During cell division the capture of dynamic microtubules by the centromere initiates chromosome movement and, ultimately, the segregation of chromosomes to each daughter cell with high fidelity.Chromosome movement involves the coordination of microtubule motor activity and microtubule polymerization dynamics. Many anti-cancer drugs disrupt cell division by suppressing microtubule dynamics. In cells, the dynamic behavior of microtubules is modulated by accessory factors such as the Kin I family of microtubule motors. These kinesin-related proteins have evolved the ability to depolymerize microtubules rather than walking along the surface lattice of the microtubule to transport cargo. The centromere is the engine for chromosome movement and is responsible for coordinating chromosome movement with microtubule dynamics. The long-term objective of this proposal is to determine how the centromere segregates chromosomes with high fidelity. The centromere is able to modulate the dynamic behavior of the microtubule ends to which it attaches. Previously we have identified a centromere-associated member of the Kin I family of microtubule motors, which is most likely to be responsible for modulating microtubule dynamics in conjunction with chromosome movement. Specifically we will test how the regulation and spatial localization of the ATP-dependent microtubule depolymerizing activity of Mitotic Centromere-associated Kinesin (MCAK) contributes to the accurate segregation of chromosomes during mitosis. To perform this study it is essential to (1) understand the mechanism by which MCAK depolymerizes microtubules, (2) determine if MCAK's microtubule depolymerizing activity is modulated by regulatory factors during cell division and, (3) determine the precise role that MCAK plays in ensuring chromosome segregation with high fidelity. By answering these questions regarding MCAK function and regulation we will make great strides in understanding how the stability of the genome is maintained over the lifetime of an organism. MCAK has been identified as a gene, which is up-regulated in certain kinds of proliferative tumors. Therefore, in the course of these studies we will uncover information and produce tools that may be important in the diagnosis or in understanding the etiology of these types of tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM069429-01A1
Application #
6819420
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Deatherage, James F
Project Start
2004-08-01
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$310,780
Indirect Cost
Name
University of Washington
Department
Physiology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Shen, Hao; Fallas, Jorge A; Lynch, Eric et al. (2018) De novo design of self-assembling helical protein filaments. Science 362:705-709
Parker, Amelia L; Teo, Wee Siang; Pandzic, Elvis et al. (2018) ?-tubulin carboxy-terminal tails exhibit isotype-specific effects on microtubule dynamics in human gene-edited cells. Life Sci Alliance 1:
Luo, Ruibai; Reed, Christine E; Sload, Jeffrey A et al. (2017) Arf GAPs and molecular motors. Small GTPases :1-14
Decarreau, Justin; Wagenbach, Michael; Lynch, Eric et al. (2017) The tetrameric kinesin Kif25 suppresses pre-mitotic centrosome separation to establish proper spindle orientation. Nat Cell Biol 19:384-390
Wordeman, Linda; Decarreau, Justin; Vicente, Juan Jesus et al. (2016) Divergent microtubule assembly rates after short- versus long-term loss of end-modulating kinesins. Mol Biol Cell 27:1300-9
Cherry, Allison E; Haas, Brian R; Naydenov, Alipi V et al. (2016) ST-11: A New Brain-Penetrant Microtubule-Destabilizing Agent with Therapeutic Potential for Glioblastoma Multiforme. Mol Cancer Ther 15:2018-29
Luo, Ruibai; Chen, Pei-Wen; Wagenbach, Michael et al. (2016) Direct Functional Interaction of the Kinesin-13 Family Member Kinesin-like Protein 2A (Kif2A) and Arf GAP with GTP-binding Protein-like, Ankyrin Repeats and PH Domains1 (AGAP1). J Biol Chem 291:21350-21362
Drum, Benjamin M L; Yuan, Can; Li, Lei et al. (2016) Oxidative stress decreases microtubule growth and stability in ventricular myocytes. J Mol Cell Cardiol 93:32-43
Vicente, Juan Jesus; Wordeman, Linda (2015) Mitosis, microtubule dynamics and the evolution of kinesins. Exp Cell Res 334:61-9
Hehnly, Heidi; Canton, David; Bucko, Paula et al. (2015) A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells. Elife 4:e09384

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