All cells respond to external cues by adopting appropriate metabolic and developmental programs in the face of changing environmental conditions. These responses occur on a variety of time-scales, from changes in metabolic flux that take place in minutes, to reprogramming of transcriptional patterns that happen over the course of an hour or so, to developmental programs that unfurl over days. However, all of these responses occur as a result of input from signaling pathways that connect the external events to the internal workings of the cell. We propose to continue our studies of the role of the major nutrient signaling pathways in yeast, Ras/PKA and Tor, in processes that occur at all three time scales metabolic regulation. We have recently dissected the role of allosteric and signal-mediated posttranslational regulation of pyruvate kinase, the key constriction point in carbon catabolism, and showed that both processes collaborate to provide exquisitely sensitive regulation of flux through the glycolytic pathway. We plan to conclude this study and extend similar analyses to other critical metabolic constriction points in the cell, including lipid and nitrogen metabolism. These studies should refine our understanding the role of signaling pathways in regulating metabolism, a key issue in evaluating and addressing various chronic diseases, such as cancer and diabetes. Stress response. Our recent studies of the major stress response regulator, Msn2, have allowed us to decipher the complex calculus used by cells to integrate input from multiple environmental signals. In addition, our studies have demonstrated the critical role of noise in this regulation, which imparts quite diverse behaviors to genetically identical cells, allowing the individual cells in a population to hedge their bets against an uncertain future. We plan to study further Msn2 regulation to define the means by which cells integrate multiple, often competing, signals and to test the role of noise in the long term surviva of the species. Quiescence. Cells spend the vast majority of their lifetime in a quiescent, non-growing state and yet our understanding of this state is woefully lacking. We plan to rectify this shortcoming by elucidating a number of quiescence properties, including defining the protein spectrum and metabolic landscape that allows survival during quiescence, and to examine the means by which signaling pathways regulate entry into and exit from quiescence. 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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular and Integrative Signal Transduction Study Section (MIST)
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Reddy, Michael K
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Pennsylvania State University
Schools of Medicine
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Chereji, Razvan V; Bharatula, Vasudha; Elfving, Nils et al. (2017) Mediator binds to boundaries of chromosomal interaction domains and to proteins involved in DNA looping, RNA metabolism, chromatin remodeling, and actin assembly. Nucleic Acids Res 45:8806-8821
Kurischko, Cornelia; Broach, James R (2017) Phosphorylation and nuclear transit modulate the balance between normal function and terminal aggregation of the yeast RNA-binding protein Ssd1. Mol Biol Cell 28:3057-3069
Rutledge, Mark T; Russo, Mariano; Belton, Jon-Matthew et al. (2015) The yeast genome undergoes significant topological reorganization in quiescence. Nucleic Acids Res 43:8299-313
Elfving, Nils; Chereji, R?zvan V; Bharatula, Vasudha et al. (2014) A dynamic interplay of nucleosome and Msn2 binding regulates kinetics of gene activation and repression following stress. Nucleic Acids Res 42:5468-82
Bravim, Fernanda; Lippman, Soyeon I; da Silva, Lucas F et al. (2013) High hydrostatic pressure activates gene expression that leads to ethanol production enhancement in a Saccharomyces cerevisiae distillery strain. Appl Microbiol Biotechnol 97:2093-107
Xu, Yi-Fan; L├ętisse, Fabien; Absalan, Farnaz et al. (2013) Nucleotide degradation and ribose salvage in yeast. Mol Syst Biol 9:665
Petrenko, Natalia; Chereji, Razvan V; McClean, Megan N et al. (2013) Noise and interlocking signaling pathways promote distinct transcription factor dynamics in response to different stresses. Mol Biol Cell 24:2045-57
Shor, Erika; Fox, Catherine A; Broach, James R (2013) The yeast environmental stress response regulates mutagenesis induced by proteotoxic stress. PLoS Genet 9:e1003680
Xu, Yi-Fan; Zhao, Xin; Glass, David S et al. (2012) Regulation of yeast pyruvate kinase by ultrasensitive allostery independent of phosphorylation. Mol Cell 48:52-62
Bravim, Fernanda; da Silva, Lucas F; Souza, Diego T et al. (2012) High hydrostatic pressure activates transcription factors involved in Saccharomyces cerevisiae stress tolerance. Curr Pharm Biotechnol 13:2712-20

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