MOLECULAR MECHANISMS OF COPPER HOMEOSTASIS AND SURVIVAL OF COPPER SHOCK

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 所有生物体都必须能够对各种内部和外部应激源做出快速和具体的反应，如温度突然变化、营养饥饿、DNA损伤剂或重金属或其他环境污染物的存在。即使是细胞通常需要的微量元素，如铜和锌，在高水平时也会变得有毒。重金属污染物的亚致死水平也可能导致持续暴露的严重问题。生物体必须能够在细胞水平上仔细地平衡这些微量元素的水平，当它们达到毒性水平时，通过排除、输出或安全地隔离它们，同时保持正常细胞功能所需的必要的最低浓度。细胞还必须有在饥饿条件下进口这些相同元素的手段。 适当的体内平衡控制需要迅速激活与过量或饥饿反应有关的基因。然而，也必须对基因表达的最终水平进行精确调整，以便微调对动态平衡挑战的反应。许多胁迫反应基因的激活途径在酵母中得到了广泛的表征。酵母CUP1基因编码一种金属硫蛋白，是有毒金属胁迫，特别是镉和铜胁迫下转录反应的一个很好的模型。我在实验室的工作主要集中在铜暴露反应过程中CUP1被激活和随后下调的机制。我们目前正在研究染色质结构和反义转录在控制铜反应中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. All organisms must be capable of responding rapidly and specifically to a variety of internal and external stressors, such as sudden changes in temperature, nutrient starvation, DNA damaging agents, or the presence of heavy metals or other environmental contaminants. Even elements that are normally required by cells in trace amounts, such as copper and zinc, become toxic at high levels. Sublethal levels of heavy metal contaminants can also lead to serious problems with continuous exposure. Organisms must be able to carefully balance the levels of these trace elements at the cellular level, by excluding, exporting, or safely sequestering them when they reach toxic levels, while retaining the essential minimal concentrations needed for normal cellular functions. Cells must also have means of importing these same elements under conditions of starvation. Proper homeostatic control requires rapid activation of genes involved in the response to surfeit or starvation. However, there must also be precise adjustment of the final levels of gene expression, in order to fine-tune the response to the challenge to homeostasis. The activation pathways for many stress-responsive genes have been extensively characterized in yeast. The yeast CUP1 gene encodes a metallothionein, and is a well-characterized model for the transcriptional response to toxic metal stress, particularly the response to cadmium and copper. Work in my laboratory has focused on the mechanisms by which CUP1 is activated and subsequently down-regulated during the response to copper exposure. We are currently studying the roles of chromatin structure and antisense transcription in the control of the copper response.