Biological Sciences

Faculty Research

William Taylor

William Taylor

Professor
Ph.D. University of Manitoba, 1994
B.S. University of Winnipeg

Office: WO 4262B 
Phone: 419.530.1966
Email: william.taylor3@utoledo.edu

 

Research

Cancer is the second leading cause of death in the United States and claims half a million people each year. We are focused on uncovering the mechanisms responsible for cancer formation in particular the errors that occur during mitotic cell division. Our research asks questions regarding two key mitotic proteins, Borealin and Sororin, revealing how they coordinate chromosome movement and separation during mitosis. We are also involved in a collaborative project in which we have developed a new class of molecules that we call CETZOLEs. These molecules kill certain types of cancer cells by inducing catastrophic accumulation of reactive oxygen species and we are in the process of evaluating the potential of these compounds as novel chemotherapeutic agents.
      In a genome-wide screen for novel mitotic genes we identified two that were poorly characterized: Borealin and Sororin. Sororin is now known to regulate the cohesin complex. Cohesin holds replicated chromosomes (also known as chromatids) together until anaphase when the chromatids are segregated to opposite poles of the cell. Cohesin was known to show multiple chromosome binding modes: dynamic during G1, stable during G2 and again dynamic during prophase along chromosome arms. Our studies uncovered part of the mechanism allowing removal of cohesin from chromosome arms during prophase. We observed that Sororin was phosphorylated by the mitotic protein kinase Cdk1 and that this modification released Sororin from chromatin and the cohesin complex. We mapped the sites of phosphorylation and found that disrupting Sororin phosphorylation blocked the separation of chromatids by altering cohesin. Studies from other labs indicated that defects we observed could alter chromosome segregation leading to cells with losses a gains of chromosomes, one of the driving forces behind cancer. Our work provided part of the mechanism responsible for this removal pathway.
      Borealin is a key component of the chromosomal passenger complex (CPC) that detects and destabilizes inappropriate attachments of chromosomes to the mitotic spindle, the structure physically drags chromosomes to opposite ends of the cell. We mapped a key site of Cdk1 phosphorylation at S219, which was crucial for full CPC function on chromosomes. A previous study identified a dimerization domain at the C-terminus of Borealin. Our follow up studies indicated that this region was critical for Borealin and the CPC to stably interact with chromosomes. For these studies, we used genetic engineering to replace the dimerization domain of Borealin with the small protein FKBP. FKBP itself dimerizes when cells are exposed to a small compound. In this way, we can induce Borealin dimerization at the time of our choosing simply by adding the dimerization compound. We also used a sensitive microscopy technique called FRAP that allows us to observe diffusion of our engineered proteins in living cells. These techniques allowed us to determine the role of Borealin dimerization in chromosome binding and chromosome separation during mitosis.
      In a more recent collaborative project with Dr. Tillekeratne in Medicinal and Biological Chemistry at UT, we have analyzed the cellular effects of novel open-chain epothilone analogues we have developed called CETZOLEs. These compounds block import of the amino acid cysteine into cancer cells essentially blocking their ability to remove toxic reactive oxygen species. Within 12 hours, the cells die by disruption of membrane structures. Importantly, these compounds are very toxic to a types of cells called mesenchymal cells. Mesenchymal cells are responsible for many of the pathological consequences of human cancers and many research groups are trying to find ways to kill mesenchymal cancer cells. Our ongoing work will test the clinical potential of these compounds in the treatment of cancer.

Current Students:

Graduate Students
Radhika Koranne

Nishanth Kuganesan

Dewmi Rathnayake

Current Laboratory Grants

deArce-Koch Memorial Foundation Biomedical Program Taylor (Co-PI) 05/14-12/16
Preclinical studies of a new class of anticancer agents for lung cancer.
The goal of this project is to investigate a new class of compounds developed in collaboration with another PI in the Department of Medicinal and Biological Chemistry at the UT. My role as a co- PI is to supervise biological studies including analysis of effects in cell culture and animal models.

Publications

Last Updated: 3/2/22