scholarly journals PP2ARts1 is a master regulator of pathways that control cell size

2014 ◽  
Vol 204 (3) ◽  
pp. 359-376 ◽  
Author(s):  
Jessica Zapata ◽  
Noah Dephoure ◽  
Tracy MacDonough ◽  
Yaxin Yu ◽  
Emily J. Parnell ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Size ◽  
Control Cell ◽  
Size Control ◽  
Regulatory Subunit ◽  
Delay Cell ◽  
Cell Cycle Entry ◽  
G1 Cyclin

Cell size checkpoints ensure that passage through G1 and mitosis occurs only when sufficient growth has occurred. The mechanisms by which these checkpoints work are largely unknown. PP2A associated with the Rts1 regulatory subunit (PP2ARts1) is required for cell size control in budding yeast, but the relevant targets are unknown. In this paper, we used quantitative proteome-wide mass spectrometry to identify proteins controlled by PP2ARts1. This revealed that PP2ARts1 controls the two key checkpoint pathways thought to regulate the cell cycle in response to cell growth. To investigate the role of PP2ARts1 in these pathways, we focused on the Ace2 transcription factor, which is thought to delay cell cycle entry by repressing transcription of the G1 cyclin CLN3. Diverse experiments suggest that PP2ARts1 promotes cell cycle entry by inhibiting the repressor functions of Ace2. We hypothesize that control of Ace2 by PP2ARts1 plays a role in mechanisms that link G1 cyclin accumulation to cell growth.

scholarly journals Growth-dependent signals drive an increase in early G1 cyclin concentration to link cell cycle entry with cell growth

2020 ◽  
Author(s):  
Robert A. Sommer ◽  
Jerry T. DeWitt ◽  
Raymond Tan ◽  
Douglas R. Kellogg
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Budding Yeast ◽  
Control Cell ◽  
Transcriptional Repressor ◽  
Cell Cycle Entry ◽  
G1 Cyclin

AbstractEntry into the cell cycle occurs only when sufficient growth has occurred. In budding yeast, the cyclin Cln3 initiates cell cycle entry by inactivating a transcriptional repressor called Whi5. Growth-dependent changes in the concentrations of Cln3 or Whi5 have been proposed to link cell cycle entry to cell growth. However, there are conflicting reports regarding the behavior and roles of Cln3 and Whi5. Here, we found no evidence that changes in the concentration of Whi5 play a major role in controlling cell cycle entry. Rather, the data suggest that cell growth triggers cell cycle entry by driving an increase in the concentration of Cln3. We further found that accumulation of Cln3 is dependent upon homologs of mammalian SGK kinases that play roles in control of cell growth and size. Together, the data are consistent with models in which Cln3 serves as the crucial link between the cell cycle and signals that control cell growth and size.

scholarly journals Dilution and titration of cell-cycle regulators may control cell size in budding yeast

2018 ◽  
Author(s):  
Frank S. Heldt ◽  
Reece Lunstone ◽  
John J. Tyson ◽  
Béla Novák
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Size ◽  
Cell Cycle Progression ◽  
Budding Yeast ◽  
Control Cell ◽  
Gene Copy Number ◽  
Size Control ◽  
Gene Copy ◽  
Cell Cycle Regulators

AbstractThe size of a cell sets the scale for all biochemical processes within it, thereby affecting cellular fitness and survival. Hence, cell size needs to be kept within certain limits and relatively constant over multiple generations. However, how cells measure their size and use this information to regulate growth and division remains controversial. Here, we present two mechanistic mathematical models of the budding yeast (S. cerevisiae) cell cycle to investigate competing hypotheses on size control: inhibitor dilution and titration of nuclear sites. Our results suggest that an inhibitor-dilution mechanism, in which cell growth dilutes the transcriptional inhibitor Whi5 against the constant activator Cln3, can facilitate size homeostasis. This is achieved by utilising a positive feedback loop to establish a fixed size threshold for the START transition, which efficiently couples cell growth to cell cycle progression. Yet, we show that inhibitor dilution cannot reproduce the size of mutants that alter the cell’s overall ploidy and WHI5 gene copy number. By contrast, size control through titration of Cln3 against a constant number of genomic binding sites for the transcription factor SBF recapitulates both size homeostasis and the size of these mutant strains. Moreover, this model produces an imperfect ‘sizer’ behaviour in G1 and a ‘timer’ in S/G2/M, which combine to yield an ‘adder’ over the whole cell cycle; an observation recently made in experiments. Hence, our model connects these phenomenological data with the molecular details of the cell cycle, providing a systems-level perspective of budding yeast size control.

scholarly journals Growth-dependent signals drive an increase in early G1 cyclin concentration to link cell cycle entry with cell growth

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Robert A Sommer ◽  
Jerry T DeWitt ◽  
Raymond Tan ◽  
Douglas R Kellogg
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Budding Yeast ◽  
Control Cell ◽  
Transcriptional Repressor ◽  
Cell Cycle Entry ◽  
G1 Cyclin

Entry into the cell cycle occurs only when sufficient growth has occurred. In budding yeast, the cyclin Cln3 is thought to initiate cell cycle entry by inactivating a transcriptional repressor called Whi5. Growth-dependent changes in the concentrations of Cln3 or Whi5 have been proposed to link cell cycle entry to cell growth. However, there are conflicting reports regarding the behavior and roles of Cln3 and Whi5. Here, we found no evidence that changes in the concentration of Whi5 play a major role in controlling cell cycle entry. Rather, the data suggest that cell growth triggers cell cycle entry by driving an increase in the concentration of Cln3. We further found that accumulation of Cln3 is dependent upon homologs of mammalian SGK kinases that control cell growth and size. Together, the data are consistent with models in which Cln3 is a crucial link between cell growth and the cell cycle.

scholarly journals The duration of mitosis and daughter cell size are modulated by nutrients in budding yeast

2017 ◽  
Vol 216 (11) ◽  
pp. 3463-3470 ◽  
Author(s):  
Ricardo M. Leitao ◽  
Douglas R. Kellogg
Keyword(s):  
Cell Cycle ◽  
Cell Size ◽  
Daughter Cell ◽  
Slow Growth ◽  
Budding Yeast ◽  
Size Control ◽  
G1 Phase ◽  
Large Reduction ◽  
Duration Of Mitosis ◽  
Cell Cycle Entry

The size of nearly all cells is modulated by nutrients. Thus, cells growing in poor nutrients can be nearly half the size of cells in rich nutrients. In budding yeast, cell size is thought to be controlled almost entirely by a mechanism that delays cell cycle entry until sufficient growth has occurred in G1 phase. Here, we show that most growth of a new daughter cell occurs in mitosis. When the rate of growth is slowed by poor nutrients, the duration of mitosis is increased, which suggests that cells compensate for slow growth in mitosis by increasing the duration of growth. The amount of growth required to complete mitosis is reduced in poor nutrients, leading to a large reduction in cell size. Together, these observations suggest that mechanisms that control the extent of growth in mitosis play a major role in cell size control in budding yeast.

scholarly journals Growth Rate and Cell Size Modulate the Synthesis of, and Requirement for, G1-Phase Cyclins at Start

2004 ◽  
Vol 24 (24) ◽  
pp. 10802-10813 ◽  
Author(s):  
Brandt L. Schneider ◽  
Jian Zhang ◽  
J. Markwardt ◽  
George Tokiwa ◽  
Tom Volpe ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Cell Size ◽  
Cell Cycle Progression ◽  
Control Mechanism ◽  
Size Control ◽  
Small Cells ◽  
Critical Threshold ◽  
Cycle Progression

ABSTRACT In Saccharomyces cerevisiae, commitment to cell cycle progression occurs at Start. Progression past Start requires cell growth and protein synthesis, a minimum cell size, and G1-phase cyclins. We examined the relationships among these factors. Rapidly growing cells expressed, and required, dramatically more Cln protein than did slowly growing cells. To clarify the role of cell size, we expressed defined amounts of CLN mRNA in cells of different sizes. When Cln was expressed at nearly physiological levels, a critical threshold of Cln expression was required for cell cycle progression, and this critical threshold varied with both cell size and growth rate: as cells grew larger, they needed less CLN mRNA, but as cells grew faster, they needed more Cln protein. At least in part, large cells had a reduced requirement for CLN mRNA because large cells generated more Cln protein per unit of mRNA than did small cells. When Cln was overexpressed, it was capable of promoting Start rapidly, regardless of cell size or growth rate. In summary, the amount of Cln required for Start depends dramatically on both cell size and growth rate. Large cells generate more Cln1 or Cln2 protein for a given amount of CLN mRNA, suggesting the existence of a novel posttranscriptional size control mechanism.

scholarly journals The duration of mitosis and daughter cell size are modulated by nutrients in budding yeast

2016 ◽  
Author(s):  
Ricardo M. Leitao ◽  
Douglas R. Kellogg
Keyword(s):  
Cell Cycle ◽  
Cell Size ◽  
Daughter Cell ◽  
Slow Growth ◽  
Budding Yeast ◽  
Size Control ◽  
G1 Phase ◽  
Large Reduction ◽  
Duration Of Mitosis ◽  
Cell Cycle Entry

AbstractThe size of nearly all cells is modulated by nutrients. Thus, cells growing in poor nutrients can be nearly half the size of cells in rich nutrients. In budding yeast, cell size is thought to be controlled almost entirely by a mechanism that delays cell cycle entry until sufficient growth has occurred in G1 phase. Here, we show that most growth of a new daughter cell occurs in mitosis. When the rate of growth is slowed by poor nutrients, the duration of mitosis is increased, which suggests that cells compensate for slow growth in mitosis by increasing the duration of growth. The amount of growth required to complete mitosis is reduced in poor nutrients, leading to a large reduction in cell size. Together, these observations suggest that mechanisms that control the extent of growth in mitosis play a major role in cell size control in budding yeast.

scholarly journals The reverse, but coordinated, roles of Tor2 (TORC1) and Tor1 (TORC2) kinases for growth, cell cycle and separase-mediated mitosis in Schizosaccharomyces pombe

Open Biology ◽  
2011 ◽  
Vol 1 (3) ◽  
pp. 110007 ◽  
Author(s):  
Nobuyasu Ikai ◽  
Norihiko Nakazawa ◽  
Takeshi Hayashi ◽  
Mitsuhiro Yanagida
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Schizosaccharomyces Pombe ◽  
Cell Size ◽  
Chromosome Segregation ◽  
Kinase Activity ◽  
Size Control ◽  
Phosphatidyl Inositol ◽  
Nutrient Utilization ◽  
A Cell

Target of rapamycin complexes (TORCs), which are vital for nutrient utilization, contain a catalytic subunit with the phosphatidyl inositol kinase-related kinase (PIKK) motif. TORC1 is required for cell growth, while the functions of TORC2 are less well understood. We show here that the fission yeast Schizosaccharomyces pombe TORC2 has a cell cycle role through determining the proper timing of Cdc2 Tyr15 dephosphorylation and the cell size under limited glucose, whereas TORC1 restrains mitosis and opposes securin–separase, which are essential for chromosome segregation. These results were obtained using the previously isolated TORC1 mutant tor2-L2048S in the phosphatidyl inositol kinase (PIK) domain and a new TORC2 mutant tor1-L2045D , which harbours a mutation in the same site. While mutated TORC1 and TORC2 displayed diminished kinase activity and FKBP12/Fkh1-dependent rapamycin sensitivity, their phenotypes were nearly opposite in mitosis. Premature mitosis and the G2–M delay occurred in TORC1 and TORC2 mutants, respectively. Surprisingly, separase/cut1—securin/cut2 mutants were rescued by TORC1/ tor2-L2048S mutation or rapamycin addition or even Fkh1 deletion, whereas these mutants showed synthetic defect with TORC2/ tor1-L2045D . TORC1 and TORC2 coordinate growth, mitosis and cell size control, such as Wee1 and Cdc25 do for the entry into mitosis.

scholarly journals RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry

2012 ◽  
Vol 209 (13) ◽  
pp. 2409-2422 ◽  
Author(s):  
Heiyoun Jung ◽  
Benjamin Hsiung ◽  
Kathleen Pestal ◽  
Emily Procyk ◽  
David H. Raulet
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Stress Responses ◽  
Transcriptional Activation ◽  
Posttranscriptional Regulation ◽  
Cellular Proliferation ◽  
Control Cell ◽  
T Cell Subsets ◽  
Cell Cycle Entry

The NKG2D stimulatory receptor expressed by natural killer cells and T cell subsets recognizes cell surface ligands that are induced on transformed and infected cells and facilitate immune rejection of tumor cells. We demonstrate that expression of retinoic acid early inducible gene 1 (RAE-1) family NKG2D ligands in cancer cell lines and proliferating normal cells is coupled directly to cell cycle regulation. Raet1 genes are directly transcriptionally activated by E2F family transcription factors, which play a central role in regulating cell cycle entry. Induction of RAE-1 occurred in primary cell cultures, embryonic brain cells in vivo, and cells in healing skin wounds and, accordingly, wound healing was delayed in mice lacking NKG2D. Transcriptional activation by E2Fs is likely coordinated with posttranscriptional regulation by other stress responses. These findings suggest that cellular proliferation, as occurs in cancer cells but also other pathological conditions, is a key signal tied to immune reactions mediated by NKG2D-bearing lymphocytes.

scholarly journals Phosphoinositide 3-Kinases p110α and p110β Regulate Cell Cycle Entry, Exhibiting Distinct Activation Kinetics in G1 Phase

2008 ◽  
Vol 28 (8) ◽  
pp. 2803-2814 ◽  
Author(s):  
Miriam Marqués ◽  
Amit Kumar ◽  
Isabel Cortés ◽  
Ana Gonzalez-García ◽  
Carmen Hernández ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tyrosine Kinases ◽  
Control Cell ◽  
Growth Factor Receptor ◽  
Maximum Activity ◽  
S Phase ◽  
Selective Action ◽  
Cell Cycle Entry ◽  
Phosphoinositide 3 Kinase ◽  
Phase Entry

ABSTRACT Phosphoinositide 3-kinase (PI3K) is an early signaling molecule that regulates cell growth and cell cycle entry. PI3K is activated immediately after growth factor receptor stimulation (at the G0/G1 transition) and again in late G1. The two ubiquitous PI3K isoforms (p110α and p110β) are essential during embryonic development and are thought to control cell division. Nonetheless, it is presently unknown at which point each is activated during the cell cycle and whether or not they both control S-phase entry. We found that p110α was activated first in G0/G1, followed by a minor p110β activity peak. In late G1, p110α activation preceded that of p110β, which showed the maximum activity at this time. p110β activation required Ras activity, whereas p110α was first activated by tyrosine kinases and then further induced by active Ras. Interference with p110α and -β activity diminished the activation of downstream effectors with different kinetics, with a selective action of p110α in blocking early G1 events. We show that inhibition of either p110α or p110β reduced cell cycle entry. These results reveal that PI3Kα and -β present distinct activation requirements and kinetics in G1 phase, with a selective action of PI3Kα at the G0/G1 phase transition. Nevertheless, PI3Kα and -β both regulate S-phase entry.

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