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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM076562-04S1
Application #
8181780
Study Section
Cellular Signaling and Dynamics Study Section (CSD)
Program Officer
Hagan, Ann A
Project Start
2007-04-01
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2011
Total Cost
$33,697
Indirect Cost
Name
Princeton University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
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
Xu, Yi-Fan; L├ętisse, Fabien; Absalan, Farnaz et al. (2013) Nucleotide degradation and ribose salvage in yeast. Mol Syst Biol 9:665
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
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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