1. Cell Biology
  2. Computational and Systems Biology

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

  1. Miriam Bracha Ginzberg
  2. Nancy Chang
  3. Heather D'Souza
  4. Nish Patel
  5. Ran Kafri  Is a corresponding author
  6. Marc W Kirschner  Is a corresponding author
  1. Harvard Medical School, United States
  2. The Hospital for Sick Children, Canada
https://doi.org/10.7554/eLife.26957
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  1. Miriam Bracha Ginzberg
  2. Nancy Chang
  3. Heather D'Souza
  4. Nish Patel
  5. Ran Kafri
  6. Marc W Kirschner
(2018)
Cell size sensing in animal cells coordinates anabolic growth rates and cell cycle progression to maintain cell size uniformity
eLife 7:e26957.
https://doi.org/10.7554/eLife.26957
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Abstract

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.

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All data presented in this study are included in the manuscript and supporting files. Source data files have been provided for all figures.

Article and author information

Author details

  1. Miriam Bracha Ginzberg

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Nancy Chang

    Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.

  3. Heather D'Souza

    Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.

  4. Nish Patel

    Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.

  5. Ran Kafri

    Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
    For correspondence
    ran.kafri@sickkids.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9656-0189

  6. Marc W Kirschner

    Department of Systems Biology, Harvard Medical School, Boston, United States
    For correspondence
    marc@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6540-6130

Funding

Canadian Institutes of Health Research (FRN-343437)

  • Ran Kafri

National Institutes of Health (R01GM026875)

  • Marc W Kirschner

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2018, Ginzberg et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Miriam Bracha Ginzberg
  2. Nancy Chang
  3. Heather D'Souza
  4. Nish Patel
  5. Ran Kafri
  6. Marc W Kirschner
(2018)
Cell size sensing in animal cells coordinates anabolic growth rates and cell cycle progression to maintain cell size uniformity
eLife 7:e26957.
https://doi.org/10.7554/eLife.26957

Share this article

https://doi.org/10.7554/eLife.26957

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Further reading

    1. Cell Biology

    Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis

    Shixuan Liu, Ceryl Tan ... Ran Kafri
    Research Advance Updated

    Proliferating animal cells maintain a stable size distribution over generations despite fluctuations in cell growth and division size. Previously, we showed that cell size control involves both cell size checkpoints, which delay cell cycle progression in small cells, and size-dependent regulation of mass accumulation rates (Ginzberg et al., 2018). While we previously identified the p38 MAPK pathway as a key regulator of the mammalian cell size checkpoint (Liu et al., 2018), the mechanism of size-dependent growth rate regulation has remained elusive. Here, we quantified global rates of protein synthesis and degradation in cells of varying sizes, both under unperturbed conditions and in response to perturbations that trigger size-dependent compensatory growth slowdown. We found that protein synthesis rates scale proportionally with cell size across cell cycle stages and experimental conditions. In contrast, oversized cells that undergo compensatory growth slowdown exhibit a superlinear increase in proteasome-mediated protein degradation, with accelerated protein turnover per unit mass, suggesting activation of the proteasomal degradation pathway. Both nascent and long-lived proteins contribute to the elevated protein degradation during compensatory growth slowdown, with long-lived proteins playing a crucial role at the G1/S transition. Notably, large G1/S cells exhibit particularly high efficiency in protein degradation, surpassing that of similarly sized or larger cells in S and G2, coinciding with the timing of the most stringent size control in animal cells. These results collectively suggest that oversized cells reduce their growth efficiency by activating global proteasome-mediated protein degradation to promote cell size homeostasis.

    1. Cell Biology
    2. Computational and Systems Biology

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

    Shixuan Liu, Miriam Bracha Ginzberg ... Ran Kafri
    Research Article

    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.