Cell Division and Cancer Laboratory
The aim of our research is to understand the molecular machinery that controls cell division to allow rational cancer chemotherapy.
Our work has identified key genes that control cell division and allowed us to see what they are doing in their normal setting: a live, developing animal. We developed tools to observe the cellular machinery that divides cells in two at the end of mitosis, and to find the genes that regulate this process.
This work is critical for an understanding of how normal growth works, but also to give us potential therapeutics that will allow us to block the uncontrolled cell division seen in cancer.
Cancers are cells that not only divide too much, but also usually divide unstably, gaining and losing chromosomes. This chromosomal instability is not seen in normal dividing cells, so it may be an ideal chemotherapy target - something that we can affect in the cancer without hurting normal cells.
Using the advantages of Drosophila genetics, we have screened for gene knockouts that can kill unstably dividing cells, but not normal ones. We have found several ways to specifically kill cells with chromosomal instability, including targeting the JNK pathway, centrosomes or cell metabolism. We are now working to explain why unstably dividing cells are sensitive to these processes, and how we can best target them.
For information about available PhD or Honours projects, please contact Dr Stephen Gregory.
Due to the timing of my funding, I will not be able to take on any further PhD students until the end of 2017.
- Molecular Genetics of Cell Division
The use of chemotherapy to effectively treat cancer is often constrained by the side effects that occur because the drugs kill all dividing cells in the body, not just the cancer.
Still worse, many advanced tumours and relapses show drug resistance, even to combined drug therapies. These multi-drug resistant cancers usually exhibit chromosomal instability, gaining and losing chromosomes as they grow. This has led to the theory that Chromosomal INstability (CIN) is responsible for generating massive genetic diversity out of which drug resistant cells can emerge. Although CIN and drug resistance creates problems for traditional therapies, it also presents a potential therapeutic target: if we can develop drugs to specifically kill cells with CIN, the cancer could be effectively treated without damaging normal cells.
We have established a straightforward screening approach using Drosophila to identify genes that can be depleted to kill cells with chromosomal instability. In our first round of screening we tested 485 kinases and phosphatases, and identified 16 that specifically enhanced cell death only in CIN cells. Much of our current work is to characterize how these genes affect cell division and to determine which pathways and mechanisms can best be targeted to specifically kill CIN cells. We are working with Drosophila mutants, tumour explants and human cell lines to identify effective treatments.
For a complete list of publications for the Cell Division and Cancer laboratory group please visit the researcher profile of Dr Stephen Gregory.
- Z. Shaukat, D.Liu, R. Hussain, M. Khan and S. L. Gregory (2015). The role of JNK signaling in responses to oxidative DNA damage. Current Drug Targets 17:154-63 Impact 3.9 Citations: 3
- A. Choo, L.V. O’Keefe, C-S. Lee, S. L. Gregory, Z. Shaukat, A. Collella, K. Lee, D. Denton, R. I. Richards (2015) Tumour suppressor WWOX moderates the mitochondrial respiratory complex.Genes Chromosomes and Cancer 54:745-61 Impact 4.0 Citations: 2
- D.Liu, Z. Shaukat, R. Saint and S. L. Gregory (2015). Chromosomal instability triggers cell death via local signaling through the innate immune receptor Toll. Oncotarget 6:38552-65 Impact 6.4
- D. Liu, Z. Shaukat, R. Hussain, M. Khan and S. L. Gregory (2015). Drosophila as a model for chromosomal instability.AIMS Genetics 2:1-12 Citations:1
- Z. Shaukat, D. Liu and S. L. Gregory (2015). Sterile inflammation in Drosophila.Mediators of Inflammation 2015:369286. Impact 3.2 Citations: 2
- Z. Shaukat, D. Liu, A. Choo, R. Hussain, L. O'Keefe, R.I. Richards, R.B. Saint, and S.L. Gregory (2015). Chromosomal instability causes sensitivity to metabolic stress. Oncogene 34 (31), 4044-4055 Impact 8.6 Citations: 7
- H. Wong, Z. Shaukat, J-B. Wang, R. Saint and S. Gregory (2013). JNK signaling is needed to tolerate chromosomal instability. Cell Cycle 13:622-631 Impact 5.2 Citations: 5
- Z. Shaukat, H. Wong, S. Nicolson, R. Saint and S. L. Gregory (2012). A screen for selective killing of cells with Chromosomal Instability induced by a spindle checkpoint defect. PLoS One 7(10):e47447 Citations: 9
- Z.I. Bassi, K.J. Verbrugghe, L. Capalbo, S. Gregory, E. Montembault, D.M. Glover and P.P. D’Avino (2011). Sticky/Citron Kinase maintains proper RhoA localization at the cleavage site during cytokinesis. Journal of Cell Biology Impact 9.6 Citations: 24
- S. Ebrahimi, H. Fraval, M. Murray, R. Saint and S. L. Gregory (2010). Polo kinase interacts with RacGAP50C and is required to localize the cytokinesis initiation complex. Journal of Biological Chemistry 285:28667-28673. Impact 5.3 Citations: 11
- S. L. Gregory, S. Ebrahimi, J. Milverton, W. H. Jones, A. Bejsovec and R. Saint (2008). Cell division requires a direct interaction between microtubule-associated RacGAP and the contractile ring component Anillin. Current Biology 18:25-29. Impact 11 Citations 104