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Harold Fisk, PhD

Associate Professor​

Primary Appointment

Molecular Genetics

Joint Appointment
Department of Cancer Biology and Genetics

Contact Information

Office:

Department of Molecular Genetics
The Ohio State University
Biological Sciences Building Room 216/272
484 W. 12th Avenue
Columbus, Ohio 43210-1292

Office phone:  (614) 292-0318
Lab phone:  (614) 247-8715
Fax:  614-292-4466
Email:  fisk.13@osu.edu

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.