The Centre of Systems Medicine has published two review articles which describe key molecular processes and signalling network topologies coordinating apoptosis signal transduction. Christian T Hellwig and Markus Rehm published a review on synergistic TRAIL-based multidrug treatments in the AACR journal Molecular Cancer Therapeutics. TRAIL and agonistic TRAIL receptor antibodies are the only therapeutically relevant anti-cancer death ligands. Synergies have been reported in various scenarios of TRAIL-based multidrug treatments, and these can be used to potentiate the efficacy of therapies targeting TRAIL death receptors. The review structures the current knowledge on the diverse molecular mechanisms that are thought to give rise to these synergies and describes how different signaling features evoking synergies can be associated with distinct classes of drugs used in TRAIL-based combination treatments. In a second review article, Maximilian L. Würstle, Maike A. Laussmann, and Markus Rehm describe the latest developments in the understanding of caspase-9 activation. Caspase-9 is an essentially required cell death protease mediating apoptosis execution through the mitochondrial pathway. The review discusses recent structural and kinetic studies on caspase-9 signalling, and describes an emerging model for the regulation of caspase-9 activation and activity that arise from the complexity of multi-protein interactions at the apoptosome. This review is available ahead of print through the journal Experimental Cell Research, and will be part of a special edition on cell death signaling to be published later this year. Both reviews can be accessed online:
A study by David Davila, Niamh M. C. Connolly, Helena Bonner, Petronela Weisová, Heiko Dussmann, Caoimhín G. Concannon, Heinrich J. Huber and Jochen H. M. Prehn was accepted to the high profile journal Cell Death and Differentiation in March 2012. The study involved collaboration between the Centre for Systems Medicine (computational modelling) and the Centre for the Study of Neurological Disorders (biological experimentation). The authors investigated the molecular signalling pathways mediating the apoptotic response of neurons undergoing excitotoxic stress, a process implicated in stroke and neurodegenerative diseases. Systems analysis identified a key network motif (known as a coherent feed-forward loop) that prevents apoptosis during physiological or short-term stress, but translates pathological long-term stress into robust apoptosis activation. This molecular framework thus provides a mechanism for cell fate decision making.