UMMS Affiliation

Department of Radiology; Sluder Lab

Publication Date

2018-11-01

Document Type

Article

Disciplines

Cell Biology | Cells | Cellular and Molecular Physiology | Enzymes and Coenzymes

Abstract

When untransformed human cells spend >1.5 hr. in prometaphase under standard culture conditions, all daughters arrest in G1 despite normal division of their mothers. We investigate what happens during prolonged prometaphase that leads to daughter cell arrest in the absence of DNA damage. We find that progressive loss of anti-apoptotic MCL-1 activity and oxidative stress act in concert to partially activate the apoptosis pathway resulting in the delayed death of some daughters and senescence for the rest. At physiological oxygen levels, longer prometaphase durations are needed for all daughters to arrest. Partial activation of apoptosis during prolonged prometaphase leads to persistent caspase activity, which activates the kinase cascade mediating the post mitotic activation of p38. This in turn activates p53 and the consequent expression of p21stops the cell cycle. This mechanism can prevent cells suffering intractable mitotic defects, which modestly prolong mitosis but allow its completion without DNA damage, from producing future cell generations that are susceptible to the evolution of a transformed phenotype.

Keywords

Apoptosis, Caspase, Cell cycle, MCL-1, Mitosis, p38 MAP kinase, Proliferation, Prometaphase

Rights and Permissions

© 2018 Uetake and Sluder. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). Publisher PDF posted as allowed by the publisher's author rights policy at: https://www.molbiolcell.org/info-for-authors

DOI of Published Version

10.1091/mbc.E18-01-0026

Source

Mol Biol Cell. 2018 Nov 1;29(22):2632-2643. doi: 10.1091/mbc.E18-01-0026. Epub 2018 Aug 22. Link to article on publisher's site

Journal/Book/Conference Title

Molecular biology of the cell

Related Resources

Link to Article in PubMed

PubMed ID

30133342

Creative Commons License

Creative Commons Attribution-Noncommercial-Share Alike 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

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