Zinc-dependent regulation of gene expression

描述：锌是一种对生命至关重要的金属元素，但过量存在时是有毒的。 因此，细胞依赖于机制来维持细胞内相对恒定的锌水平，尽管 胞外培养液的波动。以确保锌水平保持在最佳水平，以满足 细胞新陈代谢，锌转运或锌储存所需基因的表达通常依赖于 根据细胞内锌水平。尽管基因表达的这种变化是锌的动态平衡的核心， 感觉细胞内锌水平并调节这些变化的因素在很大程度上是相同的 未知。我们研究的长期目标是了解真核细胞如何感知和调节 细胞内锌水平。为了识别感知锌的蛋白质，我们利用了多功能的 裂殖酵母的遗传学研究。使用这个模型系统，我们分离出一个新的因素，即 是锌依赖的基因表达调控所必需的。这个指定为Loz1的因子包含一个 双C2H2型锌指结构域，对于锌依赖的基因表达调控是必不可少的。 这项建议描述了一种分子、遗传和生化相结合的方法来确定 Loz1受锌的调控。具体地说，我们将解决Loz1是否直接感觉到锌水平，以及 这是否需要双C2H2型锌指结构域。与公共健康相关：锌 缺乏症是一个重大的健康问题。例如，儿童缺锌会导致体内锌含量增加 有腹泻、肺炎和疟疾的风险。饮食中锌含量过低也会增加患糖尿病的风险。 败血症相关死亡率。细胞锌水平异常与一系列疾病有关 包括食道癌、前列腺癌、胰腺癌和阿尔茨海默病。这个 本申请中概述的研究将深入了解可用于感知的域的类型 细胞内锌水平。这一知识将有助于鉴定其活性是 受锌的调节，并将进一步加深我们对锌与特定疾病之间联系的了解。

DESCRIPTION: Zinc is a metal element that is essential for life, but is toxic when present in excess. Cells therefore rely on mechanisms to maintain a relatively constant intracellular level of zinc despite fluctuations in the extracellular medium. To ensure that zinc levels are maintained at an optimal level for cell metabolism, the expression of genes necessary for zinc transport or zinc storage is often dependent upon cellular zinc levels. Although such changes in gene expression are central to zinc homeostasis, the identity of the factors that sense intracellular zinc levels and mediate these changes is largely unknown. The long-term goal of our research is to understand how eukaryotic cells sense and regulate intracellular zinc levels. To identify proteins that sense zinc, we have taken advantage of the versatile genetics of Schizosaccharomyces pombe. Using this model system we have isolated a novel factor that is required for zinc-dependent regulation of gene expression. This factor, designated Loz1, contains a double C2H2-type zinc finger domain that is essential for zinc-dependent regulation of gene expression. This proposal describes a combined molecular, genetic and biochemical approach to determine how Loz1 is regulated by zinc. Specifically, we will address whether Loz1 directly senses zinc levels, and whether this requires the double C2H2-type zinc finger domain. PUBLIC HEALTH RELEVANCE: Zinc deficiency is a significant health issue. For example, zinc deficiency in children leads to an increased risk of diarrhea, pneumonia, and malaria. Low dietary zinc levels also lead to an increased risk of sepsis-related mortality. Abnormal cellular zinc levels have been associated with a range of disorders including esophageal cancers, prostate cancers, pancreatic cancers, and Alzheimer's disease. The studies outlined in this application will provide insight into the types of domains that can be used to sense intracellular zinc levels. This knowledge will aid in the identification of proteins whose activity is modulated by zinc, and will further our knowledge of the connection between zinc and specific diseases.