Mechanical cell competition kills cells via induction of lethal p53 levels
Authors
Wagstaff, Laura
Goschorska, Maja
Kozyrska, Kasia
Duclos, Guillaume
Chessel, Anatole
Hampton-O’Neil, Lea
Allen, George E
Silberzan, Pascal
Carazo, Salas Rafael E
Publication Date
2016-04-25Journal Title
Nature Communications
ISSN
2041-1723
Publisher
Nature Publishing Group
Volume
7
Number
11373
Language
English
Type
Article
Metadata
Show full item recordCitation
Wagstaff, L., Goschorska, M., Kozyrska, K., Duclos, G., Kucinski, I., Chessel, A., Hampton-O’Neil, L., et al. (2016). Mechanical cell competition kills cells via induction of lethal p53 levels. Nature Communications, 7 (11373)https://doi.org/10.1038/ncomms11373
Abstract
Cell competition is a quality control mechanism that eliminates unfit cells. How cells compete is poorly understood, but it is generally accepted that molecular exchange between cells signals elimination of unfit cells. Here we report an orthogonal mechanism of cell competition, whereby cells compete through mechanical insults. We show that MDCK cells silenced for the polarity gene scribble (scribKD) are hypersensitive to compaction, that interaction with wild-type cells causes their compaction and that crowding is sufficient for scribKD cell elimination. Importantly, we show that elevation of the tumour suppressor p53 is necessary and sufficient for crowding hypersensitivity. Compaction, via activation of Rho-associated kinase (ROCK) and the stress kinase p38, leads to further p53 elevation, causing cell death. Thus, in addition to molecules, cells use mechanical means to compete. Given the involvement of p53, compaction hypersensitivity may be widespread among damaged cells and offers an additional route to eliminate unfit cells.
Keywords
mechanical cell competition, cell death, mechanical stress, cell density, cell crowding, p53, p38, ROCK, scribble, migration
Sponsorship
This work was supported by a Cancer Research UK Programme Grant (EP and LW A12460), a Royal Society University Research fellowship to EP (UF0905080), a Wellcome Trust PhD studentship to I.K, a Cambridge Cancer Centre PhD studentship to MG and Core grant funding from the Wellcome Trust (092096) and CRUK (C6946/A14492).
Funder references
MRC (G0900424)
WELLCOME TRUST (105602/Z/14/Z)
BBSRC (BB/K006320/1)
Wellcome Trust (092096/Z/10/Z)
European Research Council (243283)
Cancer Research UK (A14492)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1038/ncomms11373
This record's URL: https://www.repository.cam.ac.uk/handle/1810/254751
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International