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
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
Sutter, Benjamin M; Wu, Xi; Laxman, Sunil et al. (2013) Methionine inhibits autophagy and promotes growth by inducing the SAM-responsive methylation of PP2A. Cell 154:403-15
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
Laxman, Sunil; Sutter, Benjamin M; Wu, Xi et al. (2013) Sulfur amino acids regulate translational capacity and metabolic homeostasis through modulation of tRNA thiolation. Cell 154:416-29
Zhang, Liang; Das, Priyabrata; Schmolke, Mirco et al. (2012) Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export. J Cell Biol 196:315-26
Laxman, Sunil; Tu, Benjamin P (2011) Multiple TORC1-associated proteins regulate nitrogen starvation-dependent cellular differentiation in Saccharomyces cerevisiae. PLoS One 6:e26081
Cai, Ling; Sutter, Benjamin M; Li, Bing et al. (2011) Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes. Mol Cell 42:426-37
Wu, Xi; Tu, Benjamin P (2011) Selective regulation of autophagy by the Iml1-Npr2-Npr3 complex in the absence of nitrogen starvation. Mol Biol Cell 22:4124-33