Elucidating how the protein levels of IAPs is regulated.

IAPs seem to be essential for the survival of many different cancer cell types. Similarly in Drosophila, the presence of the IAP DIAP1 is indispensable as loss of DIAP1 function, either by mutation or deletion, instigates spontaneous and unrestrained caspase-mediated cell death. Because IAPs directly inhibit caspases they represent the last line of defence against caspase-mediated damage. It follows, therefore, that the overall level of IAP protein is a critical determinant for cell viability.

This project is aimed at studying the molecular mechanisms that regulate the steady state levels of IAPs, thereby setting the apoptotic threshold. Self-ubiquitylation of DIAP1 renders DIAP1 intrinsically unstable as poly-ubiquitylated DIAP1 is targeted for degradation by the ubiquitin/proteasome pathway. Surprisingly, we find that DIAP1 degradation is dependent on caspases. Addition of pan-caspase inhibitors dramatically stabilises DIAP1 protein levels. Our observation indicates that DIAP1 protein stability is, to some extent, controlled by caspases. We are currently examining the link between IAP stability and their anti-apoptotic ability.