Impact of overexpression of metallothionein-1 on cell cycle progression and zinc toxicity.
Impact of overexpression of metallothionein-1 on cell cycle progression and zinc toxicity.
复制标题
金属硫蛋白-1 过度表达对细胞周期进程和锌毒性的影响。
DOI：
10.1152/ajpcell.00342.2008
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Smith PJ
中科院分区：
文献类型：
--
作者：
Smith PJ
金属硫蛋白（MT）在锌稳态中发挥重要作用，可以抵消供应过剩的影响。细胞内锌和 MT 表达均与增殖控制和细胞应激抵抗有关，尽管相互依赖性尚不清楚。该研究利用一组具有 MT-1 差异表达的细胞系，探讨了 MT-1 稳态过度表达对细胞内锌水平、细胞周期进展和锌毒性保护的影响。该小组由具有低内源性 MT 表达的亲本中国仓鼠卵巢-K1 细胞和在具有非诱导型启动子的自主复制表达载体上增强小鼠 MT-1 表达的转染子组成。通过流式细胞术和延时显微镜测定的细胞周期进展表明，MT-1 的细胞质表达增强不会影响正常的细胞周期运行，这表明 MT-1 表达的基础水平并不限制氧化应激的背景水平。使用荧光锌传感器 Zinquin 评估，MT-1 过表达与细胞质游离 Zn2+ 的稳态增加相关，特别是在高水平过表达时，进一步表明锌的可用性通常不会限制细胞周期进展。 MT-1 表达增强超过 10 倍，对抵抗 Cd2+ 和 Zn2+ 毒性具有明显影响。在Zn2+的情况下，提供的保护程度较小，表明MT-1的抵抗范围有限且具有饱和能力。该结果对于使用细胞应激反应对外源供应的锌和基于锌的全身疗法具有影响。
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.
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