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by Leigh MacMillan | Monday, Jul. 29, 2013, 8:00 AM
During cell division, the microtubule cytoskeleton of the cell rearranges into a mitotic “spindle” that drives chromosome separation. Two motor proteins – kinesin-5 and kinesin-12 – help build the mitotic spindle, and previous studies have established that kinesin-5 is the dominant motor. Kinesin-5 inhibitors (K5Is), which block cell division, are in clinical trials as cancer therapeutics.
Graduate student Emma Sturgill and Puck Ohi, Ph.D., assistant professor of Cell and Developmental Biology, now demonstrate that while kinesin-12 (human Kif15) has the capacity to drive spindle formation, its function varies depending on how it binds the mitotic spindle.
In contrast to the previous speculation that Kif15 is functionally redundant to kinesin-5, Sturgill and Ohi report in the July 22 Current Biology that Kif15 acts primarily on kinetochore fibers to regulate their length, an action that antagonizes kinesin-5. However, in cells in which kinesin-5 activity has been chronically inhibited, Kif15 mislocalizes to parallel non-kinetochore microtubules where it drives formation of the mitotic spindle. Therefore, kinesin-12 has the dual ability to produce forces that pull centrosomes (the poles of the spindle) inward and that drive centrosome separation. These activities depend on whether kinesin-12 is bound to kinetochore fibers or non-kinetochore microtubules.
The investigators conclude that Kif15 is also an important target for novel cancer therapies, and they suggest that a combination of K5Is and Kif15 inhibitors will be superior to K5Is alone.
This work was funded by the VUMC Integrated Biological Systems Training in Oncology training program (CA119925) and a pre-doctoral fellowship from the American Heart Association to E.S. Research in the Ohi laboratory is supported by the National Institutes of Health (GM086610) and by a Career Development Award from the Leukemia & Lymphoma Society to P.O.
Leigh MacMillan, (615) 322-4747
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