Fisk, Harold

Harold Fisk, Ph.D.

Primary Appointment
Department of Molecular Genetics and Molecular Virology, Immunology and Medical Genetics Human Cancer Genetics

Contact Information:

For More Information:
Please visit Dr. Fisk’s  website

Research interest:

Cell cycle regulation of centrosome duplication and mitotic spindle assembly, and their role in the generation of aneuploidy and tumorigenesis.

Research summary

My laboratory is interested in understanding how the centrosome organelle is assembled, and how defects in the regulation of this process might contribute to the aneuploidy associated with human cancer cells. Centrosomes are microtubule-organizing centers that orchestrate the assembly of the mitotic spindle apparatus. Because the mitotic spindle must be assembled in a bipolar fashion to ensure proper chromosome segregation, centrosomes must be maintained as single copy organelles. Extra centrosomes are associated with many human tumors where they can drive genomic instability through the assembly of aberrant mitotic spindles. The appearance of extra centrosomes occurs before genetic changes in breast and prostate cancer. The failure to properly regulate centrosome duplication may therefore be an important event in tumorigenesis.

We have shown that the Mps1 protein kinase localizes to centrosomes and is required for centrosome duplication. Furthermore, overexpression of Mps1 in mouse cells causes multiple rounds of centrosome duplication, leading to the production of abnormal mitotic spindles. Mps1 is normally an unstable protein, and we have shown that its function in centrosome duplication is controlled by proteasome-mediated degradation. However, Mps1 is aberrantly stable in many human tumor-derived cells. We have identified a mutant form of Mps1 from one such cell line that cannot be properly degraded, and this aberrantly stable enzyme deregulates centrosome duplication in a variety of human cell types.

The goals of my research program are to determine the precise function of Mps1 in centrosome duplication, identify the mechanisms that regulate Mps1 stability, and examine the relevance of the misregulation of Mps1 to cancer. We will use a combination of cell biological, biochemical, and molecular biological techniques to investigate Mps1 function, identify the substrates of Mps1 kinase activity, and characterize the pathways that mediate Mps1 degradation.

Selected Publications:

Fisk, H.A., and Winey, M. (2004). Spindle regulation: Mps1 flies into new areas. Curr Biol14: R1058-1060.

Fisk, H.A., Mattison, C.P., and Winey, M. (2004). A Field Guide to the Mps1 Family of Protein Kinases. Cell Cycle3: 439-442.

Fisk, H.A., Mattison, C.P., and Winey, M. (2003). Human Mps1 protein kinase is required for centrosome duplication and normal mitotic progression. Proc Natl Acad Sci U S A100: 14875-14880.

Fisk, H.A., Mattison, C.P., and Winey, M. (2002). Centrosomes and tumour suppressors. Curr Opin Cell Biol14: 700-705.

Fisk, H.A., and Winey, M. (2001). The mouse mps1p-like kinase regulates centrosome duplication. Cell106: 95-104.