MOLECULAR MECHANISMS OF COPPER HOMEOSTASIS AND SURVIVAL OF COPPER SHOCK

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 所有生物体都必须能够对各种内部和外部压力源做出快速和特异性的反应，例如温度的突然变化，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。亚致死水平的重金属污染物也可能导致严重的问题与持续接触。生物必须能够在细胞水平上仔细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最低浓度。细胞还必须有在饥饿条件下输入这些相同元素的手段。 适当的体内平衡控制需要快速激活与过量或饥饿反应有关的基因。然而，还必须精确调节基因表达的最终水平，以微调对稳态挑战的反应。 许多应激反应基因的激活途径在酵母中已被广泛表征。 酵母CUP 1基因编码金属硫蛋白，是一个很好的表征模型的转录响应有毒金属胁迫，特别是响应镉和铜。在我的实验室的工作集中在CUP 1被激活，随后在铜暴露的反应下调的机制。 我们目前正在研究的作用，染色质结构和反义转录的控制铜的反应。

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.