Department of Radiology; Sluder Lab
Cell Biology | Cells | Cellular and Molecular Physiology | Enzymes and Coenzymes
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.
Apoptosis, Caspase, Cell cycle, MCL-1, Mitosis, p38 MAP kinase, Proliferation, Prometaphase
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© 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
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
Molecular biology of the cell
Uetake Y, Sluder G. (2018). Activation of the apoptotic pathway during prolonged prometaphase blocks daughter cell proliferation. Radiology Publications and Presentations. https://doi.org/10.1091/mbc.E18-01-0026. Retrieved from https://escholarship.umassmed.edu/radiology_pubs/427
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.