The broad goal of this project is to understand the mechanistic contribution of force generation by kinesin-related motors and dynamic microtubules to chromosome segregation. Both microtubules and motors represent excellent targets for anti-cancer drugs but to make wise choices for developing therapeutics it is necessary to understand their contribution to cell division in detail. We have identified two relatively unstudied kinesin-related motors, Kif25 and Kif9 that contribute key activities to facilitate proper mitotic spindle function. We will use high resolution live cell imaging, gene editing, Rapamycin-dependent knock-sideways approaches and single molecule assays in vitro to investigate how Kif25 suppresses premature centrosome separation and how it exerts inward force on the mitotic spindle sufficient to activate the spindle assembly checkpoint. We will use similar techniques to understand how Kif9 enables dividing cells to bypass the spindle assembly checkpoint. Underlying these activities are the dynamic microtubules that serve as substrates for kinesin activity. We have developed a number of assays that allow us to quantify subtle changes in microtubule dynamics. Stable alterations in microtubule assembly dynamics are often result from loss or overexpression of kinesin-like modulators, or other drivers of tumorigenesis. We will use cell-based assays and live imaging to determine the mechanism by which altered microtubule assembly rates impact long-term chromosome instability.
During cell division chromosomes must be segregated to each daughter cell with perfect fidelity to avoid alterations in chromosome numbers that are implicated in driving tumor development. This process is critically dependent on dynamic polymers within the cell called ?microtubules? and cells have evolved numerous kinesin motor molecules that regulate microtubule assembly and disassembly. By investigating the mechanism of action of these regulators we will uncover new, tissue-specific targets for cancer therapies and increase our understanding of the molecular events that drive cell division in both normal and cancer cells.
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|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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