John Hudson

John Hudson, Ph.D.
Associate Professor
Dept. of Biological Sciences
University of Windsor

Tel: (519) 253-3000 ext. 2715

 

Research Overview

The overall goal of our research program is to reveal central cellular decisions regulating cell growth and development to determine novel mechanisms regulating diseases such as cancer. The Hudson lab specifically focuses on the role of the Polo-like kinase family (Plks1-5) of proteins with respect to their role in malignancy, the cell cycle, DNA damage pathways and development. During his post-doctoral training Dr Hudson established the Plk4 transgenic knock-out mouse model. Plk4 null mice are embryonic lethal, while Plk4 heterozygous mice are haploinsufficient and develop liver, lung and other tumours at a high frequency. In general, aberrant expression of the individual Plks has been associated with numerous cancers. Currently the laboratory is focused in several areas.

1) The role of Plk4 in the development of hepatocellular carcinoma (HCC).
We have established that the individual plk genes undergo epigenetic modifications during malignancy in both our murine Plk4 mouse model and in human tissue samples. These changes are accompanied by changes in their respective levels, in both cases, likely contributing towards the progression of disease. Interestingly, increased Plk4 promoter methylation occurs predominantly in male mice and is correlated with a gender disparity for HCC development where the rate in males is approx 30% greater. Furthermore, we have found that these epigenetic changes respond to hypomethylating drugs, valproic acid and azacytidine. These drugs are currently in use or in trials as therapeutic agents for a number of human malignancies.

2) Epigenetic regulation of the polo-like kinases (plks) in Myelodysplastic Syndromes (MDS), lymphomas and hematological neoplasms.
Myelodysplastic Syndromes (MDS, formerly known as preleukemia) and other hematological (blood related) cancers often involve changes in the expression levels of important genes. Through funding from the Seeds 4 Hope program, we have determined that the plks display different patterns of DNA methylation in cell lines derived from MDS, lymphoma, and other hematological malignancies and that this pattern is altered in response to therapeutic drugs. In collaboration with Drs Caroline Hamm and Sindu Kanjeekal at the Windsor Regional Cancer Centre, we have also begun the more long term aspect of our investigation, which is to examine the expression levels of the plk genes in clinical samples. We are focused on determining whether the levels of the plks provide clues as to why some patients respond to treatment, some development resistance to prolonged treatment or why others don’t respond at all.

3) Plk4 interacting partners.
Another major focus is the identification and characterization of Plk4 interacting partners. We have established that two key cell cycle regulatory proteins, Cdc25C and Chk2 are targeted for phosphorylation by Plk4. To date very few substrates have been documented for Plk4. Once identified and characterized, the identification of target proteins will aid us in discerning the major pathways that are affected in the Plk4 mutant mice with the hope of leading to better diagnostic and prognostic indicators for cancer as well as providing new targets for interventionist strategies.

4) The link between Plk4, genomic stability and DNA damage pathways.
Determining the role of Plk4 in DNA damage pathways and genomic stability. In contrast to the other Plks, which are known to be key players in DNA damage pathways, very little is known about the role of Plk4 in DNA damage pathways. Our working hypothesis is that Plk family members target similar or related proteins, placing these pathways or proteins under tighter controls. Plk4 localizes to centrosomes, a centre that is becoming increasingly important in the control of DNA damage pathways and as mentioned, Plk4 activity intersects with key proteins involved in the DNA damage response.

Selected Publications

  • Ward A, Morettin A, Shum D, and Hudson JW (2011) Aberrant methylation of Polo-like kinase CpG islands in Plk4 heterozygous mice. BMC Cancer 11: 71.
  • Morettin A, Ward R, Nantais J, and Hudson JW (2009) Gene expression patterns in heterozygous Plk4 murine embryonic fibroblasts BMC Genomics 10:319.
  • Petrinac S, Ganuelas ML, Bonni S, Nantais J, and Hudson JW (2009) Polo-like kinase 4 Phosphorylates Chk2. Cell Cycle 8(2):327-9.
  • Bonni S, Ganuelas ML, Petrinac S, and Hudson JW. (2008). Human Plk4 Phosphorylates Cdc25C. Cell Cycle 7(4):545-7.
  • Ko, MA, Rosario, CO, Hudson, JW, Kulkarni, S, Pollett, A, Dennis, JW, Swallow, CJ (2005). Sak/Plk4 haplo-insufficiency causes mitotic infidelity and carcinogenesis. Nature Genetics 37: 883-888.