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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM094314-03
Application #
8323563
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
Project Start
2010-09-30
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$314,820
Indirect Cost
$116,820
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Pendleton, Kathryn E; Chen, Beibei; Liu, Kuanqing et al. (2017) The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. Cell 169:824-835.e14
Ye, Cunqi; Sutter, Benjamin M; Wang, Yun et al. (2017) A Metabolic Function for Phospholipid and Histone Methylation. Mol Cell 66:180-193.e8
Chen, Jun; Sutter, Benjamin M; Shi, Lei et al. (2017) GATOR1 regulates nitrogenic cataplerotic reactions of the mitochondrial TCA cycle. Nat Chem Biol 13:1179-1186
Lee, Chien-Der; Tu, Benjamin P (2017) Metabolic influences on RNA biology and translation. Crit Rev Biochem Mol Biol 52:176-184
Walsh, Christopher T; Tu, Benjamin P; Tang, Yi (2017) Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism. Chem Rev :
Huang, Zhiguang; Cai, Ling; Tu, Benjamin P (2015) Dietary control of chromatin. Curr Opin Cell Biol 34:69-74
Shi, Lei; Tu, Benjamin P (2015) Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. Curr Opin Cell Biol 33:125-31
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
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
Savir, Yonatan; Tu, Benjamin P; Springer, Michael (2015) Competitive inhibition can linearize dose-response and generate a linear rectifier. Cell Syst 1:238-245

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