Cancer arises through mutations that trigger uncontrolled cell proliferation. Unexpectedly, oncogenes that deregulate cell proliferation often also induce apoptosis. Thus it appears that apoptosis functions as a defense, protecting an organism from potentially tumorigenic cells. It follows that a critical step in tumorigenesis is the acquisition of mutations that compromise the apoptotic response induced by oncogenes. Indeed, many mutations found in tumors inhibit apoptosis. The observation that some oncogenes are pro-apoptotic suggests that , in principle, re-establishing the link between oncogene expression and the apoptotic machinery would selectively kill cancer cells. To accomplish this a biochemical understanding of what the apoptotic machinery is and how oncogenes activate it is needed. To investigate how the apoptotic machinery is linked to pro-apoptotic oncogenes this lab uses a cell-free system that mimics E1A-dependent apoptosis. This system is based on the observation that extracts from cells transformed with E1A activate the apoptotic machinery, whereas extracts from untransformed cells do not. The basis of this difference appears to be a protein called Apoptotic Protease Activating Factor u1 (Apaf-1). Apaf-1 acts with cytochrome c to trigger activation of caspases, a family of cysteine proteases that drive the apoptotic process. However Apaf-1 is present in extracts from untransformed cells, although caspase activation does not occur. A major focus of the laboratory is understanding how E1A expression modulates Apaf-1s ability to trigger caspase activation. In addition, the mechanism by which other pro-apoptotic oncogenes activate caspases is being examined using cell-free systems.
| 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 |
