Understanding the crosstalk between cell survival and death pathways

In addition to a role in regulating apoptosis, the BCL-2 pro-survival proteins have also been described as key regulators of autophagy by binding to the pro-autophagic protein Beclin 1. Autophagy is a catabolic degradation process induced in response to starvation or stress whereby cellular proteins, organelles and cytoplasm are engulfed, digested and recycled to sustain cellular metabolism. As such, it is primarily a cell survival mechanism.

The aims of this research are two-fold.

Firstly, the role of BCL-2 pro-survival proteins in regulating autophagy is highly contentious with a dearth of in vivo data supporting a role for BCL-2 proteins in regulating autophagy in normal physiology. Using early biochemical and cell-based data, we have now engineered unique mouse models in which interactions between BCL-2 pro-survival proteins and Beclin 1 have been enhanced or diminished. These mice provide an innovative approach to obtaining direct in vivo evidence for this contentious issue. Secondly, we are investigating the role of Beclin 1 in normal physiology, in particular in the regulation of intestinal homeostasis. We are also interested in understanding how Beclin 1 can contribute to cancer development and chemoresistance.