Mechanisms of mammalian zinc-regulated gene expression
Mechanisms of mammalian zinc-regulated gene expression
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DOI：
10.1042/bst0361262
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发表时间：
2008-12-01
影响因子：
3.9
通讯作者：
Ford, Dianne
中科院分区：
文献类型：
--
作者：
Jackson, Kelly A.;Valentine, Ruth A.;Ford, Dianne
锌调节基因表达的机制是细胞锌稳态的核心。在这种情况下，证据表明锌代谢异常参与疾病的病因学，包括2型糖尿病，阿尔茨海默病和癌症，突出了锌调控基因表达的重要性。在细菌和酵母中阐明的机制提供了锌敏感性基因调控的不同可能模式的实例，涉及转录激活子和阻遏子与基因启动子区域的锌调控结合。哺乳动物的转录调控机制，介导锌诱导的转录上调，涉及转录因子MTF 1（金属反应元件结合转录因子1），已被广泛研究。在哺乳动物细胞中已经观察到相反方向的基因反应（响应于增加的锌可用性而降低的mRNA水平），但是负责这种反应的特定转录调节过程尚未被鉴定。单个锌敏感转录因子以相反方向调节基因表达的例子正在出现。虽然锌诱导的转录抑制MTF 1是一个可能的解释，在某些特定的情况下，这样的机制不能占镇压锌的所有哺乳动物基因，显示这种模式的调节，表明存在尚未表征的机制，锌调节的转录在哺乳动物细胞。此外，最近的发现揭示了锌对mRNA稳定性的影响在特定锌转运蛋白的调节中的作用。我们的研究人类基因SLC30A5（溶质载体30AS），编码锌转运蛋白ZnT5的调节，已经显示，该基因提供了一个模型系统，通过该系统研究锌诱导的转录下调和锌调节的mRNA稳定。
Mechanisms through which gene expression is regulated by zinc are central to cellular zinc homoeostasis. In this context, evidence for the involvement of zinc dyshomoeostasis in the aetiology of diseases, including Type 2 diabetes, Alzheimer's disease and cancer, highlights the importance of zinc-regulated gene expression. Mechanisms elucidated in bacteria and yeast provide examples of different possible modes of zinc- sensitive gene regulation, involving the zinc-regulated binding of transcriptional activators and repressors to gene promoter regions. A mammalian transcriptional regulatory mechanism that mediates zinc-induced transcriptional up-regulation, involving the transcription factor MTF1 (metal-response element-binding transcription factor 1), has been studied extensively. Gene responses in the opposite direction (reduced mRNA levels in response to increased zinc availability) have been observed in mammalian cells, but a specific transcriptional regulatory process responsible for such a response has yet to be identified. Examples of single zinc-sensitive transcription factors regulating gene expression in opposite directions are emerging. Although zinc-induced transcriptional repression by MTF1 is a possible explanation in some specific instances, such a mechanism cannot account for repression by zinc of all mammalian genes that show this mode of regulation, indicating the existence of as yet uncharacterized mechanisms of zinc-regulated transcription in mammalian cells. in addition, recent findings reveal a role for effects of zinc on mRNA stability in the regulation of specific zinc transporters. Our studies on the regulation of the human gene SLC30A5 (solute carrier 30AS), which codes for the zinc transporter ZnT5, have revealed that this gene provides a model system by which to study both zinc-induced transcriptional down-regulation and zinc-regulated mRNA stabilization.