All cells respond to nutrients, environmental stresses and other external signals 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 under the existing environmental conditions. An elaborate nutrient- and stress-sensing network allows cells to adapt rapidly to the ever changing environment. In particular, two main nutrient sensing conduits in yeast - the Ras/protein kinase A (PKA) pathway and the target of rapamycin (TORC1) pathway - connect internal cellular processes with nutrient status to regulate growth-specific events and modulate stress responses. We propose to continue our studies on these pathways and processes with particular focus on the stress response and quiescence. Stress response. We have determined that activation of the stress response inhibits cell growth and that nutrient pathways abrogate that inhibition as a critical function in stimulating cell proliferation. We propose to determine hw stress impinges on growth. In addition, our studies have demonstrated the critical role of noise in regulation of the stress response, which imparts quite diverse behaviors to genetically identical cells. We have suggested that this allows individual cells in a population to hedge their bets against an uncertain future, and hypothesis we plan to test directly. A variety of different stresses elicit a common core stress response and we will continue to identify the signaling pathways responsible for these diverse input and test whether most or all of the stresses filter through a common sensing mechanism. On the other hand, different stresses activate different, albeit overlapping, cohorts of genes, at least in part by directing binding of Msn2 to different promoters. We will test whether this is achieved through indirect cooperativity in which binding of one transcription factor unmasks the binding site for a second factor through nucleosome displacement, a model recently proposed but untested in vivo. Quiescence. Cells spend the vast majority of their lifetime in a quiescent, non-growing state and yet our understanding of this stat is woefully lacking. We plan to rectify this shortcoming by elucidating a number of quiescence properties, including the large scale genome organization and the global chromatin structure of quiescent cells and to ascertain the extent to which these novel structures contribute to the long term survival of cells under starvation conditions. Our studies address difficult but fundamental questions regarding the means by which cells balance growth versus survival in an uncertain environment and how information acquisition through signaling pathways inform that balancing act. We focus on yeast cells but our studies inform critical issues of human biology, particularly in evaluating the role of signaling networks in regulating metabolism and development and how perturbations in these signaling networks could lead to untoward outcomes resulting in cancer and other diseases.
Our research is directed towards understanding the means by which cells control their growth, metabolism and development in response to available resources, external stresses and environmental cues. The information we generate in this study should be very valuable in understand growth control in eukaryotic cells, with particular impact on evaluating how cells adapt to aberrant internal and external cues in pathological conditions such as cancer and diabetes.
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