A critical physiological role of zinc in the structure and function of biomembranes

Bettger, William J.; O’Dell, Boyd L.

doi:10.1016/0024-3205(81)90374-x

Cited by 598 publications

(194 citation statements)

References 122 publications

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“…The signal initiating the activation of cytosolic ICE-like proteases could be also from the cell surface. Zinc has been found to significantly affect the cell membrane by interfering with macromolecular components of the membrane, thus changing their conformation or enzyme-substrate specificity (Bettger and O'Dell, 1981). Therefore, it is possible that chelation of Zn 2+ by TPEN may activate ICE-like proteases by a pathway similar to that triggered by receptor-mediated apoptotic stimuli, for example, anti-Fas antibody.…”

Section: Discussionmentioning

confidence: 99%

The role of proteolysis in T cell apoptosis triggered by chelation of intracellular Zn2+

et al. 1997

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Our previous work showed that chelation of intracellular Zn 2+ with N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) induces apoptosis in rat thymocytes. The molecular mechanism involved in TPEN-triggered apoptosis remains unknown, except that it is a Ca 2+ -independent process. In the present study, we show that TPEN is unable to induce DNA fragmentation when added to isolated thymocyte nuclei, indicating that activation of a cytoplasmic component is essential for TPEN-induced apoptosis. Since cytosolic proteases related to interleukin-1b-converting enzyme (ICE) are implicated as key activators of apoptosis in many different systems, we investigated the possible involvement of such proteases in TPEN-induced apoptosis. We found that treatment of thymocytes with TPEN caused an early degradation of nuclear poly(ADP-ribose) polymerase (PARP) and lamin prior to DNA cleavage. This could be inhibited by ZVal-Ala-Asp-chloromethylketone (VADcmk), an inhibitor of ICE-like proteases, but not by an inhibitor of Ca 2+ -regulated serine protease. Jurkat T cells also underwent extensive DNA fragmentation when incubated with TPEN. A cytosolic fraction, prepared from TPEN-treated Jurkat cells, produced extensive DNA fragmentation when applied to isolated thymocyte nuclei, whereas the cytoplasmic extract from untreated cells was ineffective either alone or together with TPEN. The apoptosis-inducing activity in cytosolic fraction from TPEN-treated Jurkat cells was blocked by incubating cells in the presence of VADcmk or another inhibitor of ICE-like proteases, Ac -Asp -Glu -Val -Asp-aldehyde (DEVD-CHO), which has been found to competitively inhibit CPP32/apopain. An increase in enzyme activity that cleaves Ac-Asp-Glu-ValAsp-7-amino-4-methylcoumarin (DEVD-AMC), a fluorogenic substrate of CPP32/apopain and Mch3a, was detected in TPEN-treated thymocytes and Jurkat cells. In addition, the proteolytic cleavage of CPP32 resulting in the formation of two active fragments (p17 and p12) was observed in cytosolic extracts from TPEN-treated Jurkat cells, but not in extracts which were prepared from cells treated with TPEN in the presence of VADcmk or DEVD-CHO. Our results suggest that activation of cytosolic ICE-like proteases is an essential step in TPEN-induced apoptosis, and that CPP32/apopain is critically involved in this process.

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Section: Discussionmentioning

confidence: 99%

The role of proteolysis in T cell apoptosis triggered by chelation of intracellular Zn2+

et al. 1997

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“…Zinc is almost completely bound to proteins and nucleic acids or chelated by low molecular weight ligands, leading to a very low concentration of the free ionized species (Frederickson, 1989;Paski et al, 2003). In the form of its complexes with proteins and nucleic acids it participates in a huge number of processes of intermediate metabolism, regulation of gene expression, storage, synthesis and action of peptide hormones as well as in the structural maintenance of chromatin and biomembranes (Boquist et al, 1968;Bettger and O'Dell, 1981;Figlewicz et al, 1984;Mazus et al, 1984).…”

Section: The Role Of the Essential Trace Element Zinc In Metabolismmentioning

confidence: 99%

“…These functions become apparent during zinc deficiency, with markedly increased levels of lipid peroxidation in plasma membranes as well as in mitochondrial and microsomal membranes. This leads, for example, to an increased fragility of erythrocyte membranes and an impaired homeostasis of platelets (Sullivan et al, 1980;Bettger and O'Dell, 1981;Bray and Bettger, 1990;Oteiza et al, 1995).…”

Section: The Role Of the Essential Trace Element Zinc In Metabolismmentioning

confidence: 99%

Nutrient-gene interactions: a single nutrient and hundreds of target genes

Daniel¹,

Dieck²

2004

Biological Chemistry

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Based on the effects of a selective experimental zinc deficiency in a rodent model we explore the use of transcriptome profiling for assessing nutrient-gene interactions in the liver at the molecular and cellular levels. Zinc deficiency caused pleiotropic alterations in mRNA/protein levels of hundreds of genes. In the context of observed metabolic alterations in hepatic metabolism, possible mechanisms are discussed for how a low zinc status may be sensed and transmitted into changes in various metabolic pathways. However, it also becomes obvious that analysis of such complex nutrient-gene interactions beyond the descriptional level is a real challenge for systems biology.

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“…which become unnecessary for maintaining tissue function durIntracellularly, it is bound to ligands [2]. Heavy metals such as ing embryogenesis and development of adult tissues [11].…”

mentioning

confidence: 99%

Induction of necrosis by zinc in prostate carcinoma cells and identification of proteins increased in association with this induction

Iguchi

Hamatake

Ishida

et al. 1998

European Journal of Biochemistry

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Zinc exhibits inhibitory effects on apoptosis, and a deficiency in this metal generally causes this type of cell death to occur. In the present study, we found that exposure to zinc results in necrosis of prostate carcinoma cells. When zinc acetate was added to LNCaP or PC-3 cells in monolayer culture, they began to detach from the culture dishes, and viability was lost after 4Ϫ8 h. Most of the cell death was found to be due to necrosis as determined by double staining with fluorescein-isothiocyanate-labeled annexin V and ethidium bromide, and by detection of hypodiploid cells. Associated with the induction of necrosis was an increase in low molecular-mass proteins, identified by HPLC analysis to be thymosin β10, parathymosin and GAGE in LNCaP cells, and thymosin β4, parathymosin and metallothionein in PC-3. The time course of the increase of thymosin β10 in LNCaP cells and thymosin β4 in PC-3 cells was consistent with that of appearance of cell detachment and dead cells. These results indicate that zinc can induce necrosis and suggest that production of proteins including β-thymosins is involved in induction of processes leading to cell detachment.

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A critical physiological role of zinc in the structure and function of biomembranes

Cited by 598 publications

References 122 publications

The role of proteolysis in T cell apoptosis triggered by chelation of intracellular Zn2+

The role of proteolysis in T cell apoptosis triggered by chelation of intracellular Zn2+

Nutrient-gene interactions: a single nutrient and hundreds of target genes

Induction of necrosis by zinc in prostate carcinoma cells and identification of proteins increased in association with this induction

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