Glucose fuels life. Most cells prefer glucose as a carbon and energy source; some cells require it. Cells have evolved numerous sophisticated mechanisms for sensing and responding to glucose. This is especially apparent in the yeast S. cerevisiae, in which several highly evolved glucose sensing mechanisms dictate the distinctive fermentative metabolism of yeast, a lifestyle it shares with many kinds of tumor cells. Our long-term goal is to understand how yeast cells sense and respond to glucose. Two glucose signal transduction pathways responsible for regulating gene expression are well known. One pathway works through the Snfl protein kinase and the Mig1 transcriptional repressor to cause glucose repression of gene expression. Another pathway that operates through the Snf3 and Rgt2 glucose sensors in the cell membrane which signal to the Rgt1 transcription factor in the nucleus to induce expression of genes encoding glucose transporters has more recently been revealed. Over the past several years, we have been able to trace the glucose signal uninterrupted from the glucose sensors at the cell surface to Rgtl in the nucleus, providing a model for this glucose signal transduction pathway. Over the next four years, the majority of our effort (about two-thirds) will be devoted to solidifying and revising this model (Aim 1), with the goal of contributing to establishment of this novel nutrient sensing pathway as one of the paradigms of signal transduction. We recently learned that these two glucose-signaling pathways are highly interconnected in a regulatory circuit that probably evolved to ensure the cells respond rapidly and sensitively to changing levels of glucose. We will attempt to learn the logic of this network by determining the effect of inactivating each of its arms (Aim 2). Finally, the manner by which S. cerevisiae (and many tumor cells) metabolizes glucose is so unusual that it begs explanation. We will devote the remainder of our effort to analysis of glucose signaling in S. kluyveri (Aim 3), a relative of S. cerevisiae that, because it of its conventional glucose metabolism, can be considered a model for the non-transformed, normal cell.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM032540-24
Application #
7254894
Study Section
Genetics Study Section (GEN)
Program Officer
Anderson, James J
Project Start
1983-08-01
Project End
2008-08-31
Budget Start
2007-07-01
Budget End
2008-08-31
Support Year
24
Fiscal Year
2007
Total Cost
$362,679
Indirect Cost
Name
Washington University
Department
Genetics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Snowdon, Chris; Johnston, Mark (2016) A novel role for yeast casein kinases in glucose sensing and signaling. Mol Biol Cell 27:3369-3375
Simpson-Lavy, Kobi J; Bronstein, Alex; Kupiec, Martin et al. (2015) Cross-Talk between Carbon Metabolism and the DNA Damage Response in S. cerevisiae. Cell Rep 12:1865-75
Simpson-Lavy, Kobi J; Johnston, Mark (2013) SUMOylation regulates the SNF1 protein kinase. Proc Natl Acad Sci U S A 110:17432-7
Libkind, Diego; Hittinger, Chris Todd; Valerio, Elisabete et al. (2011) Microbe domestication and the identification of the wild genetic stock of lager-brewing yeast. Proc Natl Acad Sci U S A 108:14539-44
Kuttykrishnan, Sooraj; Sabina, Jeffrey; Langton, Laura L et al. (2010) A quantitative model of glucose signaling in yeast reveals an incoherent feed forward loop leading to a specific, transient pulse of transcription. Proc Natl Acad Sci U S A 107:16743-8
Hittinger, Chris Todd; Gonçalves, Paula; Sampaio, José Paulo et al. (2010) Remarkably ancient balanced polymorphisms in a multi-locus gene network. Nature 464:54-8
Sabina, Jeffrey; Johnston, Mark (2009) Asymmetric signal transduction through paralogs that comprise a genetic switch for sugar sensing in Saccharomyces cerevisiae. J Biol Chem 284:29635-43
Brown, Victoria; Sabina, Jeffrey; Johnston, Mark (2009) Specialized sugar sensing in diverse fungi. Curr Biol 19:436-41
Kim, Jeong-Ho; Johnston, Mark (2006) Two glucose-sensing pathways converge on Rgt1 to regulate expression of glucose transporter genes in Saccharomyces cerevisiae. J Biol Chem 281:26144-9
Kim, Jeong-Ho; Brachet, Valerie; Moriya, Hisao et al. (2006) Integration of transcriptional and posttranslational regulation in a glucose signal transduction pathway in Saccharomyces cerevisiae. Eukaryot Cell 5:167-73

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