UCD School of Biomolecular & Biomedical Science

Our laboratory is focussed on understanding how basic cell mechanisms such as cell proliferation and cell death become corrupted in cancer and how this knowledge can be used in the development of effective anti-cancer therapeutics.

Normal cell proliferation and cell death processes are essential for the maintenance of homeostasis and have been relatively well characterised in recent years. Mitosis has been targeted in anti-cancer strategies for many years and microtuble -targeting agents such as the taxanes and vinca alkaloids have been successfully used for the treatment of cancer. Microtuble-targeting agents induce prolonged mitotic arrest that ultimately leads to cell death, however, the factors that dictate cell fate following prolonged mitotic arrest remain poorly understood. We are investigating the  mechanism and cross-talk between these independent but equally important cell processes .
 
We are using state-of-the-art proteomic and biochemical technologies to identify components of the mitotic machinery that regulate the cell death process. We have found that mitotic specific cyclin-dependent kinase 1 directly phosphorylates the pro-apoptotic BH3 only Bcl-2 family member, Bim, an event that is mediated by a temporal interaction between cyclin B1 and Bim during mitosis.  Thus, the mitotic phosphorylation of Bim may be an important event that couples mitotic arrest to the cell death machinery. Furthermore we are investigating the functional significance of phosphorylation of pro-survival Bcl-2 proteins during mitotic cell death.

        Another focus of our research lies in understanding the molecular mechanism that allows the timely cytoplasmic division of two daughter cells during cytokinesis. Cytokinesis represents the last stage of mitosis that involves the assembly of an actomyosin contractile ring, which constricts the plasma membrane and compacts midzone microtubules to form the midbody that is located within a thin intercellular bridge  connecting two daughter cells. Abscission of the intercellular bridge finally separates daughter cells. Failed cytokinesis leads to tetraploidy, which is an important intermediate preceding aneuploidy and the onset of tumourigenesis. Thus understanding the molecular mechanism of cytokinesis and how it is deregulated has important implications for cancer research.

The centrosome is required for the completion of cytokinesis through the transport of important components to the midbody, however, the identity of molecular components involved and the biochemical events that regulate the final plasma membrane remodelling and membrane severing are only beginning to emerge. We are interested in identifying midbody components that play a role in the completion of cytokinesis and that may be exploited in the development of novel anti-cancer agents. We have recently shown that the peptidyl prolyl isomerase, cyclophilin A, is an important regulator of abscisison and therefore the completion of cytokinesis. We are currently investigating the potential of small molecule cyclophilin A inhibitors as novel anti-cancer agents.
 

• Professor Gerard I. Evan  UCSF
• Professor D. Clive Williams   TCD
• Dr Daniela Zisterer  TCD
• Dr Jean-Francois Guichou, University of Montpellier, France
• Professor Alan Chavanieu, University of Montpellier, France