Ras and Tor Signaling in Yeast

描述（由申请人提供）：酵母细胞通过调整其转录和代谢谱以最佳利用可用营养物以及通过选择使其存活潜力最大化的发育程序来响应环境中的营养物和其他信号。我们最近的研究，在基因组工具的推动下，完善了我们对单个通路内的组分和连接以及通路之间的相互联系的知识。我们建议继续这些研究，重点是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一致的反应。我们建议围绕Ras和TOR途径开发一个全面的网络拓扑结构，通过该网络，细胞传输有关营养物质可用性的信息。我们将通过进一步测量响应于关键信号组分活性增加或减少的突变株的营养转移的全局转录变化来实现这一点。我们还将应用新的计算工具来提取额外的转录因子的身份，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传导途径的信息的方法，重点是解剖特定的转录因子和哺乳动物Akt激酶的酵母同系物，我们的工作强调了TOR和Ras途径会聚的位点。我们预计，这些研究将提供一个完整的拓扑结构的营养信号网络在酵母细胞，以及提供定义全面的信号网络在较大的真核生物的手段。这种详细的信号传导网络表示应该极大地促进评估在信号传导途径中的特定步骤处的干预的后果，以实现对疾病（例如癌症或糖尿病）的治疗性治疗，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导致的。

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.