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，通过调整其转录和代谢谱来最佳利用可用的营养物质，并通过选择一个最大限度地提高其生存潜力的发育程序。我们最近的研究，在基因组工具的推动下，已经完善了我们对个体途径内的成分和联系以及途径之间的相互联系的认识。我们建议继续这些研究，重点关注细胞如何协调来自几种信号通路的输入，从而在其转录和发育程序中产生适当和一致的反应。我们建议开发Ras和TOR通路周围网络的综合拓扑，细胞通过这些通路传递有关营养可用性的信息。我们将通过进一步测量随着关键信号组分活性的增加或减少，突变菌株营养变化的全球转录变化来实现这一目标。我们还将应用新的计算工具来提取其他转录因子的身份，并定义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，重点是解剖特定的转录因子和哺乳动物Akt激酶的酵母同源物，我们的工作已经强调了TOR和Ras通路聚集的位点。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综合信号网络的方法。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的后果，以实现对疾病的治疗，如癌症或糖尿病，这些疾病通常是由于细胞无法适当平衡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.