Andrews G K
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City 66103.
Prog Food Nutr Sci. 1990;14(2-3):193-258.
The metallothioneins are small, cysteine-rich proteins that have the capacity for high affinity binding of heavy metal ions, and whose synthesis is regulated by metal ion concentrations. These properties suggest that they play pivotal roles in the metabolism of the relatively nontoxic essential metals (zinc and copper), as well as toxic heavy metals (cadmium), a concept supported by a variety of studies of cells in culture, as well as in intact animals. Expression of the metallothionein genes may have important implications in the nutritional status of the animal, in its response to stresses (inflammation, heavy metal toxicity), and in embryonic, fetal and neonatal development. The complementary DNAs and genes that encode the metallothioneins have been cloned and analyzed from a wide variety of eukaryotes. Striking features of the metallothioneins include: their high degree of amino acid sequence similarity (including conservation in the placement of cysteine residues in the molecule reflecting their function in metal binding); a conserved tripartite gene structure; and their transcriptional induction by metal ions, as well as other hormonal and environmental stimuli. The precise mechanisms and biochemical pathways by which cells transduce environmental signals into transcriptional induction of the metallothionein genes are beginning to be defined. Recent studies indicate that metal effects are exerted via positive trans-acting factors induced to interact with cis-acting DNA sequences in the promoter, in turn leading to transcriptional induction. However, the metallothionein gene promoter is structurally complex, and contains binding sites for a variety of nuclear proteins that likely regulate basal as well as induced levels of expression of these genes. Recent studies also suggest the possible involvement of post-transcriptional processes in the regulation of metallothionein levels in the cell. Furthermore, evidence of striking differences in the levels of metallothionein gene expression among various cell types in vivo have recently been documented. Although several detailed reviews of the metallothioneins have been published recently, this review will focus, in large part, on the molecular biology of the metallothioneins, with particular emphasis on recent advances in our understanding of the mechanisms regulating expression of these interesting and important genes. Given the large volume of literature on the metallothioneins and the space limitations of this review, it is impossible to comprehensively cite the studies of each of my colleagues who have contributed so much to this field. Instead the reader is often directed to reviews of this subject for much of the earlier literature, and emphasis is placed on more current publications in this field.
金属硫蛋白是一类小的、富含半胱氨酸的蛋白质，能够与重金属离子进行高亲和力结合，其合成受金属离子浓度的调节。这些特性表明它们在相对无毒的必需金属（锌和铜）以及有毒重金属（镉）的代谢中起关键作用，这一概念得到了多种细胞培养研究以及完整动物研究的支持。金属硫蛋白基因的表达可能对动物的营养状况、其对应激（炎症、重金属毒性）的反应以及胚胎、胎儿和新生儿的发育具有重要意义。编码金属硫蛋白的互补DNA和基因已从多种真核生物中克隆并进行分析。金属硫蛋白的显著特征包括：它们高度的氨基酸序列相似性（包括分子中半胱氨酸残基位置的保守性，这反映了它们在金属结合中的功能）；保守的三联体基因结构；以及它们受金属离子以及其他激素和环境刺激的转录诱导。细胞将环境信号转导为金属硫蛋白基因转录诱导的精确机制和生化途径正开始被阐明。最近的研究表明，金属效应是通过诱导与启动子中的顺式作用DNA序列相互作用的正向反式作用因子来发挥的，进而导致转录诱导。然而，金属硫蛋白基因启动子结构复杂，包含多种核蛋白的结合位点，这些核蛋白可能调节这些基因的基础表达水平以及诱导表达水平。最近的研究还表明转录后过程可能参与细胞中金属硫蛋白水平的调节。此外，最近有文献记载了体内各种细胞类型中金属硫蛋白基因表达水平存在显著差异的证据。尽管最近已经发表了几篇关于金属硫蛋白的详细综述，但本综述将在很大程度上聚焦于金属硫蛋白的分子生物学，特别强调我们对这些有趣且重要基因表达调控机制理解的最新进展。鉴于关于金属硫蛋白的文献数量众多且本综述篇幅有限，不可能全面引用为该领域做出诸多贡献的每一位同事的研究。相反，对于许多早期文献，读者常被指引阅读该主题的综述，并且重点放在该领域的最新出版物上。
