Letter | Published:

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

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


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.

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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).

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

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


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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.

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    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.

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