Journal
EMBO JOURNAL
Volume 31, Issue 21, Pages 4179-4190Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/emboj.2012.272
Keywords
centrosome separation; dynein; Eg5; resistance; spindle
Categories
Funding
- Netherlands Genomic Initiative of NOW
- ZonMW TOP project [40-00812-98-10021]
- European Molecular Biology Organization (EMBO)
- Dutch Cancer Society (KWF)
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The microtubule motor protein kinesin-5 (Eg5) provides an outward force on centrosomes, which drives bipolar spindle assembly. Acute inhibition of Eg5 blocks centrosome separation and causes mitotic arrest in human cells, making Eg5 an attractive target for anti-cancer therapy. Using in vitro directed evolution, we show that human cells treated with Eg5 inhibitors can rapidly acquire the ability to divide in the complete absence of Eg5 activity. We have used these Eg5-independent cells to study alternative mechanisms of centrosome separation. We uncovered a pathway involving nuclear envelope (NE)associated dynein that drives centrosome separation in prophase. This NE-dynein pathway is essential for bipolar spindle assembly in the absence of Eg5, but also functions in the presence of full Eg5 activity, where it pulls individual centrosomes along the NE and acts in concert with Eg5-dependent outward pushing forces to coordinate prophase centrosome separation. Together, these results reveal how the forces are produced to drive prophase centrosome separation and identify a novel mechanism of resistance to kinesin-5 inhibitors. The EMBO Journal (2012) 31, 4179-4190. doi: 10.1038/emboj.2012.272; Published online 2 October 2012
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