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GROWTH, DIFFERENTIATION, AND APOPTOSIS

Impact of overexpression of metallothionein-1 on cell cycle progression and zinc toxicity

Departments of ¹Pathology and ²Medical Biochemistry, School of Medicine, Cardiff University, Cardiff; and ³Rowett Research Institute, Aberdeen, Scotland, United Kingdom

Submitted 2 July 2008 ; accepted in final form 17 September 2008

Metallothioneins (MTs) have an important role in zinc homeostasis and may counteract the impact of oversupply. Both intracellular zinc and MT expression have been implicated in proliferation control and resistance to cellular stress, although the interdependency is unclear. The study addresses the consequences of a steady-state overexpression of MT-1 for intracellular zinc levels, cell cycle progression, and protection from zinc toxicity using a panel of cell lines with differential expression of MT-1. The panel comprised parental Chinese hamster ovary-K1 cells with low endogenous expression of MT and transfectants with enhanced expression of mouse MT-1 on an autonomously replicating expression vector with a noninducible promoter. Cell cycle progression, determined by flow cytometry and time-lapse microscopy, revealed that enhanced cytoplasmic expression of MT-1 does not impact on normal cell cycle operation, suggesting that basal levels of MT-1 expression are not limiting for background levels of oxidative stress. MT-1 overexpression correlated with a steady-state increase in cytoplasmic free Zn²⁺, assessed using the fluorescent zinc-sensor Zinquin, particularly at high levels of overexpression, further suggesting that zinc availability is normally not limiting for cell cycle progression. Enhanced MT-1 expression, over a 10-fold range, had a clear impact on resistance to Cd²⁺ and Zn²⁺ toxicity. In the case of Zn²⁺, the degree of protection afforded was less, indicating that MT-1 has a limited range and saturable capacity for effecting resistance. The results have implications for the use of cellular stress responses to exogenously supplied zinc and zinc-based systemic therapies.

cadmium; metallothioneins; flow cytometry; two-photon laser scanning microscopy; Zinquin

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