Mcl-1 dynamics influence mitotic slippage and death in mitosis

Oncotarget
Olivia SlossStephen S Taylor

Abstract

Microtubule-binding drugs such as taxol are frontline treatments for a variety of cancers but exactly how they yield patient benefit is unclear. In cell culture, inhibiting microtubule dynamics prevents spindle assembly, leading to mitotic arrest followed by either apoptosis in mitosis or slippage, whereby a cell returns to interphase without dividing. Myeloid cell leukaemia-1 (Mcl-1), a pro-survival member of the Bcl-2 family central to the intrinsic apoptosis pathway, is degraded during a prolonged mitotic arrest and may therefore act as a mitotic death timer. Consistently, we show that blocking proteasome-mediated degradation inhibits taxol-induced mitotic apoptosis in a Mcl-1-dependent manner. However, this degradation does not require the activity of either APC/C-Cdc20, FBW7 or MULE, three separate E3 ubiquitin ligases implicated in targeting Mcl-1 for degradation. This therefore challenges the notion that Mcl-1 undergoes regulated degradation during mitosis. We also show that Mcl-1 is continuously synthesized during mitosis and that blocking protein synthesis accelerates taxol induced death-in-mitosis. Modulating Mcl-1 levels also influences slippage; overexpressing Mcl-1 extends the time from mitotic entry to mitotic exi...Continue Reading

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Citations

Jul 8, 2017·Endocrine-related Cancer·Bing Cheng, Karen Crasta
Nov 1, 2018·Molecular Biology of the Cell·Zhihao TanGiulia Rancati
Oct 27, 2018·Medicinal Research Reviews·Alba Vicente-BlázquezRafael Peláez
Aug 12, 2016·Open Biology·Ailsa BennettStephen S Taylor
Feb 21, 2018·EMBO Reports·Manuel HaschkaAndreas Villunger
Jul 10, 2019·Cell Death and Differentiation·Kai T RichterIngrid Hoffmann
Mar 27, 2016·Biological Chemistry·Robert Pedley, Andrew P Gilmore
Jun 14, 2018·Scientific Reports·Alexander LorzDoron Levy
Apr 25, 2019·Cells·Robert H Whitaker, William J Placzek
Apr 24, 2020·Nature·Susanne Hellmuth, Olaf Stemmann
Feb 6, 2020·Cell Death and Differentiation·Manuel D HaschkaAndreas Villunger
Jan 8, 2020·Cell Death and Differentiation·Viacheslav V SenichkinGelina S Kopeina
Dec 14, 2018·Molecular & Cellular Oncology·Paul R ClarkeAgnieszka Skowyra
Mar 1, 2020·Cell Death & Disease·Robert H Whitaker, William J Placzek
Aug 23, 2018·Molecular Biology of the Cell·Yumi Uetake, Greenfield Sluder
Oct 14, 2020·Trends in Molecular Medicine·Sylvie Rodrigues-FerreiraClara Nahmias

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Methods Mentioned

BETA
ubiquitination
transfection
transfections
immunoprecipitation
in vitro transcription
PCR
Assay

Software Mentioned

IncuCyte ZOOM
Metamorph
Graphpad Prism

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