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Title: Transient fluctuations of intracellular zinc ions in cell proliferation

Abstract

Zinc is essential for cell proliferation, differentiation, and viability. When zinc becomes limited for cultured cells, DNA synthesis ceases and the cell cycle is arrested. The molecular mechanisms of actions of zinc are believed to involve changes in the availability of zinc(II) ions (Zn{sup 2+}). By employing a fluorescent Zn{sup 2+} probe, FluoZin-3 acetoxymethyl ester, intracellular Zn{sup 2+} concentrations were measured in undifferentiated and in nerve growth factor (NGF)-differentiated rat pheochromocytoma (PC12) cells. Intracellular Zn{sup 2+} concentrations are pico- to nanomolar in PC12 cells and are higher in the differentiated than in the undifferentiated cells. When following cellular Zn{sup 2+} concentrations for 48 h after the removal of serum, a condition that is known to cause cell cycle arrest, Zn{sup 2+} concentrations decrease after 30 min but, remarkably, increase after 1 h, and then decrease again to about one half of the initial concentration. Cell proliferation, measured by an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, decreases after both serum starvation and zinc chelation. Two peaks of Zn{sup 2+} concentrations occur within one cell cycle: one early in the G1 phase and the other in the late G1/S phase. Thus, fluctuations of intracellular Zn{sup 2+} concentrations and established modulation of phosphorylation signaling, viamore » an inhibition of protein tyrosine phosphatases at commensurately low Zn{sup 2+} concentrations, suggest a role for Zn{sup 2+} in the control of the cell cycle. Interventions targeted at these picomolar Zn{sup 2+} fluctuations may be a way of controlling cell growth in hyperplasia, neoplasia, and diseases associated with aberrant differentiation.« less

Authors:
 [1];  [1];  [2]
  1. Division of Human Nutrition, Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, TX 77555 (United States)
  2. (United States)
Publication Date:
OSTI Identifier:
22209793
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 315; Journal Issue: 14; Other Information: Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BROMIDES; CELL CYCLE; CELL PROLIFERATION; CONCENTRATION RATIO; DTPA; EDTA; ESTERS; FLUORESCENCE; GROWTH FACTORS; PENICILLIN; PHOSPHATASES; PHOSPHATES; PHOSPHORYLATION; RATS; STREPTOMYCIN; TYROSINE; ZINC IONS

Citation Formats

Li, Yuan, Maret, Wolfgang, E-mail: womaret@utmb.edu, and Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX 77555. Transient fluctuations of intracellular zinc ions in cell proliferation. United States: N. p., 2009. Web. doi:10.1016/J.YEXCR.2009.05.016.
Li, Yuan, Maret, Wolfgang, E-mail: womaret@utmb.edu, & Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX 77555. Transient fluctuations of intracellular zinc ions in cell proliferation. United States. doi:10.1016/J.YEXCR.2009.05.016.
Li, Yuan, Maret, Wolfgang, E-mail: womaret@utmb.edu, and Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX 77555. Sat . "Transient fluctuations of intracellular zinc ions in cell proliferation". United States. doi:10.1016/J.YEXCR.2009.05.016.
@article{osti_22209793,
title = {Transient fluctuations of intracellular zinc ions in cell proliferation},
author = {Li, Yuan and Maret, Wolfgang, E-mail: womaret@utmb.edu and Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX 77555},
abstractNote = {Zinc is essential for cell proliferation, differentiation, and viability. When zinc becomes limited for cultured cells, DNA synthesis ceases and the cell cycle is arrested. The molecular mechanisms of actions of zinc are believed to involve changes in the availability of zinc(II) ions (Zn{sup 2+}). By employing a fluorescent Zn{sup 2+} probe, FluoZin-3 acetoxymethyl ester, intracellular Zn{sup 2+} concentrations were measured in undifferentiated and in nerve growth factor (NGF)-differentiated rat pheochromocytoma (PC12) cells. Intracellular Zn{sup 2+} concentrations are pico- to nanomolar in PC12 cells and are higher in the differentiated than in the undifferentiated cells. When following cellular Zn{sup 2+} concentrations for 48 h after the removal of serum, a condition that is known to cause cell cycle arrest, Zn{sup 2+} concentrations decrease after 30 min but, remarkably, increase after 1 h, and then decrease again to about one half of the initial concentration. Cell proliferation, measured by an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, decreases after both serum starvation and zinc chelation. Two peaks of Zn{sup 2+} concentrations occur within one cell cycle: one early in the G1 phase and the other in the late G1/S phase. Thus, fluctuations of intracellular Zn{sup 2+} concentrations and established modulation of phosphorylation signaling, via an inhibition of protein tyrosine phosphatases at commensurately low Zn{sup 2+} concentrations, suggest a role for Zn{sup 2+} in the control of the cell cycle. Interventions targeted at these picomolar Zn{sup 2+} fluctuations may be a way of controlling cell growth in hyperplasia, neoplasia, and diseases associated with aberrant differentiation.},
doi = {10.1016/J.YEXCR.2009.05.016},
journal = {Experimental Cell Research},
number = 14,
volume = 315,
place = {United States},
year = {Sat Aug 15 00:00:00 EDT 2009},
month = {Sat Aug 15 00:00:00 EDT 2009}
}
  • Airborne nanoparticles (NPs) that enter the respiratory tract are likely to reach the alveolar region. Accumulating observations support a role for zinc oxide (ZnO) NP dissolution in toxicity, but the majority of in vitro studies were conducted in cells exposed to NPs in growth media, where large doses of dissolved ions are shed into the exposure solution. To determine the precise intracellular accumulation dynamics and fate of zinc ions (Zn 2+) shed by airborne NPs in the cellular environment, we exposed alveolar epithelial cells to aerosolized NPs at the air-liquid interface (ALI). Using a fluorescent indicator for Zn 2+, togethermore » with organelle-specific fluorescent proteins, we quantified Zn 2+ in single cells and organelles over time. We found that at the ALI, intracellular Zn 2+ values peaked 3 h post exposure and decayed to normal values by 12 h, while in submersed cultures, intracellular Zn 2+ values continued to increase over time. The lowest toxic NP dose at the ALI generated peak intracellular Zn 2+ values that were nearly 3 folds lower than the peak values generated by the lowest toxic dose of NPs in submersed cultures, and 8 folds lower than the peak values generated by the lowest toxic dose of ZnSO4 or Zn 2+. At the ALI, the majority of intracellular Zn 2+ was found in endosomes and lysosomes as early as 1 h post exposure. In contrast, the majority of intracellular Zn 2+ following exposures to ZnSO 4 was found in other larger vesicles, with less than 10% in endosomes and lysosomes. In conclusion, together, our observations indicate that low but critical levels of intracellular Zn 2+ have to be reached, concentrated specifically in endosomes and lysosomes, for toxicity to occur, and point to the focal dissolution of the NPs in the cellular environment and the accumulation of the ions specifically in endosomes and lysosomes as the processes underlying the potent toxicity of airborne ZnO NPs.« less
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