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    A Reductionist Study into the Physiology, Pathology, and Pharmacology of the Mitotic Spindle

    Sturgill, Emma Gray
    : https://etd.library.vanderbilt.edu/etd-11242014-142447
    http://hdl.handle.net/1803/14780
    : 2014-11-26

    Abstract

    Mitotic kinesins represent the new age targets of spindle-poisoning chemotherapies. The kinesin-5 Eg5 is one such example, as kinesin-5 inhibitors (K5Is) induce a lethal mitotic arrest from failed spindle assembly. Documented here is the discovery of a novel spindle assembly pathway that confers K5I-resistance to human tumor cells in culture. This “reverse-jackknifing” pathway is mechanically distinct from the canonical Eg5-driven mechanism, relying instead on the activity of the kinesin-12 Kif15. The work shown here details the molecular function and biochemical properties of Kif15, while also providing insight into the larger question of why anti-mitotic pharmacological agents fail as chemotherapies. Future efforts will evaluate the combination of K5Is with Kif15-inhibitors as a novel strategy for the treatment of neoplasias. Ultimately, this study bridges mitotic mechanisms with clinically relevant problems, being of interest to cell biologists, cancer biologists, and clinicians.
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