Cancer arises through the co-operation of mutations that allow uncontrolled cell proliferation. The loss of cell and tissue homeostasis caused by this proliferation triggers apoptotic cell death in the potential tumor cell. This death serves to limit tumor development. Thus the acquisition of additional mutations that uncouple the pro-apoptotic effects of oncogenes from the apoptotic machinery is a critical step in tumorigenesis. Complex networks of signaling pathways control the apoptotic response, and so cell survival. However, these complex networks converge on a common apoptotic machinery, of which cysteine proteases called caspases are key components. Caspases are expressed as zymogens activated by proteolytic processing. How this processing is controlled has been intensely researched in recent years. From this work two major pathways of caspase activation have emerged. One involves receptor-mediated activation of caspase-8. The other is triggered by pro-apoptotic oncogenes and chemotherapy and involves caspase-9. Both pathways have similar organization in that caspase-8 and -9 are activated autocatalytically and then go on to process other types of caspases (such as -3, -6 and-7) that cleave a wide range of cellular substrates. It is this second wave of proteolysis that brings about the morphological and biochemical changes of apoptosis. From our growing understanding of caspase activation, it has become clear that pathways coupling the apoptotic machinery to the cell's environment can be deregulated in a cancer cell upstream of, downstream of and at the point of caspase activation. By dissecting the biochemistry of oncogene-dependent-caspase activation and how it is deregulated in cancer cells we hope to identify novel targets for cancer therapy. As this approach exploits the pro-apoptotic effects of oncogenes themselves, therapies exploiting these novel targets will, at least in principle, be selective for cancer cells. The goal of this section is to understand the biochemistry of caspase activation with the aim of using this knowledge to identify novel targets for cancer therapy. To this end, the section is currently studying two areas of the apoptotic process. First, and where most effort is directed, Apaf-1-dependent caspase activation. Second, Inhibitor of Apoptosis Protein (IAP) stability and caspase inhibition.
| Martin, Angel G; Nguyen, Jack; Wells, James A et al. (2004) Apo cytochrome c inhibits caspases by preventing apoptosome formation. Biochem Biophys Res Commun 319:944-50 |
| Fearnhead, Howard O (2004) Getting back on track, or what to do when apoptosis is de-railed: recoupling oncogenes to the apoptotic machinery. Cancer Biol Ther 3:21-8 |
