Toxicological Sciences 64, 67-76 (2001)
Copyright © 2001 by the Society of Toxicology
MOLECULAR AND GENETIC TOXICOLOGY |
Zinc-Metallothionein Levels Are Correlated with Enhanced Glucocorticoid Responsiveness in Mouse Cells Exposed to ZnCl2, HgCl2, and Heat Shock
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* London Regional Cancer Centre, 790 Commissioners Road East, London, Ontario, Canada N6A 4L6; Departments of
Microbiology and Immunology,
Oncology,
Pathology, and
¶ Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada
Metallothioneins (MTs) are the major low molecular weight, zinc-binding proteins in mammalian cells. It has been hypothesized that they play a role in the function of zinc-dependent signal transduction proteins and transcription factors. We investigated the capacity of zinc and other metal ions and conditions to increase both Zn-associated MT levels and the receptiveness of cells to transcriptional activation mediated by the zinc-dependent glucocorticoid receptor (GR). We studied, in a GR-responsive mouse mammary-tumor cell line, the ability of dexamethasone (DEX) to stimulate transcription of a chloramphenicol acetyltransferase (CAT) gene controlled by a mouse mammary-tumor virus promoter. In cells pretreated with 20 to 100 µM ZnCl2, DEX-induced CAT activity correlated with zinc-induced MT levels. However, 0.05 to 0.5 µM CdCl2 had no effect on CAT activity, despite an increase in Cd-associated MT. Copper-associated MT was detected in cells treated with 20 µM CuCl2, but there was no change in the level of Zn-MT, nor was CAT activity altered in cells exposed to 5 to 20 µM CuCl2. These results may reflect a functional difference between zinc-associated MT, and MT associated with other metals. Significantly more CAT activity was observed in both heat-shocked cells and in cells exposed to 40 or 50 nM HgCl2. Although absolute amounts of MT were unchanged by these two treatments, a higher percentage of total cellular zinc was associated with the MT protein fractions after treatment. Changes in GR levels could not account for variations in CAT activity. These data indicate that hormonal signalling can be altered by exposure to metal salts and heat shock, and the effect is correlated with the level of Zn-MT.
Key Words: metallothionein; metals; zinc; glucocorticoid receptor; heat shock.
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