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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11242014-142447 |
| Date | 26 November 2014 |
| Creators | Sturgill, Emma Gray |
| Contributors | Matthew Tyska, Irina Kaverina, Ethan lee, Alissa Weaver |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-11242014-142447/ |
| Rights | restrictone, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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