Control of apoptosis during cell division and in response to anti-cancer drugs

The development of cancer is characterised by the loss of controls over cell cycle progression and resistance to cell death. Much has been learned about the control of these fundamental processes, but the interactions between them are still not understood. In particular, it is not known how cell survival is controlled during mitosis. Defects in mitosis and a subsequent failure to initiate apoptosis can result in the propagation of chromosome aneuploidy, a characteristic feature of many cancer cells. Most importantly, the relationship between mitotic controls and cell death is critical for responses to anti-cancer drugs such as taxol (paclitaxel), vinca alkaloids and a new generation of enzyme inhibitors that target mitotic cells. However, because we do not fully understand the cellular responses to these drugs, in particular how they can induce cell death, we cannot yet optimise the use of existing drugs, reduce the severe toxic side effects and design the most effective trials for new reagents. Recently, my group has made significant progress in understanding the mechanisms controlling cell death by apoptosis during mitosis and in the mitotic arrest induced by drugs such as taxol. We now wish to bring together our efforts in a coordinated programme of research to determine the molecular mechanisms underlying the control of cell survival during cell division and in response to anti-mitotic drugs in order to provide basic information that will facilitate a better understand mechanisms of cancer development and resistance to anti-cancer drugs, and to engender novel strategies for the selective killing of cancer cells. Our strategy is to use a range of approaches in biochemistry and cell biology to identify and characterise the key proteins involved in the control of cell death during mitosis and mitotic arrest, and to understand the temporal control of these processes within cells. Control of processes during cell division is mainly at the post-transcriptional level and we will focus on two major interacting mechanisms that control proteins during this period of the cell cycle, namely protein phosphorylation and ubiquitin-mediated proteolysis. We intend to use the basic knowledge that we derive from these approaches to test the functions of specific proteins and their modifications in the responses to anti-cancer drugs in human cancer cells.