How cell growth and proliferation are coordinated with metabolism and the metabolic state of a cell remains poorly understood. Previous studies have established that cells must attain a sufficiently favorable metabolic state in order to initiate a program of growth and division. Knowledge of these mechanisms that connect cellular metabolism to cell growth control will provide novel strategies for the treatment of complex metabolic diseases such as cancer. This research proposal aims to understand the mechanisms by which key metabolic and nutritional signals ultimately control cell growth and proliferation. A unique model system wherein a highly synchronized yeast cell population undergoes robust oscillations in oxygen consumption during continuous growth will be used to investigate such mechanisms of growth control. During these metabolic cycles, cell division is precisely gated to a temporal window when the rate of cellular oxygen consumption decreases substantially, which is highly reminiscent of cancer cell division. Cell division initiates only following completion of a burst of mitochondrial respiration that is accompanied by a transient upregulation of growth genes. Just prior to entry into this growth phase, the cell population exists in a metabolic phase that resembles quiescence or G0. Interestingly, addition of select metabolites can trigger exit from this quiescent phase and induce immediate entry into the growth phase. These metabolites are key activators of growth control pathways. This yeast metabolic cycle system will be utilized to understand how cell growth and proliferation are precisely coordinated with metabolic signals and cellular metabolic state. This outstanding problem will be addressed by investigating the mechanisms by which carbon sources signal commitment to growth. In parallel, this system will be used to understand how the conserved TOR growth control pathway becomes active during the switch to growth.

Public Health Relevance

We have established a model system that will enable the study of the metabolic and nutritional signals that ultimately control cell growth and proliferation. We hope these studies will provide novel insights into the mechanisms of cell growth control and contribute towards our understanding of complex metabolic diseases such as cancer. Project Narrative: We have established a model system that will enable the study of the metabolic and nutritional signals that ultimately control cell growth and proliferation. We hope these studies will provide novel insights into the mechanisms of cell growth control and contribute towards our understanding of complex metabolic diseases such as cancer.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM094314-05
Application #
8725187
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Gaillard, Shawn R
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Lee, Chien-Der; Tu, Benjamin P (2015) Glucose-Regulated Phosphorylation of the PUF Protein Puf3 Regulates the Translational Fate of Its Bound mRNAs and Association with RNA Granules. Cell Rep 11:1638-50
Dutchak, Paul A; Laxman, Sunil; Estill, Sandi Jo et al. (2015) Regulation of Hematopoiesis and Methionine Homeostasis by mTORC1 Inhibitor NPRL2. Cell Rep 12:371-9
Shi, Lei; Tu, Benjamin P (2015) Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. Curr Opin Cell Biol 33:125-31
Huang, Zhiguang; Cai, Ling; Tu, Benjamin P (2015) Dietary control of chromatin. Curr Opin Cell Biol 34:69-74
Savir, Yonatan; Tu, Benjamin P; Springer, Michael (2015) Competitive inhibition can linearize dose-response and generate a linear rectifier. Cell Syst 1:238-245
Laxman, Sunil; Sutter, Benjamin M; Shi, Lei et al. (2014) Npr2 inhibits TORC1 to prevent inappropriate utilization of glutamine for biosynthesis of nitrogen-containing metabolites. Sci Signal 7:ra120
Shi, Lei; Tu, Benjamin P (2014) Protein acetylation as a means to regulate protein function in tune with metabolic state. Biochem Soc Trans 42:1037-42
Kuang, Zheng; Cai, Ling; Zhang, Xuekui et al. (2014) High-temporal-resolution view of transcription and chromatin states across distinct metabolic states in budding yeast. Nat Struct Mol Biol 21:854-63
Shi, Lei; Tu, Benjamin P (2013) Acetyl-CoA induces transcription of the key G1 cyclin CLN3 to promote entry into the cell division cycle in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 110:7318-23
Cai, Ling; McCormick, Mark A; Kennedy, Brian K et al. (2013) Integration of multiple nutrient cues and regulation of lifespan by ribosomal transcription factor Ifh1. Cell Rep 4:1063-71

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