Exploring and exploiting Bcl-2'S anti-apoptotic function in diffuse large B-cell lymphoma: BH4 domain versus the hydrophobic cleft

This project aspires 1. to demonstrate cancer cells dual addiction to anti-apoptotic Bcl-2 by exploiting the properties of BH3 mimetics and BH4-targeting tools 2. to screen and/or develop novel, in vivo applicable petidomimetics and TAT-IDPs peptide derivatives targeting Bcl-2 via its BH4-domain via a Celltox-TM Green Cytotoxicity Assay 3. to establish the effect of TAT-IDPs and derivatives on the survival and function of platelets from healthy volunteers and cancer patients.nrpages: 128status: publishe

New Insights in the IP3 Receptor and Its Regulation

The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is a Ca2+-release channel mainly located in the endoplasmic reticulum (ER). Three IP3R isoforms are responsible for the generation of intracellular Ca2+ signals that may spread across the entire cell or occur locally in so-called microdomains. Because of their ubiquitous expression, these channels are involved in the regulation of a plethora of cellular processes, including cell survival and cell death. To exert their proper function a fine regulation of their activity is of paramount importance. In this review, we will highlight the recent advances in the structural analysis of the IP3R and try to link these data with the newest information concerning IP3R activation and regulation. A special focus of this review will be directed towards the regulation of the IP3R by protein-protein interaction. Especially the protein family formed by calmodulin and related Ca2+-binding proteins and the pro- and anti-apoptotic/autophagic Bcl-2-family members will be highlighted. Finally, recently identified and novel IP3R regulatory proteins will be discussed. A number of these interactions are involved in cancer development, illustrating the potential importance of modulating IP3R-mediated Ca2+ signaling in cancer treatment.status: publishe

Alterations in Ca2+ Signalling via ER-mitochondria contact site remodelling in cancer

Inter-organellar contact sites establish microdomains for localised Ca2+-signalling events. One of these microdomains is established between the ER and the mitochondria. Importantly, the so-called mitochondria-associated ER membranes (MAMs) contain, besides structural proteins and proteins involved in lipid exchange, several Ca2+-transport systems, mediating efficient Ca2+ transfer from the ER to the mitochondria. These Ca2+ signals critically control several mitochondrial functions, thereby impacting cell metabolism, cell death and survival, proliferation and migration. Hence, the MAMs have emerged as critical signalling hubs in physiology, while their dysregulation is an important factor that drives or at least contributes to oncogenesis and tumour progression. In this book chapter, we will provide an overview of the role of the MAMs in cell function and how alterations in the MAM composition contribute to oncogenic features and behaviours