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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

Zinc Is a Potent Inhibitor of the Apoptotic Protease, caspase-3. A Novel Target for Zinc in the Inhibition of Apoptosis

D K Perry, M J Smyth, H R Stennicke, G S Salvesen, P Duriez, G G Poirier, Y A Hannun

J Biol Chem. 1997 Jul 25;272(30):18530-3.

PMID: 9228015

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4249340	Caspase Substrate, chromogenic			Price

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