteolysis in the low micromolar range. To rule out an effect of Zn2+ on PARP, a protein with two zinc finger domains, we used recombinant caspase-3 and a chromogenic tetrapeptide substrate containing the caspase-3 cleavage site. In this system, Zn2+ inhibited caspase-3 with an IC50 of 0.1 microM. These results identify caspase-3 as a novel target of Zn2+ inhibition in apoptosis and suggest a regulatory role for Zn2+ in modulating the upstream apoptotic machinery.

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Citation

Perry, David K., Smyth, Mirrian J., Stennicke, Henning R., Salvesen, Guy S., Duriez, Patrick, Poirier, Guy G. and Hannun, Yusuf A. (1997) Zinc is a potent inhibitor of the apoptotic protease, caspase-3. a novel target for zinc in the inhibition of apoptosis The Journal of Biological Chemistry, 272, (30), pp. 18530-18533. (doi:10.1074/jbc.272.30.18530). (PMID:9228015).

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Published date: 25 July 1997

Identifiers

Local EPrints ID: 164823
URI: http://eprints.soton.ac.uk/id/eprint/164823
ISSN: 0021-9258
PURE UUID: 4087a6de-aa68-4f2d-80de-d72ee9529a91

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Date deposited: 04 Oct 2010 14:27
Last modified: 18 Jul 2017 12:28

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Contributors

Author: David K. Perry
Author: Mirrian J. Smyth
Author: Henning R. Stennicke
Author: Guy S. Salvesen
Author: Patrick Duriez
Author: Guy G. Poirier
Author: Yusuf A. Hannun

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