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Faculty Research

William Taylor

 

William Taylor

Associate Professor
Ph.D. University of Manitoba, 1994

Office:          WO 4262B 
Phone No:   419.530.1966
Email:          william.taylor3@utoledo.edu

 

Research

Animal cells have evolved multiple pathways to block entry into mitosis, and contain a large number of proteins that orchestrate cell division once they have entered mitosis. My long-term goals are to understand how cell division is controlled and to identify novel proteins that control the normal progression through the cell cycle. To achieve these goals I have focused on searching for novel genes that function in G2 and M, and determining their specific functions in these processes. Previous work allowed us to identify several genes that encode proteins important in cell cycle regulation.

Current work is focused on two proteins, Borealin and Sororin. Borealin participates in chromosome attachment to the spindle and regulates cytokinesis. Sororin is an essential regulator of sister chromatid cohesion.

Taylor Lab

Identification of novel cell cycle genes.

We used Affymetrix gene arrays to analyze transcriptional repression by the Rb family proteins p130 and p107. We found that most genes that are repressed in a p130/p107-dependent manner encode proteins needed for cell cycle progression and many are needed for mitosis. We also found several genes with unknown functions that are repressed by p130 and p107. We hypothesize that some of these genes represent novel cell cycle genes. We have followed up on two genes in particular, which have since been implicated in several important mitotic processes.

Borealin.

Borealin is an E2F target, which is downregulated in response to DNA damage in a p53 and Rb-dependent manner. Like other genes linked to proliferation, Borealin levels are elevated in a variety of human tumors. Borealin is phosphorylated at multiple residues when cells enter mitosis. Many of these phosphorylation events are catalyzed by Cdk1. Phosphorylation of S219 in particular is required for proper Borealin function in mitosis. For example, cells expressing the S219A mutant of Borealin contain more micronuclei than control cells expressing wild-type Borealin. Borealin functions as part of the chromosomal passenger complex (CPC), which also contains INCENP, Survivin and Aurora B. One of the roles of the CPC is to monitor spindle-chromosome attachments. Borealin joins the complex through the N-terminal third of the protein; the function of the C-terminus of Borealin is not well understood. Surprisingly, mutants of Borealin lacking the C-terminal 2/3rds of the protein still can properly localize and maintain at least some wild-type Borealin function. Ongoing studies will investigate which regions of Borealin are most important in its various functions in mitosis.

 Sororin.

Sororin showed up on our affymetrix screen as an E2F target. Subsequent studies from other labs indicated that Sororin interacted with components of the cohesin complex which normally holds sister chromatids together until the cell reaches anaphase. We observed that recombinant Sororin could be phosphorylated on several residues by Cdk1. By mutating all nine potential Cdk1 sites, we observed that phosphorylation of Sororin plays a key role in its association with the cohesin complex and its subcellular localization during mitosis. Cdk1 mediated phosphorylation appears to release Sororin from the cohesin complex allowing separation of sister chromatid arms (but not centromeres) in prometaphase. Ongoing work is focused on determining the consequences of constitutive phosphorylation of Sororin at Cdk1 sites.

Summary

Tumor cells frequently acquire mutations that inactivate tumor suppressors such as p53 and Rb, and activate oncogenes such as Ras. Some of these changes alter the fidelity of cell division leading to further defects in genomic stability. Our studies are focused on the mechanics of cell division in order to gain insight into the defects that occur in cancer leading to genetic alterations at the chromosomal level. These insights will help in the design of novel diagnostic and therapeutic tools.

 

Publications at University of Toledo

Tipton AR, Ji W, Sturt-Gillespie B, Bekier ME 2nd, Wang K, Taylor WR, Liu ST. Monopolar spindle 1 (MPS1) kinase promotes production of closed MAD2 (C-MAD2) conformer and assembly of the mitotic checkpoint complex. J Biol Chem. 2013 Dec 6;288(49):35149-58. doi: 10.1074/jbc.M113.522375. Epub 2013 Oct 22.

Date, D, Dreier, MR, Borton, MT, Bekier, ME and Taylor, WR. (2012). Effects of Phosphatase and Proteasome Inhibitors on Borealin Phosphorylation and Degradation. Journal of Biochemistry, in press.

Dreier MR, Bekier, ME and Taylor, WR. (2011). Regulation of Sororin by Cdk1-mediated phosphorylation. J Cell Sci.124: 2976-87. (highlighted in “In This Issue” section of the journal)

Kaur, H, Bekier ME, and Taylor, WR. (2010). Regulation of Borealin by Phosphorylation at Serine 219. Journal of Cellular Biochemistry. J Cell Biochem. 111:1291-8

Bekier ME, Fischbach, R, Lee, L and Taylor, WR. (2009). Length of mitotic arrest induced by microtubule stabilizing drugs determines cell death after mitotic exit. Molecular Cancer Therapeutics 8: 1646-1654.

Dreier MR, Grabovich AZ, Katusin JD, Taylor WR. (2009). Short and long-term tumor cell responses to Aurora kinase inhibitors. Exp Cell Res. 315: 1085-99

Kosik A, Bekier ME, Katusin JD, Kaur H, Zhou X, Diakonova M, Chadee DN, Taylor WR. (2009).   Investigating the role of Aurora kinases in RAS signaling. J Cell Biochem. 106:33-41.

Date, DA, Jacob CJ, Bekier, ME, Stiff, AC, Jackson, MW and Taylor, WR. (2007). borealin is repressed in response to p53/Rb signaling. Cell Biology International 31: 1470-1481.

Kaur, H, Stiff, A, Date, D, and Taylor, WR. (2007).Analysis of mitotic phosphorylation of borealin. BMC Cell Biology 8:5. (17p)(selected as Image of the Month, and Highly Accessed).

 

Selected Doctoral and Post-Doctoral Publications

Stark, GR and Taylor, WR. (2006). Control of the G2/M transition. Molecular Biotechnology. 32:227-48.

Jackson, MW, Agarwal, MK, Yang, J, Bruss, P, Uchiumi, T, Agarwal, ML, Stark, GR and Taylor, WR. (2005). p53/Rb-dependent transcriptional repression during cell cycle exit at G2. J. of Cell Science 118: 1821-1832.

Clifford, B, Beljin, M, Stark, GR, and Taylor, WR. (2003). G2 arrest in response to topoisomerase II inhibitors: The role of p53. Can. Res. 63: 4074–4081.

Taylor, WR, Schonthal, AH, Galante, J, and Stark GR. (2001). p130/E2F4 binds to and represses the cdc2 promoter in response to p53. J. Biol. Chem. 276: 1998–2006.

Taylor, WR, Agarwal, ML, Agarwal, A, Stacey, DW, and Stark, GR. (1999a). p53 inhibits entry into mitosis when DNA synthesis is blocked. Oncogene 18: 283-296.

Taylor, WR, DePrimo, SE, Agarwal, A, Agarwal, ML, Schonthal, AH, Katula, KS, and Stark GR. (1999b). Mechanisms of G2 arrest in response to overexpression of p53. Mol. Biol. Cell 10: 3607-3622.

Agarwal, ML, Agarwal, A, Chernova, OB, Taylor, WR, Sharma, YK, and Stark, GR. (1998a). A p53-dependent S-phase checkpoint protects cells lacking a G1 checkpoint from DNA damage in response to starvation for pyrimidine nucleotides. Proc. Natl. Acad. Sci. USA 95: 14775-14780.

Huang, A, Fan, H, Taylor, WR, and Wright, JA. (1997). Ribonucleotide reductase R2 gene expression and changes in drug sensitivity and genome stability. Cancer Res. 57: 4876-4881.

Agarwal, ML, Agarwal, A, Taylor, WR, and Stark, GR. (1995). p53 controls both G2/M and G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. Proc. Natl. Acad. Sci. USA 92: 8493-8497.

Taylor, WR, Greenberg, AH, Turley, EA, and Wright, JA. (1993). Cell motility, invasion and malignancy induced by overexpression of K-FGF or bFGF. Exp. Cell Res. 204: 295-301.

Taylor, WR, Egan, SE, Mowat, M, Greenberg, AH, and Wright, JA. (1992). Evidence for synergistic interactions between ras, myc and a mutant form of p53 in cellular transformation and tumor dissemination. Oncogene 7: 1383-1390.

 

Current Students

Graduate Students:

Michael Bekier

Maisha Rashid

Last Updated: 3/22/15