Zinc is a potent inhibitor of the apoptotic protease, caspase-3. a novel target for zinc in the inhibition of apoptosis
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. Journal of Biological Chemistry, 272, (30), 18530-18533. (doi:10.1074/jbc.272.30.18530). (PMID:9228015).
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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.
|Subjects:||Q Science > QD Chemistry
Q Science > QR Microbiology > QR180 Immunology
Q Science > QH Natural history > QH301 Biology
|Divisions:||University Structure - Pre August 2011 > School of Medicine > Cancer Sciences
|Date Deposited:||04 Oct 2010 14:27|
|Last Modified:||01 Jun 2011 03:17|
|Contributors:||Perry, David K. (Author)
Smyth, Mirrian J. (Author)
Stennicke, Henning R. (Author)
Salvesen, Guy S. (Author)
Duriez, Patrick (Author)
Poirier, Guy G. (Author)
Hannun, Yusuf A. (Author)
|Date:||25 July 1997|
|RDF:||RDF+N-Triples, RDF+N3, RDF+XML, Browse.|
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