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The new Aviv FDS optics purchased through an NSF MRI RR grant sits in the back of the chamber and moves over the spinning rotor to scan all cells at once.
The long range goal of our research is a detailed molecular understanding of microtubule assembly and disassembly. Microtubules are dynamic structures, undergoing spatial and temporal assembly and disassembly within the cell nucleus and cytoplasm. This dynamic behavior is under cell cycle regulation and is essential for normal cell function and growth. Microtubules are composed of tubulin and microtubule-associated proteins (MAPs). We are pursuing fundamental investigations of guanine nucleotide binding to tubulin, the effect of divalent cations on assembly and nucleotide hydrolysis, the role of MAPs in assembly and microtubule bundling, the importance of tubulin isotypes and their posttranslational modification in modulating microtubule dynamics and the interaction of anticancer drugs with microtubules and tubulin isotypes.
Our current focus is on the vinca alkaloid-induced self-association of tubulin. We are comparing different vincas to evaluate the relationship between chemical modifications, tubulin spiral assembly and antimitotic efficacy. A knowledge of the energetics of these processes is essential to an understanding of microtubule dynamics and drug cytotoxicity (See AUC Current Projects).
Methods of analysis include: analytical ultracentrifugation, electron microscopy, DIC video-enhanced microscopy, light scattering, affinity purification, western blotting and computer modeling. The conclusions from these studies are relevant to the thermodynamics of microtubule assembly, the mechanisms of axonal transport, mitosis and morphogenesis, as well as potentially improving the therapeutic efficacy of antimitotic drugs in controlling and curing cancer. These studies are being extended to other drugs like Dolastatin 10 which also induce tubulin self-association and have therapeutic potential.
In addition, a number of collaborative projects are investigating the hydrodynamics and self-association of macromolecules by analytical ultracentrifugation. The systems being looked at include kinesin and NCD motor domains, B23 (a nucleolar protein), histone (H1)-DNA interactions and SMAD proteins (See AUC Current Projects).
We are currently focusing on the development of analysis tools for investigating mixed-association, particularly the formation of 1:1 and 2:1 complexes of tubulin heterodimers with motor domain monomers and dimers. These experiments are important because they independently verify the affinity of motor domains, particularly single head or monomeric constructs, for tubulin, and allow for the dissection of cooperative interactions and the dependence upon both GXP and AXP nucleotides in the absence of processive ATP hydrolysis. (related information, Kinesin home page) This work also serves as the foundation for quantitative studies of tubulin interactions with other proteins like Kin-I, Clip-170 and OP18 that are involved in the regulation of microtubule dynamics and cell cycle. These studies are probing the role of anti-mitotic drugs in disrupting this regulation and will potentially lead to the development of new drugs for new sites of action. The analytical ultracentrifugation is conducted in the UMMC Analytical Ultracentrifuge Facility.
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