Ras and Tor Signaling in Yeast

描述(由申请人提供)：酵母细胞对环境中的营养物质和其他信号作出反应，调整它们的转录和代谢特征，以最大限度地利用可用的营养物质，并选择最大限度地发挥其生存潜力的发育计划。我们最近的研究，在基因组工具的推动下，提炼了我们对单个途径内的组成部分和联系以及途径之间的相互联系的知识。我们建议继续这些研究，重点放在细胞如何协调来自几个信号通路的输入，以在其转录和发育程序中产生适当和连贯的反应。我们建议围绕RAS和TOR通路开发一个全面的网络拓扑，细胞通过这些通路传递有关营养可获得性的信息。我们将通过进一步测量全球转录变化来响应关键信号成分活性增加或减少的突变菌株的营养变化来实现这一点。我们还将应用新的计算工具来提取其他转录因子的身份，并确定染色质结构在介导营养诱导的转录变化中的作用。然后，我们计划解决细胞整合来自不同信号通路的信息的方法，重点是对特定转录因子和哺乳动物Akt激酶的酵母同源物的剖析，我们的工作重点是TOR和Ras通路汇聚的位置。我们预计，这些研究将提供酵母细胞中营养信号网络的完整拓扑结构，并提供在更大的真核生物中定义全面信号网络的方法。这种详细的信号网络表示应该极大地促进评估在信号通路的特定步骤进行干预以实现癌症或糖尿病等疾病的治疗的后果，这些疾病通常是由于细胞未能适当地平衡来自多个信号的输入而引起的。

DESCRIPTION (provided by applicant): Yeast cells respond to nutrients and other signals in the environment both by adjusting their transcriptional and metabolic profiles to make optimum use of the available nutrients and by selecting a developmental program that maximizes their potential for survival. Our recent studies, fueled by genomic tools, have refined our knowledge of the components and connections within individual pathways and the interconnections between pathways. We propose to continue these studies, focusing on how the cell coordinates input from several signaling pathways to yield an appropriate and coherent response in its transcriptional and developmental programs. We propose to develop a comprehensive topology of the network around the Ras and TOR pathways through which the cell transmits information regarding nutrient availability. We will accomplish this by further measurements of global transcriptional changes in response to nutrient shifts of mutant strains with increased or diminished activities of key signaling components. We will also apply new computation tools to extract identities of additional transcription factors and define the role of chromatin structure in mediating nutrition induced transcriptional changes. We then plan to address the means by which the cell integrates information from different signaling pathways, focusing on dissection of specific transcription factors and the yeast homolog of the mammalian Akt kinase, which our work has highlighted as the loci at which the TOR and Ras pathways converge. We anticipate that these studies will provide a complete topology of the nutrient signaling network in yeast cells as well as provide means of defining comprehensive signaling networks in larger eukaryotes. Such detailed signaling network representations should enormously facilitate assessing the consequences of intervention at specific steps in a signaling pathway to achieve a therapeutic treatment of diseases, such as cancer or diabetes, which often result from the cell's failure to properly balance input from multiple signals.