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Am J Physiol Cell Physiol 283 (2): 609-622

Copyright © 2002 by the American Physiological Society.

Vol. 283, Issue 2, C609-C622, August 2002

DNA damage-induced [Zn2+]i transients: correlation with cell cycle arrest and apoptosis in lymphoma cells

Paul J. Smith1, Marie Wiltshire1, Sharon Davies1, Suet-Feung Chin2, Anthony K. Campbell3, and Rachel J. Errington3

Departments of 1 Pathology and 3 Medical Biochemistry, University of Wales College of Medicine, Cardiff, CF14 4XN; and 2 Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 2QH, United Kingdom

Reactive changes in free intracellular zinc cation concentration ([Zn2+]i) were monitored, using the fluorescent probe Zinquin, in human lymphoma cells exposed to the DNA-damaging agent VP-16. Two-photon excitation microscopy showed that Zinquin-Zn2+ forms complexes in cytoplasmic vesicles. [Zn2+]i increased in both p53wt (wild type) and p53mut (mutant) cells after exposure to low drug doses. In p53mut cells noncompetent for DNA damage-induced apoptosis, elevated [Zn2+]i was maintained at higher drug doses, unlike competent p53wt cells that showed a collapse of the transient before apoptosis. In p53wt cells, the [Zn2+]i rise paralleled an increase in p53 and bax-to-bcl-2 ratio but preceded an increase in p21WAF1, active cell cycle arrest in G2, or nuclear fragmentation. Reducing [Zn2+]i, using N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine, caused rapid apoptosis in both p53wt and p53mut cells, although cotreatment with VP-16 exacerbated apoptosis only in p53wt cells. This may reflect changed thresholds for proapoptotic caspase-3 activation in competent cells. We conclude that the DNA damage-induced transient is p53-independent up to a damage threshold, beyond which competent cells reduce [Zn2+]i before apoptosis. Early stress responses in p53wt cells take place in an environment of enhanced Zn2+ availability.

flow cytometry; two-photon laser scanning microscopy; zinc

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