Cell Division and Proteolysis

Research interests

We study human cell division, and in particular the contribution of ubiquitin-mediated proteolysis to the highly coordinated sequence of events that give rise to two identical daughter cells (cytokinesis). We use time-lapse imaging of live cells both to measure degradation of fluorescent-tagged substrates, & to study the role of substrate proteolysis in cell division. We have recently identified Aurora kinases as substrates whose proteolysis contributes to coordinated mitotic exit and cytokinesis. Ongoing projects in the lab explore the following questions:

How does proteolysis of different substrates contribute to the success of cytokinesis?

We are developing biochemical approaches for purification of ubiquitinated substrates from dividing cells. We aim to profile those targeted during cell division and identify those contributing to cytokinesis.

How is substrate proteolysis regulated in space and time?

This question is pursued through detailed study of Aurora A and Aurora B kinases. The relationships between proteolysis, binding partners, dynamic localization and function of these kinases are not understood. However, forced expression of either Aurora kinase can lead to failure of cytokinesis and generation of aneuploid cells (characteristic of aggressive cancers) showing that these relationships are important for the stability of the genome. Aurora A is regarded as a particularly promising target for intervention in cancers and we aim to describe novel routes - with therapeutic potential - to the control of Aurora A levels in the cell.

3 key publications

1. Floyd, S, Pines, J, Lindon, C (2008) APCCdh1 targets Aurora kinase to control reorganization of the mitotic spindle at anaphase. Current Biology 18: 1649-58

2. Pines, J, Lindon, C (2005). Proteolysis – anytime, any place, anywhere? Nat. Cell Biol. 7: 731-735

3. Lindon, C, Pines, J (2004). Ordered proteolysis in anaphase inactivates Plk1 to contribute to proper mitotic exit in human cells. J. Cell Biol. 164: 233-241

Page compiled 4 Sept 2009