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

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Shixuan Liu ◽  
Miriam Bracha Ginzberg ◽  
Nish Patel ◽  
Marc Hild ◽  
Bosco Leung ◽  
...  
Keyword(s):  
Cell Size ◽  
P38 Mapk ◽  
Large Scale ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Small Cells ◽  
Animal Cells ◽  
Size Uniformity ◽  
Size Heterogeneity

Animal 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.

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 Large cells activate global protein degradation to maintain cell size homeostasis

2021 ◽  
Author(s):  
Shixuan Liu ◽  
Ceryl Tan ◽  
Chloe Melo-Gavin ◽  
Kevin G. Mark ◽  
Miriam Bracha Ginzberg ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Synthesis ◽  
Protein Degradation ◽  
Cell Size ◽  
Cell Cycle Progression ◽  
Mapk Pathway ◽  
Cellular Growth ◽  
Small Cells ◽  
Animal Cells ◽  
Size Dependent

Proliferating animal cells maintain a stable size distribution over generations despite fluctuations in cell growth and division size. This tight control of cell size involves both cell size checkpoints (e.g., delaying cell cycle progression for small cells) and size-dependent compensation in rates of mass accumulation (e.g., slowdown of cellular growth in large cells). We previously identified that the mammalian cell size checkpoint is mediated by a selective activation of the p38 MAPK pathway in small cells. However, mechanisms underlying the size-dependent compensation of cellular growth remain unknown. In this study, we quantified global rates of protein synthesis and degradation in naturally large and small cells, as well as in conditions that trigger a size-dependent compensation in cellular growth. Rates of protein synthesis increase proportionally with cell size in both perturbed and unperturbed conditions, as well as across cell cycle stages. Additionally, large cells exhibit elevated rates of global protein degradation and increased levels of activated proteasomes. Conditions that trigger a large-size-induced slowdown of cellular growth also promote proteasome-mediated global protein degradation, which initiates only after growth rate compensation occurs. Interestingly, the elevated rates of global protein degradation in large cells were disproportionately higher than the increase in size, suggesting activation of protein degradation pathways. Large cells at the G1/S transition show hyperactivated levels of protein degradation, even higher than similarly sized or larger cells in S or G2, coinciding with the timing of the most stringent size control in animal cells. Together, these findings suggest that large cells maintain cell size homeostasis by activating global protein degradation to induce a compensatory slowdown of growth.

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

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Miriam Bracha Ginzberg ◽  
Nancy Chang ◽  
Heather D'Souza ◽  
Nish Patel ◽  
Ran Kafri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Size ◽  
Growth Rates ◽  
Cell Cycle Progression ◽  
Cellular Growth ◽  
Small Cells ◽  
Live Cells ◽  
Control Mechanisms ◽  
Animal Cells ◽  
Size Uniformity

Cell size uniformity in healthy tissues suggests that control mechanisms might coordinate cell growth and division. We derived a method to assay whether cellular growth rates depend on cell size, by monitoring how variance in size changes as cells grow. Our data revealed that, twice during the cell cycle, growth rates are selectively increased in small cells and reduced in large cells, ensuring cell size uniformity. This regulation was also observed directly by monitoring nuclear growth in live cells. We also detected cell-size-dependent adjustments of G1 length, which further reduce variability. Combining our assays with chemical/genetic perturbations confirmed that cells employ two strategies, adjusting both cell cycle length and growth rate, to maintain the appropriate size. Additionally, although Rb signaling is not required for these regulatory behaviors, perturbing Cdk4 activity still influences cell size, suggesting that the Cdk4 pathway may play a role in designating the cell’s target size.

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.

The Effect of a Temperature Gradient on the Early Development of the Frog

1928 ◽  
Vol 5 (4) ◽  
pp. 309-336
Author(s):  
I. L. DEAN ◽  
M. E. SHAW ◽  
M. A. TAZELAAR
Keyword(s):  
Cell Size ◽  
Small Cells ◽  
Tail Bud ◽  
Animal Cells ◽  
Differential Growth ◽  
Experimental Conditions ◽  
Animal Pole ◽  
Stage Of Development ◽  
Permanent Effect ◽  
Two Sides

1. Temperature gradients were passed through the developing frog's egg and embryos. These gradients were applied either (a) apico-basally, when they were either (i) adjuvant, or (ii) antagonistic to the egg's own main gradient; or (b) transversely to the egg's main axis--lateral gradients. 2. (a) By this means considerable modification of segmentation and of cell size was induced, and was especially marked in the mid-blastula. Adjuvant gradients accentuated the normal differences in cell size between the animal and vegetative poles. Antagonistic gradients produced a double gradient in cell size, the smallest cells being in the region of the equator, and animal cells, in extreme cases, larger than yolk cells. (b) Several cases of the non-formation or obliteration of the blastocoel were obtained by all methods of treatment. (c) Too high temperature with adjuvant gradient produced inhibition at the animal pole, the large retarded cells being very sharply marked off from the surrounding small cells. (d) Lateral gradients produced a great difference in cell size on the two sides of the eggy and, as in the cases of "inhibition," a sharp line of demarcation may appear between the large cells of the cooled side and the small cells of the heated side. (e) When two sets of exactly similar eggs were treated simultaneously in opposite ways, then those subjected to the adjuvant gradient were always, at the close of the experiment, at a more advanced stage of development than those subjected to an antagonistic gradient. Because of this the yolk cells of the "adjuvant" eggs were smaller than those of the "antagonistic" eggs, although the former were cooled and the latter heated. (f) There seems to be a slight permanent effect of the gradient applied during segmentation. Eggs treated with antagonistic gradient tend to develop into microcephalous tadpoles and vice versa. 3. (a) Antagonistic gradients during gastrulation cause a reduction of the gastrular angle. (For definition see Bellamy (1919).) (b) Antagonistic gradient causes the eggs to gastrulate sooner than adjuvant eggs under exactly similar experimental conditions. (c) In the neurula stage the differential effect of the gradient is seen in the inhibition of the head and dorsal region in those subjected to antagonistic gradient, and inhibition of tail and ventral region in those subjected to adjuvant gradient. (d) Whether this alteration of relative sizes of head and tail regions is maintained in later development has not yet been ascertained. (e) Eggs exposed to lateral gradients in all stages of gastrulation showed marked asymmetries, some of which were apparently regulated later, while others persisted till the death of the tadpole. 4. Side-to-side treatment in the tail bud stage caused the development of marked asymmetry as the result of differential growth of the two sides. As in the case of 3 (e) some tadpoles appeared to regulate back to normal, whereas others remained markedly asymmetrical till death.

scholarly journals Bufalin Induces Mitochondria-Dependent Apoptosis in Pancreatic and Oral Cancer Cells by Downregulating hTERT Expression via Activation of the JNK/p38 Pathway

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Xin Tian ◽  
Shundong Dai ◽  
Jing Sun ◽  
Shenyi Jiang ◽  
Chengguang Sui ◽  
...  
Keyword(s):  
Dna Damage ◽  
Oral Cancer ◽  
Cell Viability ◽  
Cancer Cells ◽  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Ros Production ◽  
Oral Cancer Cells ◽  
P38 Pathway

Bufalin, a digoxin-like active component of the traditional Chinese medicine Chan Su, exhibits potent antitumor activities in many human cancers. Bufalin induces mitochondria-dependent apoptosis in cancer cells, but the detailed molecular mechanisms are largely unknown. hTERT, the catalytic subunit of telomerase, protects against mitochondrial damage by binding to mitochondrial DNA and reducing mitochondrial ROS production. In the present study, we investigated the effects of bufalin on the cell viability, ROS production, DNA damage, and apoptosis of CAPAN-2 human pancreatic and CAL-27 human oral cancer cells. Bufalin reduced CAPAN-2 and CAL-27 cell viability with IC50values of 159.2 nM and 122.6 nM, respectively. The reduced cell viability was accompanied by increased ROS production, DNA damage, and apoptosis and decreased expression of hTERT. hTERT silencing in CAPAN-2 and CAL-27 cells by siRNA resulted in increased caspase-9/-3 cleavage and DNA damage and decreased cell viability. Collectively, these data suggest that bufalin downregulates hTERT to induce mitochondria-dependent apoptosis in CAPAN-2 and CAL-27 cells. Moreover, bufalin increased the phosphorylation of JNK and p38-MAPK in CAPAN-2 and CAL-27 cells, and blocking the JNK/p38-MAPK pathway using the JNK inhibitor SP600125 or the p38-MAPK inhibitor SB203580 reversed bufalin-induced hTERT downregulation. Thus, the JNK/p38 pathway is involved in bufalin-induced hTERT downregulation and subsequent induction of apoptosis by the mitochondrial pathway.

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.

Sign in / Sign up

Export Citation Format

Share Document