Project P4A

"Role of differential BH3-only protein activation in the synergistic interaction of the death receptor and mitochondrial cell death pathway"

People involved: Thomi Brunner, Andrej Bluwstein, Janine Demgenski.

The death receptor and the mitochondrial apoptosis pathway represent two distinct cell death signalling processes. Recent evidence, however, suggest specific crosstalk between the two pathways at the level of Bcl-2 homolog interactions. This is particularly relevant for the synergistic induction of cell death by TRAIL and chemotherapy in tumour cells. The aim of this proposal is thus to investigate the molecular events underlying this synergistic induction of cell death. Specifically, we will address whether the simultaneous activation of a specific pattern of BH3-only proteins and inactivation of anti-apoptotic Bcl-2 homologs is required for the synergistic induction of cell death by TRAIL and chemotherapy, while activation of single BH3-only proteins fails to do so. Moreover, we aim at investigating the role of post-translational modifications of Bcl-2 homologs on their subcellular redistribution in response to apoptotic stress and the consequences for triggering the mitochondrial apoptosis pathway. Using co-precipitations and proteomics we also aim at characterizing the Bcl-2 family interactome during these processes. Importantly, we will integrate the data obtained in this project and data generated by the other members of the DACH research group in the development of a computational model of Bcl-2 family member interactions during apoptosis.

Scientific goals:
-Understanding the Bcl-2 interactome during synergistic apoptosis induction by TRAIL and chemotherapy
-Analysis of the mechanism of TRAIL receptor-mediated Bim activation
-Role of stress and phosphorylation on subcellular localization of Bim and Bmf

Co-operations within FOR2036:
Christoph Borner, Freiburg
Georg Haeker, Arnim Weber, Freiburg
Thomas Kaufmann, Bern