DNA damage-induced [Zn(2+)](i) transients: correlation with cell cycle arrest and apoptosis in lymphoma cells.

Abstract

Reactive changes in free intracellular zinc cation concentration ([Zn(2+)](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-Zn(2+) forms complexes in cytoplasmic vesicles. [Zn(2+)](i) increased in both p53(wt) (wild type) and p53(mut) (mutant) cells after exposure to low drug doses. In p53(mut) cells noncompetent for DNA damage-induced apoptosis, elevated [Zn(2+)](i) was maintained at higher drug doses, unlike competent p53(wt) cells that showed a collapse of the transient before apoptosis. In p53(wt) cells, the [Zn(2+)](i) rise paralleled an increase in p53 and bax-to-bcl-2 ratio but preceded an increase in p21(WAF1), active cell cycle arrest in G(2), or nuclear fragmentation. Reducing [Zn(2+)](i), using N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine, caused rapid apoptosis in both p53(wt) and p53(mut) cells, although cotreatment with VP-16 exacerbated apoptosis only in p53(wt) 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 [Zn(2+)](i) before apoptosis. Early stress responses in p53(wt) cells take place in an environment of enhanced Zn(2+) availability.

• Authors: Paul J Smith, Marie Wiltshire, Sharon Davies, Suet-Feung Chin, Anthony K Campbell, Rachel J Errington
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 283 Issue 2 Pg. C609-22 (Aug 2002) ISSN: 0363-6143 [Print] United States
• PMID: 12107071 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chelating Agents
• Ethylenediamines
• Fluorescent Dyes
• Nucleic Acid Synthesis Inhibitors
• Quinolones
• Tosyl Compounds
• Tumor Suppressor Protein p53
• Etoposide
• Zinc
• N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
• zinquin

Topics

• Apoptosis (drug effects)
• Cell Cycle (physiology)
• Chelating Agents (pharmacology)
• Cytoplasm (metabolism)
• DNA Damage (physiology)
• Ethylenediamines (pharmacology)
• Etoposide (pharmacology)
• Fluorescent Dyes
• Humans
• Lymphoma (genetics, pathology, physiopathology)
• Nucleic Acid Synthesis Inhibitors (pharmacology)
• Osmolar Concentration
• Quinolones
• Subcellular Fractions (metabolism)
• Tosyl Compounds
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (physiology)
• Zinc (metabolism)