Claire E. Walczak, Ph.D.

Asst. Professor Biochemistry and Molecular Biology
Indiana University Bloomington

Background
B.S. Chemistry, 1987 from Rensselaer Polytechnic Institute, Troy NY
Ph.D. Biochemistry, 1993 from UW-Madison, Madison, WI
Post-doc, Cell Biology, 1993 at UCSF, San Francisco, CA

Research Interests

My lab is interested in the mechanisms of mitosis. Because of the global importance of this event, the cell has devised an elegant macromolecular machine, the mitotic spindle, to ensure accurate chromosome segregation. Our goals include understanding how a cell builds a mitotic spindle, how the cell segregates chromosomes on the spindle, and how these processes are regulated during mitosis. Understanding this process is important because blocking cell division is a major approach in cancer chemotherapy.

We use a combination of molecular biology, biochemistry, and cell biology to probe protein function in mitosis. Most recently, we have focused on XKCM1, which is a novel type of kinesin that acts to regulate microtubule dynamics by increasing the frequency of depolymerization. XKCM1 may play a key role in the coupling of microtubule dynamics to chromosome movement, and likely serves as a paradigm for understanding regulators of microtubule dynamics as well as the evolutionary diversity of the kinesin-related protein family of motors.

The focus of our lab is to use XKCM1 as a tool to dissect the molecular mechanisms of microtubule dynamics and chromosome movement and to identify other proteins important in this process. Our rationale is that if we can understand in detail the molecular mechanisms that govern cell division then we will be able to understand what goes wrong in the uncontrolled divisions of cancer cells. Interestingly the anti-cancer drugs taxol, vincristine and vinblastine target the microtubule cytoskeleton and block mitosis by suppressing microtubule dynamics. These drugs have been extremely effective in treating breast cancer, ovarian cancer and certain leukemias and lymphomas. Inhibition of XKCM1 in Xenopus egg extracts gives a taxol-like effect suggesting that XKCM1 might function as a therapeutic target. Because XKCM1 is mitosis-specific, it may be a better target than the microtubule itself.

Our previous work involved a biochemical characterization of the mechanism of XKCM1-induced microtubule depolymerization as well as a functional characterization of its role in spindle assembly and regulating dynamics in extracts and in cells. We have assays in hand to examine its function in a pure system with microtubules and protein, in reconstituted extracts and in cells. We are currently focusing on a structure/function analysis of XKCM1 to determine what domains of the protein are required for its biochemical activity. In particular, we are interested in understanding how XKCM1 differs from kinesin such that XKCM1 destabilizes microtubules whereas kinesin and other kinesin family members translocate along them. We are also interested in understanding what other proteins XKCM1 interacts with and how these interacting proteins may regulate its biochemical activity and its cellular function.

Our long term interests include understanding how the cell carries out mitosis and what role the cytoskeleton and its associated proteins play in this process. We also maintain a strong interest in how the cytoskeleton and cytoskeleton-associated proteins function in other processes such as cell motility, axon guidance, vesicle transport, and development, and we hope to develop future projects in these areas

Selected Publications:

Walczak, C.E., Mitchison, T.J., and Desai, A. (1996). XKCM1: A Xenopus Kinesin-Related Protein That Regulates Microtubule Dynamics During Mitotic Spindle Assembly. Cell 84: 37-47.

Desai, A., Verma, S., Mitchison, T.J., and Walczak, C.E. (1999). Kin I Kinesins are Microtubule Destabilizing Enzymes. Cell 96: 69-78.

Walczak, C.E. (2000). Microtubule Dynamics and Tubulin Interacting Proteins. Curr. Opin. Cell Biol. 12:52-56.

Niederstrasser, H., Salehi-Had, H., Gan, E.C., Walczak, C.E., and Nogales, E. (2002). XKCM1 Acts on a Single Protofilament and Requires the C-terminus of Tubulin. J. Mol. Biol. 317: 817-828.

Kline-Smith, S.L. and Walczak, C.E. (in press). The Microtubule-Destabilizing Kinesin XKCM1 Regulates Microtubule Dynamic Instability in Cells. Mol. Biol. Cell.

More Information:
The Walczak Lab: http://php.indiana.edu/~walczak/