1. Cell Biology
  2. Computational and Systems Biology
Download icon

CDK control pathways integrate cell size and ploidy information to control cell division

  1. James Oliver Patterson  Is a corresponding author
  2. Souradeep Basu  Is a corresponding author
  3. Paul Rees
  4. Paul Nurse
  1. The Francis Crick Institute, United Kingdom
  2. Swansea University, United Kingdom
Research Article
  • Cited 0
  • Views 87
  • Annotations
Cite this article as: eLife 2021;10:e64592 doi: 10.7554/eLife.64592

Abstract

Maintenance of cell size homeostasis is a property that is conserved throughout eukaryotes. Cell size homeostasis is brought about by the co-ordination of cell division with cell growth, and requires restriction of smaller cells from undergoing mitosis and cell division, whilst allowing larger cells to do so. Cyclin-CDK is the fundamental driver of mitosis and therefore ultimately ensures size homeostasis. Here we dissect determinants of CDK activity in vivo to investigate how cell size information is processed by the cell cycle network in fission yeast. We develop a high-throughput single-cell assay system of CDK activity in vivo and show that inhibitory tyrosine phosphorylation of CDK encodes cell size information, with the phosphatase PP2A aiding to set a size threshold for division. CDK inhibitory phosphorylation works synergistically with PP2A to prevent mitosis in smaller cells. Finally, we find that diploid cells of equivalent size to haploid cells exhibit lower CDK activity in response to equal cyclin-CDK enzyme concentrations, suggesting that CDK activity is reduced by increased DNA levels. Therefore, scaling of cyclin-CDK levels with cell size, CDK inhibitory phosphorylation, PP2A, and DNA-dependent inhibition of CDK activity, all inform the cell cycle network of cell size, thus contributing to cell-size homeostasis.

Data availability

Analysed data has been uploaded to Figshare with the handle 10779/crick.14633037.

The following data sets were generated

Article and author information

Author details

  1. James Oliver Patterson

    Cell Cycle Laboratory, The Francis Crick Institute, London, United Kingdom
    For correspondence
    jamesop@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1993-4500
  2. Souradeep Basu

    Cell Cycle Laboratory, The Francis Crick Institute, London, United Kingdom
    For correspondence
    saz.basu@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4448-8688
  3. Paul Rees

    College of Engineering, Swansea University, Swansea, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Paul Nurse

    Cell Cycle Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

Funding

Boehringer Ingelheim Fonds

  • James Oliver Patterson

Cancer Research UK (FC01121)

  • James Oliver Patterson
  • Souradeep Basu
  • Paul Nurse

Medical Research Council (FC01121)

  • James Oliver Patterson
  • Souradeep Basu
  • Paul Nurse

Wellcome Trust (FC01121)

  • James Oliver Patterson
  • Paul Rees
  • Paul Nurse

Wellcome Trust (214183)

  • James Oliver Patterson
  • Souradeep Basu
  • Paul Nurse

The Lord Leonard and Lady Estelle Wolfson Foundation

  • James Oliver Patterson
  • Souradeep Basu
  • Paul Nurse

Biotechnology and Biological Sciences Research Council (BB/P026818/1)

  • James Oliver Patterson
  • Paul Rees

Biotechnology and Biological Sciences Research Council (BB/N005163/1)

  • Paul Rees

National Science Foundation (1458626)

  • Paul Rees

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

Reviewing Editor

  1. Silke Hauf, Virginia Tech, United States

Publication history

  1. Received: November 4, 2020
  2. Accepted: May 24, 2021
  3. Accepted Manuscript published: June 11, 2021 (version 1)

Copyright

© 2021, Patterson 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.

Metrics

  • 87
    Page views
  • 16
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cancer Biology
    2. Cell Biology
    Chaitra Rao et al.
    Research Article Updated

    The epithelial-to-mesenchymal transition (EMT) is considered a transcriptional process that induces a switch in cells from a polarized state to a migratory phenotype. Here, we show that KSR1 and ERK promote EMT-like phenotype through the preferential translation of Epithelial-Stromal Interaction 1 (EPSTI1), which is required to induce the switch from E- to N-cadherin and coordinate migratory and invasive behavior. EPSTI1 is overexpressed in human colorectal cancer (CRC) cells. Disruption of KSR1 or EPSTI1 significantly impairs cell migration and invasion in vitro, and reverses EMT-like phenotype, in part, by decreasing the expression of N-cadherin and the transcriptional repressors of E-cadherin expression, ZEB1 and Slug. In CRC cells lacking KSR1, ectopic EPSTI1 expression restored the E- to N-cadherin switch, migration, invasion, and anchorage-independent growth. KSR1-dependent induction of EMT-like phenotype via selective translation of mRNAs reveals its underappreciated role in remodeling the translational landscape of CRC cells to promote their migratory and invasive behavior.

    1. Cell Biology
    Dianne Lumaquin et al.
    Tools and Resources

    Lipid droplets are lipid storage organelles found in nearly all cell types from adipocytes to cancer cells. Although increasingly implicated in disease, current methods to study lipid droplets in vertebrate models rely on static imaging or the use of fluorescent dyes, limiting investigation of their rapid in vivo dynamics. To address this, we created a lipid droplet transgenic reporter in whole animals and cell culture by fusing tdTOMATO to Perilipin-2 (PLIN2), a lipid droplet structural protein. Expression of this transgene in transparent casper zebrafish enabled in vivo imaging of adipose depots responsive to nutrient deprivation and high-fat diet. Simultaneously, we performed a large-scale in vitro chemical screen of 1280 compounds and identified several novel regulators of lipolysis in adipocytes. Using our Tg(-3.5ubb:plin2-tdTomato) zebrafish line, we validated several of these novel regulators and revealed an unexpected role for nitric oxide in modulating adipocyte lipid droplets. Similarly, we expressed the PLIN2-tdTOMATO transgene in melanoma cells and found that the nitric oxide pathway also regulated lipid droplets in cancer. This model offers a tractable imaging platform to study lipid droplets across cell types and disease contexts using chemical, dietary, or genetic perturbations.