Title page for ETD etd-04012008-102118


Type of Document Dissertation
Author Learman, Sarah Sebring
Author's Email Address slearman@vt.edu
URN etd-04012008-102118
Title Small-Molecule Control of Kinesin-5 Proteins
Degree PhD
Department Biology
Advisory Committee
Advisor Name Title
Walker, Richard A. Committee Chair
Cimini, Daniela Committee Member
Kim, Sunyoung Committee Member
Sible, Jill C. Committee Member
Wojcik, Edward J. Committee Member
Keywords
  • albumin
  • ATPase
  • HsEg5
  • inhibitor
  • kinesin
  • microtubule(s)
  • mitosis
  • monastrol
Date of Defense 2008-03-21
Availability unrestricted
Abstract
Mitosis, or cell division, is the mechanism by which cells divide and is an intricate process requiring the action and control of numerous proteins. Such proteins serve either as structural entities within the mitotic spindle, or perform the “work” within the apparatus. In particular, Kinesin-5 motor proteins, a subset within the kinesin motor protein superfamily, are primarily responsible for organization of microtubules (MTs) within the mitotic apparatus, and are consequently vital for efficient mitosis. These proteins utilize energy from ATP hydrolysis in order to “walk” along antiparallel MTs, positioning them into the bipolar mitotic spindle. Loss of Kinesin-5 activity results in formation of a monoastral spindle and subsequent cell cycle arrest.

Recently, a wide variety of small molecules have been identified that possess the ability to inhibit certain Kinesin-5 motors. Such compounds, including monastrol (the first Kinesin-5 inhibitor identified), have been employed to study Kinesin-5 activity. A thorough understanding of Kinesin-5 function, combined with the ability to specifically target these proteins with small molecules, may provide the capability to control cell division and may therefore have significant implications in anti-cancer therapies.

The following dissertation describes research that utilizes small molecules to probe the function (ATPase activity and MT interactions) of various Kinesin-5 proteins and provides information that will lead to a better understanding of exactly how such proteins function in vivo. Further, a greater knowledge of Kinesin-5 protein activity as well as specific interactions with small-molecule compounds, may lead to the development of more potent, less toxic anti-cancer drugs.

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