Faculty

My research interest focuses on microtubules and their protein component tubulin. Microtubules participate in essential cellular processes such as vesicle transport and segregation of chromosomes during mitosis and meiosis. Because of the role of microtubules in mitosis they are the target of a group of anti-tumor agents. A major aim of the laboratory is to determine the binding interactions between these agents and tubulin. Such information can be used for the synthesis of analogues with greater activity and to explain how cells become resistant to anti-tubulin drugs by altering the tubulin molecule. We are using yeast tubulin as a model because of the ease of conducting site-directed mutagenesis in this organism. Although wild-type yeast does not bind a number of agents that bind to mammalian tubulin, we have been able to create a taxol binding site in yeast tubulin using the mutagenesis approach. We are now able to probe the taxol site in detail by mutating amino acids around the site. Similar studies are planned for other anti-tubulin compounds.

We are also interested in the role of guanine nucleotides in microtubule assembly and stability. This problem is also being approached with the use of yeast tubulin mutagenesis.

Representative Publications

Bode, C. J., Gupta, M. L., Jr., Reiff, E. A., Suprenant, K. A., Georg, G. I., and Himes, R. H. (2002)

Epothilone and paclitaxel: unexpected differences in promoting the assembly and stabilization of yeast microtubules. Biochemistry 41:3870-3874.

Gupta, M. L., Jr., Bode, C. J., Thrower, D. A., Pearson, C. G., Suprenant, K. A., Bloom, K. S., and Himes, R. H. (2002)

β-Tubulin C354 Mutations that severely decrease microtubule dynamics do not prevent nuclear migration in yeast. Mol. Biol. Cell 13: 2919-2932.

Newton, C. N., DeLuca, J. G., Himes, R. H., Miller, H. P., Jordan, M. A., and Wilson, L. (2002)

Intrinsically tempered dynamic instability behavior of HeLa cell Microtubules in vitro. J. Biol. Chem. 277: 42456-42462.

Vidya, R., Eggen, M., Georg, G. I., and Himes, R. H. (2003)

Cryptophycin affinity labels: synthesis and biological activity of a benzophenone analogue of cryptophycin 24. Bioorg. Med. Chem Letts. 13:757-760.

Bode, C. J., Gupta, M. L., Jr., Suprenant, K. A., and Himes, R. H. (2003)

The two α-tubulin isotypes have opposing effects on microtubule dynamics in vitro. EMBO Reports 4: 94-99.

Gupta, M. L., Jr., Bode, C. J., Georg, G. I., and Himes, R. H. (2003)

Understanding tubulin-taxol interactions: mutations that impart taxol binding to yeast tubulin. Proc. Natl. Acad. Sci. 100:6394-6397.

Eichenmüller, B., Kedersha, N., Solovyeva, E., Lang, J., Himes, R. H., and Suprenant, K. A. (2003)

Vaults bind directly to microtubules via their caps and not their barrels. Cell Mot. Cytoskel. 56:225-236.

Ramdas, V., Eggen, M., Georg, G. I., and Himes, R. H. (2003)

Synthesis of cryptophycins via an N-acyl-beta-lactam macrolactonization. J. Org. Chem. 68:9687-9693.

Buck, S. B., Huff, J. K., Himes, R. H., and Georg, G. I. (2004)

Total synthesis and anti-tubulin activity of C10 analogues of cryptophycin-24. J. Med. Chem. 47:696-702.

Barboni, L., Giarlo, G., Ricciutelli, M., Ballini, R., Georg, G. I., VanderVelde, D. G., Himes, R. H., Lakdawala, A., and Snyder, J. P. (2004)

Synthesis, modeling, and anti-tubulin activity of a D-seco paclitaxel analog. Org. Letts. 6:461-464.