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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM076562-06
Application #
8464139
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Reddy, Michael K
Project Start
2007-04-01
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
6
Fiscal Year
2013
Total Cost
$382,854
Indirect Cost
$125,915
Name
Pennsylvania State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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
Shor, Erika; Fox, Catherine A; Broach, James R (2013) The yeast environmental stress response regulates mutagenesis induced by proteotoxic stress. PLoS Genet 9:e1003680
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
Xu, Yi-Fan; Letisse, Fabien; Absalan, Farnaz et al. (2013) Nucleotide degradation and ribose salvage in yeast. Mol Syst Biol 9:665
Tsitron, Julia; Ault, Addison D; Broach, James R et al. (2011) Decoding complex chemical mixtures with a physical model of a sensor array. PLoS Comput Biol 7:e1002224
Klosinska, Maja M; Crutchfield, Christopher A; Bradley, Patrick H et al. (2011) Yeast cells can access distinct quiescent states. Genes Dev 25:336-49
Tolkunov, Denis; Zawadzki, Karl A; Singer, Cara et al. (2011) Chromatin remodelers clear nucleosomes from intrinsically unfavorable sites to establish nucleosome-depleted regions at promoters. Mol Biol Cell 22:2106-18
Talarek, Nicolas; Cameroni, Elisabetta; Jaquenoud, Malika et al. (2010) Initiation of the TORC1-regulated G0 program requires Igo1/2, which license specific mRNAs to evade degradation via the 5'-3' mRNA decay pathway. Mol Cell 38:345-55
Lippman, Soyeon I; Broach, James R (2009) Protein kinase A and TORC1 activate genes for ribosomal biogenesis by inactivating repressors encoded by Dot6 and its homolog Tod6. Proc Natl Acad Sci U S A 106:19928-33
Zawadzki, Karl A; Morozov, Alexandre V; Broach, James R (2009) Chromatin-dependent transcription factor accessibility rather than nucleosome remodeling predominates during global transcriptional restructuring in Saccharomyces cerevisiae. Mol Biol Cell 20:3503-13

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