Mcl-1 dynamics influence mitotic slippage and death in mitosis

Sloss, O; Topham, C; Diez, M; Taylor, S

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 exit in the presence of taxol, while inhibiting Mcl-1 accelerates it. We suggest that Mcl-1 competes with Cyclin B1 for binding to components of the proteolysis machinery, thereby slowing down the slow degradation of Cyclin B1 responsible for slippage. Thus, modulating Mcl-1 dynamics influences both death-in-mitosis and slippage. However, because mitotic degradation of Mcl-1 appears not to be under the control of an E3 ligase, we suggest that the notion of network crosstalk is used with caution.

Citation

Sloss, O., Topham, C., Diez, M., & Taylor, S. (2016). Mcl-1 dynamics influence mitotic slippage and death in mitosis. Oncotarget, 7, 5176-5192. https://doi.org/10.18632/oncotarget.6894

• Journal Article Type: Article
• Acceptance Date: Dec 17, 2015
• Publication Date: Jan 12, 2016
• Deposit Date: Jan 19, 2016
• Publicly Available Date: Apr 5, 2016
• Journal: Oncotarget
• Electronic ISSN: 1949-2553
• Publisher: Impact Journals
• Volume: 7
• Pages: 5176-5192
• DOI: https://doi.org/10.18632/oncotarget.6894
• Publisher URL: http://dx.doi.org/10.18632/oncotarget.6894
• Related Public URLs: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget