scholarly journals PP2ARts1enforces a proportional relationship between cell size and growth rate

2018 ◽  
Author(s):  
Ricardo M. Leitao ◽  
Annie Pham ◽  
Quincy Okobi ◽  
Douglas R. Kellogg
Keyword(s):  
Growth Rate ◽  
Cell Size ◽  
Cell Cycle Progression ◽  
Mechanistic Explanation ◽  
Regulatory Subunit ◽  
Daughter Cells ◽  
Duration Of Mitosis ◽  
Proportional Relationship ◽  
Underlying Mechanisms ◽  
The Relationship

AbstractCell size is proportional to growth rate. Thus, cells growing slowly in poor nutrients can be nearly half the size of cells growing rapidly in rich nutrients. The relationship between cell size and growth rate appears to hold across all orders of life, yet the underlying mechanisms are unknown. In budding yeast, most growth occurs during mitosis, and the proportional relationship between cell size and growth rate is therefore enforced primarily by modulating growth in mitosis. When growth is slow, the duration of mitosis is increased to allow more time for growth, yet the amount of growth required to complete mitosis is reduced, leading to birth of small daughter cells. Previous studies found that PP2A associated with the Rts1 regulatory subunit (PP2ARts1) works in a TORC2-dependent feedback loop that sets cell size and growth rate to match nutrient availability. However, it was unknown whether PP2ARts1influences growth in mitosis. Here, we show that PP2ARts1is required for the proportional relationship between cell size and growth rate during mitosis. Moreover, nutrients and PP2ARts1influence the duration of mitosis, and thus the extent of growth in mitosis, via Wee1 and Pds1/securin, two conserved regulators of mitotic progression. Together, the data suggest a model in which the same global signals that set growth rate also set the critical amount of growth required for cell cycle progression, which would provide a simple mechanistic explanation for the proportional relationship between size and growth rate.

scholarly journals Cell size and growth rate are modulated by TORC2-dependent signals

2017 ◽  
Author(s):  
Rafael Lucena ◽  
Maria Alcaide-Gavilán ◽  
Katherine Schubert ◽  
Maybo He ◽  
Matthew Domnauer ◽  
...  
Keyword(s):  
Growth Rate ◽  
Cell Size ◽  
Nutrient Availability ◽  
Feedback Loop ◽  
Budding Yeast ◽  
Regulatory Subunit ◽  
Underlying Mechanisms

SummaryThe size of all cells, from bacteria to vertebrates, is proportional to the growth rate set by nutrient availability, but the underlying mechanisms are unknown. Here, we show that nutrients modulate TORC2 signaling, and that cell size is proportional to TORC2 signaling in budding yeast. The TORC2 network controls production of ceramide lipids, which play roles in signaling. We discovered that ceramide-dependent signals control both growth rate and cell size. Thus, cells that can not make ceramides fail to modulate their growth rate or size in response to changes in nutrients. PP2A associated with the Rts1 regulatory subunit (PP2ARts1) is embedded in a feedback loop that controls TORC2 signaling and plays an important role in mechanisms that modulate TORC2 signaling in response to nutrients. Together, the data suggest a model in which growth rate and cell size are mechanistically linked by ceramide-dependent signals arising from the TORC2 network.

scholarly journals Hybrid systems approach to modeling stochastic dynamics of cell size

2016 ◽  
Author(s):  
Cesar Augusto Vargas-Garcia ◽  
Abhyudai Singh
Keyword(s):  
Growth Rate ◽  
Cell Size ◽  
Size Variation ◽  
Model Parameters ◽  
Constant Growth Rate ◽  
Division Rate ◽  
Size Dependent ◽  
Daughter Cells ◽  
Constant Growth ◽  
Over Time

A ubiquitous feature of all living cells is their growth over time followed by division into two daughter cells. How a population of genetically identical cells maintains size homeostasis, i.e., a narrow distribution of cell size, is an intriguing fundamental problem. We model size using a stochastic hybrid system, where a cell grows exponentially over time and probabilistic division events are triggered at discrete time intervals. Moreover, whenever these events occur, size is randomly partitioned among daughter cells. We first consider a scenario, where a timer (i.e., cell-cycle clock) that measures the time since the last division event regulates cellular growth and the rate of cell division. Analysis reveals that such a timer-driven system cannot achieve size homeostasis, in the sense that, the cell-to-cell size variation grows unboundedly with time. To explore biologically meaningful mechanisms for controlling size we consider three different classes of models: i) a size-dependent growth rate and timer-dependent division rate; ii) a constant growth rate and size-dependent division rate and iii) a constant growth rate and division rate that depends both on the cell size and timer. We show that each of these strategies can potentially achieve bounded intercellular size variation, and derive closed-form expressions for this variation in terms of underlying model parameters. Finally, we discuss how different organisms have adopted the above strategies for maintaining cell size homeostasis.

scholarly journals Sinorhizobium meliloti, a Slow-Growing Bacterium, Exhibits Growth Rate Dependence of Cell Size under Nutrient Limitation

mSphere ◽  
2018 ◽  
Vol 3 (6) ◽  
Author(s):  
Xiongfeng Dai ◽  
Zichu Shen ◽  
Yiheng Wang ◽  
Manlu Zhu
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Cell Size ◽  
Sinorhizobium Meliloti ◽  
Cell Cycle Progression ◽  
Bacterial Species ◽  
Progression Rate ◽  
Content Type ◽  
E Coli ◽  
Slow Growing

ABSTRACTBacterial cells need to coordinate the cell cycle with biomass growth to maintain cell size homeostasis. For fast-growing bacterial species likeEscherichia coliandBacillus subtilis, it is well-known that cell size exhibits a strong dependence on the growth rate under different nutrient conditions (known as the nutrient growth law). However, cell size changes little with slow growth (doubling time of >90 min) forE. coli, posing the interesting question of whether slow-growing bacteria species also observe the nutrient growth law. Here, we quantitatively characterize the cell size and cell cycle parameter of a slow-growing bacterium,Sinorhizobium meliloti, at different nutrient conditions. We find thatS. melilotiexhibits a threefold change in its cell size when its doubling time varies from 2 h to 6 h. Moreover, the progression rate of its cell cycle is much longer than that ofE. coli, suggesting a delicate coordination between the cell cycle progression rate and the biomass growth rate. Our study shows that the nutrient growth law holds robustly regardless of the growth capacity of the bacterial species, generalizing its applicability among the bacterial kingdom.IMPORTANCEThe dependence of cell size on growth rate is a fundamental principle in the field of bacterial cell size regulation. Previous studies of cell size regulation mainly focus on fast-growing bacterial species such asEscherichia coliandBacillussubtilis. We find here thatSinorhizobium meliloti, a slow-growing bacterium, exhibits a remarkable growth rate-dependent cell size pattern under nutrient limitation, generalizing the applicability of the empirical nutrient growth law of cell size. Moreover,S. melilotiexhibits a much slower speed of cell cycle progression thanE. colidoes, suggesting a delicate coordination between the cell cycle progression rate and the biomass growth rate.

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 A Conserved PP2A Regulatory Subunit Enforces Proportional Relationships Between Cell Size and Growth Rate

Genetics ◽  
2019 ◽  
Vol 213 (2) ◽  
pp. 517-528 ◽  
Author(s):  
Ricardo M. Leitao ◽  
Akshi Jasani ◽  
Rafael A. Talavera ◽  
Annie Pham ◽  
Quincy J. Okobi ◽  
...  
Keyword(s):  
Growth Rate ◽  
Cell Size ◽  
Regulatory Subunit

scholarly journals Integrated biphasic growth rate, gene expression, and cell-size homeostasis behaviour of singleB. subtiliscells

2019 ◽  
Author(s):  
Niclas Nordholt ◽  
Johan H. van Heerden ◽  
Frank J. Bruggeman
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Cell Division ◽  
Protein Expression ◽  
Cell Size ◽  
Cell Cycle Progression ◽  
Bacterial Cells ◽  
Cycle Progression ◽  
Average Cell ◽  
Cycle Dependent

ABSTRACTThe growth rate of single bacterial cells is continuously disturbed by random fluctuations in biosynthesis rates and by deterministic cell-cycle events, such as division, genome duplication, and septum formation. It is not understood whether, and how, bacteria reject these disturbances. Here we quantified growth and constitutive protein expression dynamics of singleBacillus subtiliscells, as a function of cell-cycle-progression. Variation in birth size and growth rate, resulting from unequal cell division, is largely compensated for when cells divide again. We analysed the cell-cycle-dynamics of these compensations and found that both growth and protein expression exhibited biphasic behaviour. During a first phase of variable duration, the absolute rates were approximately constant and cells behaved as sizers. In the second phase, rates increased and growth behaviour exhibited characteristics of a timer-strategy. This work shows how cell-cycle-dependent rate adjustments of biosynthesis and growth are integrated to compensate for physio-logical disturbances caused by cell division.IMPORTANCEUnder constant conditions, bacterial populations can maintain a fixed average cell size and constant exponential growth rate. At the single cell-level, however, cell-division can cause significant physiological perturbations, requiring compensatory mechanisms to restore the growth-related characteristics of individual cells toward that of the average cell. Currently, there is still a major gap in our understanding of the dynamics of these mechanisms, i.e. how adjustments in growth, metabolism and biosynthesis are integrated during the bacterial cell-cycle to compensate the disturbances caused by cell division. Here we quantify growth and constitutive protein expression in individual bacterial cells at sub-cell-cycle resolution. Significantly, both growth and protein production rates display structured and coordinated cell-cycle-dependent dynamics. These patterns reveal the dynamics of growth rate and size compensations during cell-cycle progression. Our findings provide a dynamic cell-cycle perspective that offers novel avenues for the interpretation of physiological processes that underlie cellular homeostasis in bacteria.

scholarly journals The PP1 regulator PPP1R2 coordinately regulates AURKA and PP1 to control centrosome phosphorylation and maintain central spindle architecture

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Alan-Michael Bresch ◽  
Nadiya Yerich ◽  
Rong Wang ◽  
Ann O. Sperry
Keyword(s):  
Protein Phosphatase ◽  
Cell Cycle Progression ◽  
Protein Phosphatase 1 ◽  
Regulatory Subunit ◽  
Aurora A Kinase ◽  
Central Spindle ◽  
Phosphorylation State ◽  
Daughter Cells ◽  
Spindle Structure ◽  
In Cells

Abstract Background Maintenance of centrosome number in cells is essential for accurate distribution of chromosomes at mitosis and is dependent on both proper centrosome duplication during interphase and their accurate distribution to daughter cells at cytokinesis. Two essential regulators of cell cycle progression are protein phosphatase 1 (PP1) and Aurora A kinase (AURKA), and their activities are each regulated by the PP1 regulatory subunit, protein phosphatase 1 regulatory subunit 2 (PPP1R2). We observed an increase in centrosome number after overexpression of these proteins in cells. Each of these proteins is found on the midbody in telophase and overexpression of PPP1R2 and its mutants increased cell ploidy and disrupted cytokinesis. This suggests that the increase in centrosome number we observed in PPP1R2 overexpressing cells was a consequence of errors in cell division. Furthermore, overexpression of PPP1R2 and its mutants increased midbody length and disrupted midbody architecture. Additionally, we show that overexpression of PPP1R2 alters activity of AURKA and PP1 and their phosphorylation state at the centrosome. Results Overexpression of PPP1R2 caused an increase in the frequency of supernumerary centrosomes in cells corresponding to aberrant cytokinesis reflected by increased nuclear content and cellular ploidy. Furthermore, AURKA, PP1, phospho PPP1R2, and PPP1R2 were all localized to the midbody at telophase, and PP1 localization there was dependent on binding of PPP1R2 with PP1 and AURKA as well as its phosphorylation state. Additionally, overexpression of both PPP1R2 and its C-terminal AURKA binding site altered enzymatic activity of AURKA and PP1 at the centrosome and disrupted central spindle structure. Conclusions Results from our study reveal the involvement of PPP1R2 in coordinating PP1 and AURKA activity during cytokinesis. Overexpression of PPP1R2 or its mutants disrupted the midbody at cytokinesis causing accumulation of centrosomes in cells. PPP1R2 recruited PP1 to the midbody and interference with its targeting resulted in elongated and severely disrupted central spindles supporting an important role for PPP1R2 in cytokinesis.

scholarly journals Cell size sensing in animal cells coordinates anabolic growth rates with cell cycle progression to maintain uniformity of cell size

2017 ◽  
Author(s):  
Miriam B. Ginzberg ◽  
Nancy Chang ◽  
Ran Kafri ◽  
Marc W. Kirschner
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Cell Size ◽  
Growth Rates ◽  
Cell Cycle Progression ◽  
Time Lapse ◽  
Small Cells ◽  
Live Cells ◽  
Control Mechanisms ◽  
Animal Cells

AbstractThe uniformity of cell size in healthy tissues suggests that control mechanisms might coordinate cell growth and division. We derived a method to assay whether growth rates of individual cells depend on cell size, by combining time-lapse microscopy and immunofluorescence to monitor how variance in cell size changes as cells grow. This analysis revealed two periods in the cell cycle when cell size variance decreases in a manner incompatible with unregulated growth, suggesting that cells sense their own size and adjust their growth rate to correct aberrations. Monitoring nuclear growth in live cells confirmed that these decreases in variance reflect a process that selectively inhibits the growth of large cells while accelerating growth of small cells. We also detected cell-size-dependent adjustments of G1 length, which further reduce variability. Combining our assays with chemical and genetic perturbations confirmed that cells employ two strategies, adjusting both cell cycle length and growth rate, to maintain the appropriate size.

scholarly journals Conserved Ark1-related kinases control TORC2 signaling

2019 ◽  
Author(s):  
Maria Alcaide-Gavilán ◽  
Selene Banuelos ◽  
Rafael Lucena ◽  
Douglas R. Kellogg
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Plasma Membrane ◽  
Cell Growth ◽  
Cell Size ◽  
Cell Cycle Progression ◽  
Coordinated Control ◽  
Cycle Progression ◽  
Membrane Growth ◽  
Slow Growing

AbstractIn all orders of life, cell cycle progression is dependent upon cell growth, and the extent of growth required for cell cycle progression is proportional to growth rate. Thus, cells growing rapidly in rich nutrients are substantially larger than slow growing cells. In budding yeast, a conserved signaling network surrounding Tor complex 2 (TORC2) controls growth rate and cell size in response to nutrient availability. Here, a search for new components of the TORC2 network identified a pair of redundant kinase paralogs called Ark1 and Prk1. Previous studies found that Ark/Prk play roles in endocytosis. Here, we show that Ark/Prk are embedded in the TORC2 network, where they appear to influence TORC2 signaling independently of their roles in endocytosis. We also show that reduced endocytosis leads to increased cell size, which indicates that cell size homeostasis requires coordinated control of plasma membrane growth and endocytosis. The discovery that Ark/Prk are embedded in the TORC2 network suggests a model in which TORC2-dependent signals control both plasma membrane growth and endocytosis, which would ensure that the rates of each process are matched to each other and to the availability of nutrients so that cells achieve and maintain an appropriate size.

scholarly journals A conserved Lkb1 signaling axis modulates TORC2 signaling in budding yeast

2018 ◽  
Author(s):  
Maria Alcaide-Gavilán ◽  
Rafael Lucena ◽  
Katherine Schubert ◽  
Karen Artiles ◽  
Jessica Zapata ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Cell Growth ◽  
Carbon Source ◽  
Cell Size ◽  
Nutrient Availability ◽  
Cell Cycle Progression ◽  
Budding Yeast ◽  
Small Cells ◽  
Cycle Progression

ABSTRACTNutrient availability, growth rate and cell size are closely linked. For example, in budding yeast, the rate of cell growth is proportional to nutrient availability, cell size is proportional to growth rate, and growth rate is proportional to cell size. Thus, cells grow slowly in poor nutrients and are nearly half the size of cells growing in rich nutrients. Moreover, large cells grow faster than small cells. A signaling network that surrounds Tor kinase complex 2 (TORC2) plays an important role in enforcing these proportional relationships. Cells that lack components of the TORC2 network fail to modulate their growth rate or size in response to changes in nutrient availability. Here, we show that budding yeast homologs of the Lkb1 tumor suppressor kinase are required for normal modulation of TORC2 signaling and in response to changes in carbon source. Lkb1 kinases activate Snf1/AMPK to initiate transcription of genes required for utilization of poor carbon sources. However, Lkb1 influences TORC2 signaling via a novel pathway that is independent of Snf1/AMPK. Of the three Lkb1 homologs in budding yeast, Elm1 plays the most important role in modulating TORC2. Elm1 activates a pair of related kinases called Gin4 and Hsl1. Previous work found that loss of Gin4 and Hsl1 causes cells to undergo unrestrained growth during a prolonged mitotic arrest, which suggests that play a role in linking cell cycle progression to cell growth. We found that Gin4 and Hsl1 also control the TORC2 network. In addition, Gin4 and Hsl1 are themselves influenced by signals from the TORC2 network, consistent with previous work showing that the TORC2 network constitutes a feedback loop. Together, the data suggest a model in which the TORC2 network sets growth rate in response to carbon source, while also relaying signals via Gin4 and Hsl1 that set the critical amount of growth required for cell cycle progression. This kind of close linkage between control of cell growth and size would suggest a simple mechanistic explanation for the proportional relationship between cell size and growth rate.

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