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. Central to the death machinery are a family of cysteine proteases called caspases. These proteases are expressed as inactive precursors (zymogens) that are activated by proteolytic cleavage. Caspases can cleave and so activate other caspases but inactive caspases can also undergo autocatalytic activation when recruited into multi-protein complexes. For example, ligands such as Fas or TNF bind to their cognate receptors causing the formation of a protein complex called the DISC that contains and activates caspase-8 or -10. Once active these initiators can, in turn, activate effector 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. While in some instances caspase-8 can apparently activate capase-3 directly, in other cases caspase-8 acts indirectly by activating Bid which releases cytochrome c from mitochondria into the cytosol. Like caspase-8, caspase-2 which is activated by different apoptotic stimuli, can also generate as yet unknown factors that release cytochrome c. In the cytosol cytochrome c interacts with Apoptotic Protease Activating Factor-1 (Apaf-1), which then binds and activates caspase-9, forming an Apaf-1/caspase-9 holoenzyme. This holoenzyme then activates the effector caspases. Thus activation of the Apaf-1/caspase-9 holoezyme may play a critical role in integrating and amplifying the signals from diverse apoptotic stimuli. 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 |
