Armendáriz Angela D, Olivares Felipe, Pulgar Rodrigo, Loguinov Alex, Cambiazo Veronica, Vulpe Christopher D, González Mauricio
Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Biol Res. 2006;39(1):125-42. doi: 10.4067/s0716-97602006000100015.
The role of metallothioneins (MT) in copper homeostasis is of great interest, as it appears to be partially responsible for the regulation of intracellular copper levels during adaptation to extracellular excess of the metal. To further investigate a possible role of MTs in copper metabolism, a genomics approach was utilized to evaluate the role of MT on gene expression. Microarray analysis was used to examine the effects of copper overload in fibroblast cells from normal and MT I and II double knock-out mice (MT-/-). As a first step, we compared genes that were significantly upregulated in wild-type and MT-/- cells exposed to copper. Even though wild-type and mutant cells are undistinguishable in terms of their morphological features and rates of growth, our results show that MT-/- cells do not respond with induction of typical markers of cellular stress under copper excess conditions, as observed in the wild-type cell line, suggesting that the transcription initiation rate or the mRNA stability of stress genes is affected when there is an alteration in the copper store capacity. The functional classification of other up-regulated genes in both cell lines indicates that a large proportion (>80%) belong to two major categories: 1) metabolism; and 2) cellular physiological processes, suggesting that at the transcriptional level copper overload induces the expression of genes associated with diverse molecular functions. These results open the possibility to understand how copper homeostasis is being coordinated with other metabolic pathways.
金属硫蛋白（MT）在铜稳态中的作用备受关注，因为在适应细胞外金属过量的过程中，它似乎部分负责调节细胞内铜水平。为了进一步研究MT在铜代谢中的可能作用，采用了基因组学方法来评估MT对基因表达的作用。利用微阵列分析来检测铜过载对来自正常小鼠以及MT I和II双敲除小鼠（MT-/-）的成纤维细胞的影响。作为第一步，我们比较了在暴露于铜的野生型和MT-/-细胞中显著上调的基因。尽管野生型和突变型细胞在形态特征和生长速率方面无法区分，但我们的结果表明，与野生型细胞系中观察到的情况不同，MT-/-细胞在铜过量条件下不会通过诱导细胞应激的典型标志物做出反应，这表明当铜储存能力发生改变时，应激基因的转录起始速率或mRNA稳定性会受到影响。两种细胞系中其他上调基因的功能分类表明，很大一部分（>80%）属于两个主要类别：1）代谢；2）细胞生理过程，这表明在转录水平上，铜过载会诱导与多种分子功能相关的基因表达。这些结果为理解铜稳态如何与其他代谢途径协调提供了可能。
