title: Intracellular zinc depletion induces caspase activation and p21 Waf1/Cip1 cleavage in human epithelial cell lines.
abstract: To better understand the mechanisms by which zinc deficiency induces epithelial cell death, studies were done of the effects of intracellular zinc depletion induced by the zinc chelator TPEN on apoptosis-related events in human malignant epithelial cell lines LIM1215 (colonic), NCI-H292 (bronchial), and A549 (alveolar type II). In TPEN-treated cells, depletion of zinc was followed by activation of caspase-3 (as demonstrated by enzymatic assay and Western blotting), DNA fragmentation, and morphologic changes. Increase in caspase-3 activity began 12 h after addition of TPEN, suggesting that zinc may suppress a step just before the activation of this caspase. Caspase-6, a mediator of caspase-3 processing, also increased, but later than caspase-3. Effects of TPEN on apoptosis were completely prevented by exogenous ZnSO4 and partially prevented by peptide caspase inhibitors. A critical substrate of caspase-3 may be the cell cycle regulator p21Waf1/Cip1, which was rapidly cleaved in TPEN-treated cells to a 15-kDa fragment before further degradation.
authors.affiliation: Department of Medicine, University of Adelaide, Queen Elizabeth Hospital, Woodville, South Australia.
authors.forename: F
authors.initials: F
authors.lastname: Chai
authors.forename: A Q
authors.initials: AQ
authors.lastname: Truong-Tran
authors.forename: A
authors.initials: A
authors.lastname: Evdokiou
authors.forename: G P
authors.initials: GP
authors.lastname: Young
authors.forename: P D
authors.initials: PD
authors.lastname: Zalewski
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D053178:Caspase 6; D020169:Caspases / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005029:Ethylenediamines / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000172:deficiency / Q000502:physiology*
chemical_list: C493956:CDKN1A protein, human; D002614:Chelating Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D005029:Ethylenediamines; C505407:CASP3 protein, human; C505514:CASP6 protein, human; D053148:Caspase 3; D053178:Caspase 6; D020169:Caspases; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine