Special Fellow of the Leukemia and Lymphoma Society
Department of Molecular Genetics
The Ohio State University
Biological Sciences Building Room 211/272
484 W. Twelfth St.
Columbus, OH 43210-1292
Centrosomes are microtubule organizing centers whose function may contribute to tumorigenesis, because they make many contributions to the fidelity of chromosome segregation. Centrosomes not only act as poles of the mitotic spindle apparatus, but they also regulate cytokinesis and the decision to enter the cell cycle. It is therefore easy to imagine how defects in centrosome function might cause chromosome segregation errors. Because most human tumors are aneuploid as a result of errors in chromosome segregation, it is consequently not surprising that defects in the number, structure, and function of centrosomes are associated with many human tumors.
Like the genome, centrosomes are single copy organelles that must be precisely duplicated prior to cell division. I previously demonstrated that vertebrate Mps1 proteins are required for centrosome duplication, and that overexpression of Mps1 causes multiple rounds of centrosome duplication in mouse cells.
Mps1 is normally an unstable protein, and its function in centrosome duplication is controlled by proteasome-mediated degradation. I have found that Mps1 is aberrantly stable in many human tumor-derived cells, and have identified a mutant form of Mps1 from one such cell line. This mutant form of Mps1 cannot be properly degraded, and deregulates centrosome duplication in a variety of human cell types.
The goal of my research program is to understand the mechanisms of centrosome duplication in mammalian cells, and to determine how this process is regulated and integrated into the cell cycle. Initially, my lab will focus on the precise function of Mps1, its regulation, and its relevance to cancer. We will investigate the function of Mps1 by identifying Mps1 substrates, and by characterizing the contribution of Mps1 phosphorylation to their function. Towards this end, a major effort in my lab will be to develop a cell-based assay to biochemically reconstitute centrosome duplication. This will allow us to characterize relationships between Mps1 and other centrosomal proteins, and ultimately to define the molecular pathway for this critical process. My lab will also investigate two additional functions of Mps1, in the spindle checkpoint, and in cytokinesis. Finally, my lab will explore the relationships between Mps1 stability, centrosome duplication, and tumorigenesis by characterizing additional instances of Mps1 misregulation in human tumor-derived cells, and by utilizing the mouse as an experimental model to explore the consequences for tumorigenesis of stabilizing Mps1.
1. Fisk, H.A., C.P. Mattison, and M. Winey, A Field Guide to the Mps1 Family of Protein Kinases. Cell Cycle, 2004. 3(4): p. 439-442.
2. Fisk, H.A., C.P. Mattison, and M. Winey, Human Mps1 protein kinase is required for centrosome duplication and normal mitotic progression. Proc Natl Acad Sci U S A, 2003. 100(25): p. 14875-80.
3. Fisk, H.A., C.P. Mattison, and M. Winey, Centrosomes and tumour suppressors. Curr Opin Cell Biol, 2002. 14(6): p. 700-5.
4. Fisk, H.A. and M. Winey, The mouse mps1p-like kinase regulates centrosome duplication. Cell, 2001. 106(1): p. 95-104.