Commitment to cell division depends on cells growing to a certain size, called the critical size. The main objective of this proposal is to find out why critical size must be achieved, and what it is about size that allows the cell cycle to go forward. Previously, we discovered that size is linked to the steady-state levels of a critical G1 cyclin called Cln3 in yeast, whose homolog in mammalian cells is cyclin D. It appears that Cln3 is titrated against the number of DNA-bound SBF transcription factor complexes in the cell, and the number of these is simply set by genomic sequence. That is, the amount of Cln3, which grows as the cells grow, is titrated against something fixed, the number of DNA binding sites for a transcription factor complex. This allows cells to measure critical size. In the first two Aims, we will confirm, extend, and explore this titration model, in S. cerevisiae, and also in other species, to establish the generality of this mechanism. In addition, we have found that size control mechanisms remain even when the Cln3 pathway is abolished. One of these additional size control mechanisms seems to apply only in slowly growing, carbon-limited cells, and that mechanism seems to involve a cellular measurement of the storage carbohydrates glycogen and trehalose. In the third Aim, we will explore this new mechanism, with particular attention to the possibility that metabolic control pathways, and cell cycle control pathways, are more directly connected that is generally appreciated. These studies could be related to the Warburg effect in cancer cells.

Public Health Relevance

We will study the mechanism of how cells commit to a round of cell division, and in particular how and why cells must grow to a certain critical size before they can undertake division. Cancer is a disease of persistent, inappropriate cell division, and the mechanisms regulating commitment are often defective in cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM039978-23
Application #
8310155
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Hamlet, Michelle R
Project Start
1988-04-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
23
Fiscal Year
2012
Total Cost
$343,300
Indirect Cost
$123,300
Name
State University New York Stony Brook
Department
Genetics
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Wang, Hongyin; Carey, Lucas B; Cai, Ying et al. (2009) Recruitment of Cln3 cyclin to promoters controls cell cycle entry via histone deacetylase and other targets. PLoS Biol 7:e1000189
Di Talia, Stefano; Wang, Hongyin; Skotheim, Jan M et al. (2009) Daughter-specific transcription factors regulate cell size control in budding yeast. PLoS Biol 7:e1000221
Honey, Sangeet; Futcher, Bruce (2007) Roles of the CDK phosphorylation sites of yeast Cdc6 in chromatin binding and rereplication. Mol Biol Cell 18:1324-36
Jorgensen, Paul; Edgington, Nicholas P; Schneider, Brandt L et al. (2007) The size of the nucleus increases as yeast cells grow. Mol Biol Cell 18:3523-32
Futcher, Bruce (2006) Metabolic cycle, cell cycle, and the finishing kick to Start. Genome Biol 7:107
Oliva, Anna; Rosebrock, Adam; Ferrezuelo, Francisco et al. (2005) The cell cycle-regulated genes of Schizosaccharomyces pombe. PLoS Biol 3:e225
Pyne, Saumyadipta; Skiena, Steven; Futcher, Bruce (2005) Copy correction and concerted evolution in the conservation of yeast genes. Genetics 170:1501-13
Schneider, Brandt L; Zhang, Jian; Markwardt, J et al. (2004) Growth rate and cell size modulate the synthesis of, and requirement for, G1-phase cyclins at start. Mol Cell Biol 24:10802-13
Wijnen, Herman; Landman, Allison; Futcher, Bruce (2002) The G(1) cyclin Cln3 promotes cell cycle entry via the transcription factor Swi6. Mol Cell Biol 22:4402-18
Edgington, N P; Futcher, B (2001) Relationship between the function and the location of G1 cyclins in S. cerevisiae. J Cell Sci 114:4599-611

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