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. ? ? ?
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