Letter | Published:

Competing memories of mitogen and p53 signalling control cell-cycle entry

Nature volume 549, pages 404408 (21 September 2017) | Download Citation

Abstract

Regulation of cell proliferation is necessary for immune responses, tissue repair, and upkeep of organ function to maintain human health1. When proliferating cells complete mitosis, a fraction of newly born daughter cells immediately enter the next cell cycle, while the remaining cells in the same population exit to a transient or persistent quiescent state2. Whether this choice between two cell-cycle pathways is due to natural variability in mitogen signalling or other underlying causes is unknown. Here we show that human cells make this fundamental cell-cycle entry or exit decision based on competing memories of variable mitogen and stress signals. Rather than erasing their signalling history at cell-cycle checkpoints before mitosis, mother cells transmit DNA damage-induced p53 protein and mitogen-induced cyclin D1 (CCND1) mRNA to newly born daughter cells. After mitosis, the transferred CCND1 mRNA and p53 protein induce variable expression of cyclin D1 and the CDK inhibitor p21 that almost exclusively determines cell-cycle commitment in daughter cells. We find that stoichiometric inhibition of cyclin D1–CDK4 activity by p21 controls the retinoblastoma (Rb) and E2F transcription program in an ultrasensitive manner. Thus, daughter cells control the proliferation–quiescence decision by converting the memories of variable mitogen and stress signals into a competition between cyclin D1 and p21 expression. We propose a cell-cycle control principle based on natural variation, memory and competition that maximizes the health of growing cell populations.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , & Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell 157, 935–949 (2014)

  2. 2.

    et al. The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit. Cell 155, 369–383 (2013)

  3. 3.

    & Cyclin D1 production in cycling cells depends on Ras in a cell-cycle-specific manner. Curr. Biol. 9, 1075–1084 (1999)

  4. 4.

    The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995)

  5. 5.

    & Life and death decisions by the E2F transcription factors. Curr. Opin. Cell Biol. 19, 649–657 (2007)

  6. 6.

    et al. Development of an optimized backbone of FRET biosensors for kinases and GTPases. Mol. Biol. Cell 22, 4647–4656 (2011)

  7. 7.

    et al. Stochastic ERK activation induced by noise and cell-to-cell propagation regulates cell density-dependent proliferation. Mol. Cell 52, 529–540 (2013)

  8. 8.

    , , , & Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82, 675–684 (1995)

  9. 9.

    . et al. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377, 552–557 (1995)

  10. 10.

    & The DNA damage response during DNA replication. Curr. Opin. Cell Biol. 17, 568–575 (2005)

  11. 11.

    & Dynamics of CDKN1A in single cells defined by an endogenous fluorescent tagging toolkit. Cell Reports 14, 1800–1811 (2016)

  12. 12.

    et al. Validation of cyclin D1/CDK4 as an anticancer drug target in MCF-7 breast cancer cells: effect of regulated overexpression of cyclin D1 and siRNA-mediated inhibition of endogenous cyclin D1 and CDK4 expression. Breast Cancer Res. Treat. 95, 185–194 (2006)

  13. 13.

    & The DNA damage response: putting checkpoints in perspective. Nature 408, 433–439 (2000)

  14. 14.

    et al. 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress. Nat. Cell Biol. 13, 243–253 (2011)

  15. 15.

    et al. DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression. Nat. Commun. 8, 14728 (2017)

  16. 16.

    , , , & Endogenous replication stress in mother cells leads to quiescence of daughter cells. Cell Reports 19, 1351–1364 (2017)

  17. 17.

    & Ubiquitination of p53 and p21 is differentially affected by ionizing and UV radiation. Mol. Cell. Biol. 17, 355–363 (1997)

  18. 18.

    , , , & A general chemical method to regulate protein stability in the mammalian central nervous system. Chem. Biol. 17, 981–988 (2010)

  19. 19.

    . et al. New functional activities for the p21 family of CDK inhibitors. Genes Dev. 11, 847–862 (1997)

  20. 20.

    , & p21Cip1 Promotes cyclin D1 nuclear accumulation via direct inhibition of nuclear export. J. Biol. Chem. 277, 8517–23 (2002)

  21. 21.

    , , & Dosage of Dyrk1a shifts cells within a p21-cyclin D1 signaling map to control the decision to enter the cell cycle. Mol. Cell 52, 87–100 (2013)

  22. 22.

    et al. Activation of cyclin D1-kinase in murine fibroblasts lacking both p21Cip1 and p27Kip1. Oncogene 21, 8067–74 (2002)

  23. 23.

    & Ultrasensitivity part II: multisite phosphorylation, stoichiometric inhibitors, and positive feedback. Trends Biochem. Sci. 39, 556–569 (2014)

  24. 24.

    & The hallmarks of cancer. Cell 100, 57–70 (2000)

  25. 25.

    et al. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell 132, 487–498 (2008)

  26. 26.

    , , & Generation of transgene-free induced pluripotent mouse stem cells by the piggyBac transposon. Nat. Methods 6, 363–369 (2009)

Download references

Acknowledgements

We thank K. Aoki and M. Matsuda for EKAR sensors, J. Stewart-Ornstein and G. Lahav for the p21-and p53-tagged MCF7 cell line, J. Ferrell, K. Cimprich, S. Collins, A. Hayer, S. Cappell, L. Pack, C. Liu, Y. Fan, L. Daigh, A. Jaimovich and S. Spencer for discussions, and the Stanford Shared FACS Facility for cell sorting. This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2013R1A6A3A03025832) and NIGMS R01 grants (GM11837, GM063702 and PGM107615).

Author information

Affiliations

  1. Department of Chemical & Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA

    • Hee Won Yang
    • , Mingyu Chung
    • , Takamasa Kudo
    •  & Tobias Meyer

Authors

  1. Search for Hee Won Yang in:

  2. Search for Mingyu Chung in:

  3. Search for Takamasa Kudo in:

  4. Search for Tobias Meyer in:

Contributions

H.Y. designed and carried out all experiments and data analysis. M.C. helped with the experimental set-up and idea for the cyclin D1, p21 and Rb staining experiments. M.C. and T.K. contributed to the image analysis. H.Y. and T.M. conceived the project and wrote the manuscript. All authors discussed the results and the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Hee Won Yang or Tobias Meyer.

Reviewer Information Nature thanks R. Medema, J. Purvis and A. Raj for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Reporting Summary

Videos

  1. 1.

    Examples of ERK and Cdk2 activities classified by three different Cdk2 paths.

    Top: time-lapse microscopy of DHB-mCherry and processed ERK images. Bottom: traces of Cdk2 activity (green) and ERK activity (Red). Scale bar is 10 µm.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature23880

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.