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.

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 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 Size uniformity of animal cells is actively maintained by a p38 MAPK-dependent regulation of G1-length

2017 ◽  
Author(s):  
Shixuan Liu ◽  
Miriam B. Ginzberg ◽  
Nish Patel ◽  
Marc Hild ◽  
Bosco Leung ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Size ◽  
P38 Mapk ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Small Cells ◽  
Animal Cells ◽  
Cycle Progression ◽  
Size Uniformity

AbstractAnimal cells within a tissue typically display a striking regularity in their size. To date, the molecular mechanisms that control this uniformity are still unknown. We have previously shown that size uniformity in animal cells is promoted, in part, by size-dependent regulation of G1 length. To identify the molecular mechanisms underlying this process, we performed a large-scale small molecule screen and found that the p38 MAPK pathway is involved in coordinating cell size and cell cycle progression. Small cells display higher p38 activity and spend more time in G1 than larger cells. Inhibition of p38 MAPK leads to loss of the compensatory G1 length extension in small cells, resulting in faster proliferation, smaller cell size and increased size heterogeneity. We propose a model wherein the p38 pathway responds to changes in cell size and regulates G1 exit accordingly, to increase cell size uniformity.One-sentence summaryThe p38 MAP kinase pathway coordinates cell growth and cell cycle progression by lengthening G1 in small cells, allowing them more time to grow before their next division.

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 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 A G1 sizer mechanism coordinates growth and division in the mouse epidermis

2019 ◽  
Author(s):  
Shicong Xie ◽  
Jan M. Skotheim
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Size ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Single Cells ◽  
Mouse Skin ◽  
Mouse Epidermis ◽  
Cycle Progression

SummaryCell size homeostasis is often achieved by coupling cell cycle progression to cell growth. Studies of cell size homeostasis in single-celled bacteria and yeast have observed several distinct phenomena. Growth can be coupled to division through a range of mechanisms, including a ‘sizer’, wherein cells of varying birth size divide at similar final sizes [1–3], and an ‘adder’, wherein cells increase in size a fixed amount per cell cycle [4–6]. Importantly, intermediate control mechanisms are observed, and even the same organism can exhibit distinct control phenomena depending on growth conditions [2,7,8]. While studying unicellular organisms in laboratory conditions may give insight into their growth control in the wild, this is less apparent for studies of mammalian cells growing outside the organism. Sizer, adder, and intermediate mechanisms have been observed in vitro [9–12], but it is unclear how these diverse size homeostasis phenomena relate to mammalian cell proliferation in vivo. To address this gap, we analyzed time-lapse images of the mouse epidermis taken over one week during normal tissue turnover [13]. We quantified the 3D volume growth and cell cycle progression of single cells within the mouse skin. In dividing epidermal stem cells, we found that cell growth is coupled to division through a sizer mechanism operating largely in the G1 phase. Thus, while the majority of tissue culture studies to-date identified adder mechanisms, our analysis demonstrates that sizer mechanisms are important in vivo and highlights the need to determine their underlying molecular origin.

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 Budding yeast relies on G1 cyclin specificity to couple cell cycle progression with morphogenetic development

2021 ◽  
Vol 7 (23) ◽  
pp. eabg0007
Author(s):  
Deniz Pirincci Ercan ◽  
Florine Chrétien ◽  
Probir Chakravarty ◽  
Helen R. Flynn ◽  
Ambrosius P. Snijders ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Budding Yeast ◽  
Quantitative Model ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Model Cell ◽  
Mitotic Cyclin ◽  
Substrate Phosphorylation ◽  
The Cost

Two models have been put forward for cyclin-dependent kinase (Cdk) control of the cell cycle. In the qualitative model, cell cycle events are ordered by distinct substrate specificities of successive cyclin waves. Alternatively, in the quantitative model, the gradual rise of Cdk activity from G1 phase to mitosis leads to ordered substrate phosphorylation at sequential thresholds. Here, we study the relative contributions of qualitative and quantitative Cdk control in Saccharomyces cerevisiae. All S phase and mitotic cyclins can be replaced by a single mitotic cyclin, albeit at the cost of reduced fitness. A single cyclin can also replace all G1 cyclins to support ordered cell cycle progression, fulfilling key predictions of the quantitative model. However, single-cyclin cells fail to polarize or grow buds and thus cannot survive. Our results suggest that budding yeast has become dependent on G1 cyclin specificity to couple cell cycle progression to essential morphogenetic events.

scholarly journals Oncogenic role of ALX3 in cervical cancer cells through KDM2B-mediated histone demethylation of CDC25A

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jinhong Qi ◽  
Li Zhou ◽  
Dongqing Li ◽  
Jingyuan Yang ◽  
He Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Cervical Squamous Cell Carcinoma ◽  
Cycle Progression ◽  
Normal Tissues ◽  
Positive Regulator ◽  
Cervical Cancer Cells

Abstract Background Cell division cycle 25A (CDC25A) is a well-recognized regulator of cell cycle progression and is involved in cancer development. This work focused on the function of CDC25A in cervical cancer cell growth and the molecules involved. Methods A GEO dataset GSE63514 comprising data of cervical squamous cell carcinoma (CSCC) tissues was used to screen the aberrantly expressed genes in cervical cancer. The CDC25A expression in cancer and normal tissues was predicted in the GEPIA database and that in CSCC and normal cells was determined by RT-qPCR and western blot assays. Downregulation of CDC25A was introduced in CSCC cells to explore its function in cell growth and the cell cycle progression. The potential regulators of CDC25A activity and the possible involved signaling were explored. Results CDC25A was predicted to be overexpressed in CSCC, and high expression of CDC25A was observed in CSCC cells. Downregulation of CDC25A in ME180 and C33A cells reduced cell proliferation and blocked cell cycle progression, and it increased cell apoptosis. ALX3 was a positive regulator of CDC25A through transcription promotion. It recruited a histone demethylase, lysine demethylase 2B (KDM2B), to the CDC25A promoter, which enhanced CDC25A expression through demethylation of H3k4me3. Overexpression of ALX3 in cells blocked the inhibitory effects of CDC25A silencing. CDC25A was found as a positive regulator of the PI3K/Akt signaling pathway. Conclusion This study suggested that the ALX3 increased CDC25A expression through KDM2B-mediated demethylation of H3K4me3, which induced proliferation and cell cycle progression of cervical cancer cells.

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