Faculty Research: William Taylor
Professor and Department Associate Chair
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 UToledo, 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.