Zinc Is a Potent Inhibitor of the Apoptotic Protease, Caspase-3

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

doi:10.1074/jbc.272.30.18530

Cited by 443 publications

(141 citation statements)

References 28 publications

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“…The point of convergence of these pathways at the level of eIF4G is most likely the activation of one or more`executioner' caspases (Longthorne and Williams, 1997; Kamada et al, 1997;Cohen, 1997). This is consistent with the ability of the caspase inhibitors (Z-VAD.FMK and Z-DEVD.FMK; Dolle et al, 1994;Fearnhead et al, 1995;Perry et al, 1997;Juo et al, 1997), but not calpain or proteosome inhibitors (data not shown), to block the disappearance of eIF4G regardless of the apoptosis-inducing stimulus.…”

Section: Discussionsupporting

confidence: 57%

“…Both Z-VAD.FMK and Z-DEVD.FMK have relatively broad speci®cities against a number of caspases (Kidd, 1998). ZnCl 2 is an inhibitor of caspase-3 but it is not clear whether it is also active against other caspases (Perry et al, 1997). Although it is likely that several di erent caspases become activated under the conditions of our experiments the lack of e ect of ZnCl 2 on eIF4G cleavage might suggest that caspase-3 activity is not required.…”

Section: Discussionmentioning

confidence: 73%

“…76 kDa cleavage product (Figure 6b). However exposure of the cells to a reported inhibitor of caspase-3, ZnCl 2 (Perry et al, 1997), was without e ect in these cells. The cleavage of PARP in the cycloheximide-treated cells was also inhibited by Z-VAD.FMK and Z-DEVD.FMK but not by ZnCl 2 (data not shown).…”

Section: Cycloheximide Treatment Induces Apoptosis and Cleavage Of Eimentioning

confidence: 87%

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Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

1998

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We have investigated the e ect of inducing apoptosis in BJAB and Jurkat cells on the cellular content of several polypeptide chain initiation factors. Serum deprivation results in inhibition of protein synthesis and induction of apoptosis in BJAB cells; at early times, there is selective degradation of polypeptide initiation factor eIF4G but no major losses of other key initiation factors. The disappearance of full length eIF4G is accompanied by the appearance of smaller forms of the protein, including a major product of approximately 76 kDa. Apoptosis induced by cycloheximide results in similar e ects. Both total cytoplasmic eIF4G and eIF4G associated with eIF4E are degraded with a half-life of 2 ± 4 h under these conditions. Treatment of serum-starved or cycloheximide-treated cells with Z-VAD.FMK or Z-DEVD.FMK, which inhibit caspases required for apoptosis, protects eIF4G from degradation and blocks the appearance of the ca. 76 kDa product. Exposure of BJAB cells to rapamycin rapidly inhibits protein synthesis but does not lead to acute degradation of eIF4G. In both BJAB and Jurkat cells induction of apoptosis with anti-Fas antibody or etoposide also results in the selective loss of eIF4G, which is inhibitable by Z-VAD.FMK. These data suggest that eIF4G is selectively targeted for cleavage as cells undergo apoptosis and is a substrate for proteases activated during this process.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 73%

Section: Cycloheximide Treatment Induces Apoptosis and Cleavage Of Eimentioning

confidence: 87%

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Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

1998

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“…Since MT may be involved in zinc homeostasis, it can regulate the supply of zinc to p53 protein for its optimum activity and also protect the cells from toxicity to metals and free radicals. Lastly, zinc is known to inhibit the activation of both caspase 3 (Perry et al, 1997) and Ca/Mg-dependent endonuclease (Cohen and Duke, 1984), which play critical roles in the execution of apoptosis. MT, as a zinc binding protein, may also act as an anti-apoptotic factor.…”

Section: Discussionmentioning

confidence: 99%

Potential role of p53 on metallothionein induction in human epithelial breast cancer cells

Fan

Cherian

2002

Br J Cancer

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The expression and induction of metallothionein has been associated with protection against oxidative stress and apoptosis. This study examines the effect of tumour suppressor protein p53 on metallothionein expression following CdCl 2 treatment in eight human epithelial breast cancer cell lines differing in p53 and oestrogen-receptor status. Cells were treated with 10 mM CdCl 2 for 24 h and metallothionein protein levels were measured by cadmium binding assay. MCF7 cells which are p53-positive (p53+) and oestrogen-receptor-positive showed a large induction in metallothionein synthesis by 10.79+1.36-fold. Other breast cancer cell lines which are p53-negative (p537) and oestrogen-receptor-negative or weakly oestrogenreceptor-positive showed a small induction ranging from 1.40+0.10 to 3.65+0.30-fold. RT -PCR analysis showed an induction of metallothionein mRNA in MCF7 cells by about 1.61+0.08-fold, while in HCC1806 cells (p537, oestrogenreceptor-negative) by 1.11+0.13-fold, and in MDA-MB-231 (p537, oestrogen-receptor-negative) by 1.25+0.06-fold. Metallothionein localisation was determined by immunohistochemical staining. Prior to metal treatment, metallothionein was localised mainly in the cytoplasm of MCF7 and MDA-MB-231 cells. After treatment with 10 mM CdCl 2 for 24 h, MCF7 cells showed intense nuclear and cytoplasmic staining for metallothionein, while MDA-MB-231 cells showed staining in the cytoplasm with weak nuclear staining. Apoptosis induced by 10 -40 mM CdCl 2 at time points between 4 and 48 h was examined with TUNEL assay. In MCF7 cells, apoptosis increased with higher concentrations of CdCl 2 , it peaked at 6 -8 h and appeared again at 48 h for all concentrations of CdCl 2 tested. In MDA-MB-231 cells, apoptosis remained at low levels for 10 -40 mM CdCl 2 at all time points. Studies on cadmium uptake showed similar uptake and accumulation of cadmium at 8 and 24 h in all the cell lines. The data demonstrate that treatment of epithelial breast cancer cells with 10 mM CdCl 2 for 24 h caused a greater induction of metallothionein protein and mRNA expression in p53+ and oestrogen-receptor-positive cells as compared to p537 and oestrogen-receptor-negative or weakly oestrogen-receptor-positive cells. This effect may be associated with the occurrence of apoptosis and suggests a role for p53 and oestrogen-receptor on the expression and induction of metallothionein in epithelial cells.

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“…Zinc is an essential element for life and is known to play important roles in biological processes including gene expression, apoptosis, enzyme regulation, immune system and neurotransmission [1][2][3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

A novel small molecule fluorescent sensor for Zn2+ based on pyridine–pyridone scaffold

Hagimori

Mizuyama

Yamaguchi

et al. 2011

Talanta

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Zinc Is a Potent Inhibitor of the Apoptotic Protease, Caspase-3

Cited by 443 publications

References 28 publications

Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

Potential role of p53 on metallothionein induction in human epithelial breast cancer cells

A novel small molecule fluorescent sensor for Zn2+ based on pyridine–pyridone scaffold

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