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.

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 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 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 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.

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 Computationally enhanced quantitative phase microscopy reveals autonomous oscillations in mammalian cell growth

2020 ◽  
Vol 117 (44) ◽  
pp. 27388-27399
Author(s):  
Xili Liu ◽  
Seungeun Oh ◽  
Leonid Peshkin ◽  
Marc W. Kirschner
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Cell Growth ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Cell Tracking ◽  
Fundamental Property ◽  
Quantitative Phase ◽  
Phase Microscopy ◽  
Quantitative Phase Microscopy

The fine balance of growth and division is a fundamental property of the physiology of cells, and one of the least understood. Its study has been thwarted by difficulties in the accurate measurement of cell size and the even greater challenges of measuring growth of a single cell over time. We address these limitations by demonstrating a computationally enhanced methodology for quantitative phase microscopy for adherent cells, using improved image processing algorithms and automated cell-tracking software. Accuracy has been improved more than twofold and this improvement is sufficient to establish the dynamics of cell growth and adherence to simple growth laws. It is also sufficient to reveal unknown features of cell growth, previously unmeasurable. With these methodological and analytical improvements, in several cell lines we document a remarkable oscillation in growth rate, occurring throughout the cell cycle, coupled to cell division or birth yet independent of cell cycle progression. We expect that further exploration with this advanced tool will provide a better understanding of growth rate regulation in mammalian cells.

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