Role of yeast Ume3 & Plcl in oxidative stress response

氧化应激引起的细胞损伤与多种疾病的病因有关，包括多种癌症和神经退行性疾病，如帕金森氏病、阿尔茨海默病和肌萎缩侧索硬化症。理解细胞对这种压力的防御反应是至关重要的。这项提案中描述的实验使用模型系统酿酒酵母来检查细胞如何改变其基因表达程序以应对氧化应激。这项建议的主要目的是确定酵母细胞周期蛋白C同系物Ume3p氧化应激激活降解的机制。正常情况下，Ume3p的功能是抑制大量应激诱导基因的转录。当细胞暴露在氧化应激下时，Ume3p的降解被触发，从而允许这些基因的表达。这种应激诱导的降解需要磷脂酶C(PLCLP)和PKCI MAP激酶途径。这一建议旨在确定a)plclp和Pkclp是否在与哺乳动物细胞相似的信号转导途径中发挥作用，b)哪些基因必须表达才能使细胞在氧化应激中生存，以及c)哪些基因在感受氧化应激和触发Ume3p破坏方面起关键作用。

Cellular damage caused by oxidative stress has been implicated in the etiology of a number of diseases including many types of cancer and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and Amyotrophic Lateral Sclerosis. Understanding the cellular defensive response to such stress is critical. Experiments described in this proposal use the model system Saccharomyces cerevisiae to examine how cells change their gene expression program in response to oxidative stress. The main goal of this proposal is to determine the mechanism for oxidative stress-activated degradation of the yeast cyclin C homolog Ume3p. Ume3p normally functions to repress transcription of a large set of stress-induced genes. When cells are exposed to oxidative stress, Ume3p degradation is triggered, allowing expression of these genes. This stress-induced degradation is known to require Plclp (phospholipase C) and the PKCI MAP kinase pathway. This proposal is aimed at determining a) whether Plclp and Pkclp act in the same pathway, in a signal transduction pathway analogous to that seen in mammalian cells, b) which genes must be expressed for cells to survive oxidative stress and c) which genes are critical for sensing oxidative stress and triggering Ume3p destruction.