scholarly journals Hidden long-range memories of growth and cycle speed correlate cell cycles in lineage trees

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Erika E Kuchen ◽  
Nils B Becker ◽  
Nina Claudino ◽  
Thomas Höfer
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Long Range ◽  
Human Cancer ◽  
Embryonic Stem ◽  
Minimum Size ◽  
Cycle Duration ◽  
Correlation Pattern ◽  
Cell Cycles ◽  
Lineage Trees

Cell heterogeneity may be caused by stochastic or deterministic effects. The inheritance of regulators through cell division is a key deterministic force, but identifying inheritance effects in a systematic manner has been challenging. Here, we measure and analyze cell cycles in deep lineage trees of human cancer cells and mouse embryonic stem cells and develop a statistical framework to infer underlying rules of inheritance. The observed long-range intra-generational correlations in cell-cycle duration, up to second cousins, seem paradoxical because ancestral correlations decay rapidly. However, this correlation pattern is naturally explained by the inheritance of both cell size and cell-cycle speed over several generations, provided that cell growth and division are coupled through a minimum-size checkpoint. This model correctly predicts the effects of inhibiting cell growth or cycle progression. In sum, we show how fluctuations of cell cycles across lineage trees help in understanding the coordination of cell growth and division.

scholarly journals Long-range memory of growth and cycle progression correlates cell cycles in lineage trees

2018 ◽  
Author(s):  
Erika E Kuchen ◽  
Nils Becker ◽  
Nina Claudino ◽  
Thomas Höfer
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Mammalian Cell ◽  
Latent Variable ◽  
Cycle Length ◽  
Growth Control ◽  
Minimum Size ◽  
Cell Cycles ◽  
Lineage Trees

Mammalian cell proliferation is controlled by mitogens. However, how proliferation is coordinated with cell growth is poorly understood. Here we show that statistical properties of cell lineage trees – the cell-cycle length correlations within and across generations – reveal how cell growth controls proliferation. Analyzing extended lineage trees with latent-variable models, we find that two antagonistic heritable variables account for the observed cycle-length correlations. Using molecular perturbations of mTOR and MYC we identify these variables as cell size and regulatory license to divide, which are coupled through a minimum-size checkpoint. The checkpoint is relevant only for fast cell cycles, explaining why growth control of mammalian cell proliferation has remained elusive. Thus, correlated fluctuations of the cell cycle encode its regulation.

scholarly journals Positive Feedback Between PU.1 and the Cell Cycle Controls Myeloid Differentiation

Science ◽  
2013 ◽  
Vol 341 (6146) ◽  
pp. 670-673 ◽  
Author(s):  
Hao Yuan Kueh ◽  
Ameya Champhekar ◽  
Stephen L. Nutt ◽  
Michael B. Elowitz ◽  
Ellen V. Rothenberg
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Positive Feedback ◽  
Regulatory Gene ◽  
Control Cell ◽  
Stem Cell Differentiation ◽  
Myeloid Differentiation ◽  
Cycle Duration ◽  
Gene Circuits ◽  
Cell Cycles

Regulatory gene circuits with positive-feedback loops control stem cell differentiation, but several mechanisms can contribute to positive feedback. Here, we dissect feedback mechanisms through which the transcription factor PU.1 controls lymphoid and myeloid differentiation. Quantitative live-cell imaging revealed that developing B cells decrease PU.1 levels by reducing PU.1 transcription, whereas developing macrophages increase PU.1 levels by lengthening their cell cycles, which causes stable PU.1 accumulation. Exogenous PU.1 expression in progenitors increases endogenous PU.1 levels by inducing cell cycle lengthening, implying positive feedback between a regulatory factor and the cell cycle. Mathematical modeling showed that this cell cycle–coupled feedback architecture effectively stabilizes a slow-dividing differentiated state. These results show that cell cycle duration functions as an integral part of a positive autoregulatory circuit to control cell fate.

Wachstumsparameter in normalen und durch Actinomycin verlängerten Zellzyklen von Tetrahymena / Growth Parameters in Normal and Actinomycin-induced prolonged Cell Cycles of Tetrahymena

1969 ◽  
Vol 24 (12) ◽  
pp. 1624-1629 ◽  
Author(s):  
Günter Cleffmann
Keyword(s):  
Cell Cycle ◽  
Protein Synthesis ◽  
Cell Division ◽  
Dna Replication ◽  
Cell Growth ◽  
Rna Synthesis ◽  
Growth Parameters ◽  
Average Duration ◽  
Cell Cycles ◽  
Growing Cell

Actinomycin in low concentration (0,2 μg/ml — 0,5 μg/ml) prolongs the average duration of the cell cycle of Tetrahymena considerably, but does not inhibit cell division completely. Some parameters of the growing cell have been tested in cell cycles extended in this way and compared to those of normally growing cells. The RNA synthesis of treated cells is reduced to such an extent that the RNA content per cell decreases during the prolonged cell cycle. Nevertheless cell growth, protein synthesis and DNA replication proceed at almost the same rate as in untreated cells. These findings indicate that the presence of actinomycin does not interfere with RNA fractions necessary for growth but reduce the synthesis of RNA fractions which are essential for cell division. Therefore a longer period is needed for their accumulation.

scholarly journals All trans-retinoic acid analogs promote cancer cell apoptosis through non-genomic Crabp1 mediating ERK1/2 phosphorylation

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Shawna D. Persaud ◽  
Sung Wook Park ◽  
Mari Ishigami-Yuasa ◽  
Naoko Koyano-Nakagawa ◽  
Hiroyuki Kagechika ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Retinoic Acid ◽  
Cancer Cell ◽  
Cell Apoptosis ◽  
Cell Cycle Progression ◽  
Embryonic Stem ◽  
Cycle Duration ◽  
Cancer Cell Apoptosis ◽  
All Trans Retinoic Acid ◽  
Physiological Relevance

Abstract All trans retinoic acid (atRA) is one of the most potent therapeutic agents, but extensive toxicity caused by nuclear RA receptors (RARs) limits its clinical application in treating cancer. AtRA also exerts non-genomic activities for which the mechanism remains poorly understood. We determine that cellular retinoic acid binding protein 1 (Crabp1) mediates the non-genomic activity of atRA, and identify two compounds as the ligands of Crabp1 to rapidly and RAR-independently activate extracellular signal regulated kinase 1/2 (ERK1/2). Non-canonically activated ERK activates protein phosphatase 2A (PP2A) and lengthens cell cycle duration in embryonic stem cells (ESC). This is abolished in Crabp1-null ESCs. Re-expressing Crabp1 in Crabp1-negative cancer cells also sensitizes their apoptotic induction by atRA. This study reveals a physiological relevance of the non-genomic action of atRA, mediated by Crabp1, in modulating cell cycle progression and apoptosis induction, and provides a new cancer therapeutic strategy whereby compounds specifically targeting Crabp1 can modulate cell cycle and cancer cell apoptosis in a RAR-independent fashion, thereby avoiding atRA’s toxicity caused by its genomic effects.

scholarly journals Downward regulation of cell size in Paramecium tetraurelia: effects of increased cell size, with or without increased DNA content, on the cell cycle

1982 ◽  
Vol 57 (1) ◽  
pp. 315-329
Author(s):  
C.D. Rasmussen ◽  
J.D. Berger
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Dna Synthesis ◽  
Cell Size ◽  
Dna Content ◽  
Cell Mass ◽  
Cycle Duration ◽  
Restrictive Temperature ◽  
Permissive Temperature ◽  
Rates Of Growth

Two temperature-sensitive cell-cycle mutants were used to generate abnormally large cells (size estimated by protein content) with either normal or increased DNA contents. The first mutant, cc1, blocks DNA synthesis, but allows cell growth at the restrictive temperature. The cells do not progress through the cell cycle while at the restrictive temperature, but do recover and complete the cell cycle when returned to permissive conditions. The progeny have increased cell size and normal DNA content. Downward regulation of cell size occurs during the ensuing cell cycle at permissive temperature. Two processes are involved. First, the G1 period is reduced or eliminated. As initial cell size increases there is a progressive shortening of the cell cycle to 75% of normal. This limit cell-cycle duration is reached when the initial mass of the cell is equal to or greater than that of normal cells at the time of DNA synthesis initiation (0.25 of a cell cycle). Cells with the limit cell cycle begin macronuclear DNA synthesis immediately after fission. The durations of the S period and fission are normal. Second, the rate of cell growth is unaffected by the increase in cell size, and results in the partitioning of excess cell mass between the daughter cells at the next fission. The second mutant, cc2, blocks cell division, but allows DNA synthesis to occur at a reduced rate so that cells with up to about 140% of the normal initial DNA content and twice the normal cell mass can be produced. The pattern of cell-cycle shortening is the same as in ccl. The rates of growth and both the rate and amount of DNA synthesis are proportional to the initial DNA content. This suggests that the rates of growth and DNA synthesis are limited by the transcriptional activity of the macronucleus in both cc1 and cc2 cells when they begin the cell cycle with experimentally increased cell mass. Increases in both cell size and initial DNA content are required to bring about increases in the rates of growth and DNA accumulation.

Characterization of the unusually rapid cell cycles during rat gastrulation

Development ◽  
1993 ◽  
Vol 117 (3) ◽  
pp. 873-883 ◽  
Author(s):  
A. Mac Auley ◽  
Z. Werb ◽  
P.E. Mirkes
Keyword(s):  
Cell Cycle ◽  
Cycle Time ◽  
Mammalian Cells ◽  
Primitive Streak ◽  
Cycle Duration ◽  
Embryonic Cells ◽  
Cell Cycle Time ◽  
Cell Cycles ◽  
A Cell ◽  
Cycle Regulation

The onset of gastrulation in rodents is associated with the start of differentiation within the embryo proper and a dramatic increase in the rate of growth and proliferation. We have determined the duration of the cell cycle for mesodermal and ectodermal cells of rat embryos during gastrulation (days 8.5 to 9.5 of gestation) using a stathmokinetic analysis. These embryonic cells are the most rapidly dividing mammalian cells yet described. Most cells of the ectoderm and mesoderm had a cell cycle time of 7 to 7.5 hours, but the cells of the primitive streak divided every 3 to 3.5 hours. Total cell cycle time was reduced by shortening S and G2, as well as G1, in contrast to cells later in development, when cell cycle duration is modulated largely by varying the length of G1. In the ectoderm and mesoderm, G1 was 1.5 to 2 hours, S was 3.5 to 4 hours, and G2 was 30 to 40 minutes. G1, S and G2 were shortened even further in the cells of the primitive streak: G1 was less than 30 minutes, S was 2 to 2.75 hours, and G2 was less than 20 minutes. Thus, progress of cells through all phases of the cell cycle is extensively modified during rodent embryogenesis. Specifically, the increased growth rate during gastrulation is associated with radical changes in cell cycle structure and duration. Further, the commitment of cells to become mesoderm and endoderm by entering the primitive streak is associated with expression of a very short cell cycle during transit of the primitive streak, such that developmental decisions determining germ layer fate are reflected in differences in cell cycle regulation.

scholarly journals A Short-Term Advantage for Syngamy in the Origin of Eukaryotic Sex: Effects of Cell Fusion on Cell Cycle Duration and Other Effects Related to the Duration of the Cell Cycle—Relationship between Cell Growth Curve and the Optimal Size of the Species, and Circadian Cell Cycle in Photosynthetic Unicellular Organisms

2012 ◽  
Vol 2012 ◽  
pp. 1-25 ◽  
Author(s):  
J. M. Mancebo Quintana ◽  
S. Mancebo Quintana
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Fusion ◽  
Growth Curve ◽  
Evolutionary Biology ◽  
Optimal Size ◽  
Cycle Duration ◽  
Unicellular Algae ◽  
Cell Cycle Duration ◽  
Unicellular Organisms

The origin of sex is becoming a vexatious issue for Evolutionary Biology. Numerous hypotheses have been proposed, based on the genetic effects of sex, on trophic effects or on the formation of cysts and syncytia. Our approach addresses the change in cell cycle duration which would cause cell fusion. Several results are obtained through graphical and mathematical analysis and computer simulations. (1) In poor environments, cell fusion would be an advantageous strategy, as fusion between cells of different size shortens the cycle of the smaller cell (relative to the asexual cycle), and the majority of mergers would occur between cells of different sizes. (2) The easiest-to-evolve regulation of cell proliferation (sexual/asexual) would be by modifying the checkpoints of the cell cycle. (3) A regulation of this kind would have required the existence of the G2 phase, and sex could thus be the cause of the appearance of this phase. Regarding cell cycle, (4) the exponential curve is the only cell growth curve that has no effect on the optimal cell size in unicellular species; (5) the existence of a plateau with no growth at the end of the cell cycle explains the circadian cell cycle observed in unicellular algae.

scholarly journals Size control in mammalian cells involves modulation of both growth rate and cell cycle duration

2017 ◽  
Author(s):  
Clotilde Cadart ◽  
Sylvain Monnier ◽  
Jacopo Grilli ◽  
Rafaele Attia ◽  
Emmanuel Terriac ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Cell Division ◽  
Cell Growth ◽  
Single Cell ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Size Control ◽  
Cycle Duration ◽  
Mathematical Framework

SummaryDespite decades of research, it remains unclear how mammalian cell growth varies with cell size and across the cell division cycle to maintain size control. Answers have been limited by the difficulty of directly measuring growth at the single cell level. Here we report direct measurement of single cell volumes over complete cell division cycles. The volume added across the cell cycle was independent of cell birth size, a size homeostasis behavior called “adder”. Single-cell growth curves revealed that the homeostatic behavior relied on adaptation of G1 duration as well as growth rate modulations. We developed a general mathematical framework that characterizes size homeostasis behaviors. Applying it on datasets ranging from bacteria to mammalian cells revealed that a near-adder is the most common type of size control, but only mammalian cells achieve it using modulation of both cell growth rate and cell-cycle progression.

scholarly journals Cell Cycle Kinetics and Development of Hydra Attenuata

1974 ◽  
Vol 16 (2) ◽  
pp. 349-358 ◽  
Author(s):  
R. D. CAMPBELL ◽  
C. N. DAVID
Keyword(s):  
Cell Cycle ◽  
Nuclear Dna ◽  
Cell Function ◽  
Control Point ◽  
Interstitial Cells ◽  
Total Cell ◽  
Cycle Duration ◽  
Cell Cycles ◽  
Cell Cycle Duration ◽  
Hydra Attenuata

The cell cycle parameters of interstitial cells in Hydra attenuata have been determined. Interstitial cells were classified according to cluster size in which they occur (1, 2, 4, 8 or 16 cells) and morphology using maceration preparations and histological sections. The lengths of G1, S, G2 and M were determined by standard methods of cell cycle analysis using pulse-chase and continuous labelling with [3H]- and [14C]thymidine. Nuclear DNA contents were measured microfluorimetrically. All classes of interstitial cells proliferate but the cell cycle of large interstitial cells occurring singly or in pairs is longer than that of interstitial cells occurring in clusters of 4, 8 and 16 cells. The S-phase is 11-12 h long and G1 is less than 1 h for all classes of interstitial cells. G2 is 3-4 h long for interstitial cells in clusters of 4, 8 and 16 cells giving these cells a total cell cycle duration of 16-17 h. In contrast, large interstitial cells occurring as singles and in clusters of 2 have G2 durations ranging from 4 to 22 h. Two subpopulations can be discerned among these cells, one having a G1 of about 6 h and a total cell cycle of about 19 h, the other having an average G2 of 14 h and a total cell cycle of about 27 h. The differences in cell cycle duration appear to be associated with interstitial cell function. Cells having a short cell cycle are probably committed to nematocyte differentiation, while large interstitial cells having long and variable cell cycles appear to be undetermined stem cells responsible for proliferating further interstitial cells. The variable length of G2 in these cells suggest it as a possible control point.

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