The focus of research in my lab is on protein stability in cancer. Non-silent mutations often destabilize proteins which as a consequence misfold, aggregate or are degraded. However, mutant oncogenes obviously pass cellular quality checkpoints.
How do oncogenes manage to survive and remain functional? We believe that molecular chaperones stabilize them and thus critically contribute to tumor progression.
I. We focus on the HSP70 molecular chaperone superfamily. Our experimental model is based on transgenes where the diphtheria toxin receptor is under control of individual HSP70 chaperone promoters. This allows us to manipulate and investigate tumor progression depending on the need for a defined molecular chaperone from the HSP70 superfamily.
II. In our previous work we demonstrated that protein biogenesis is usually an efficient process and discovered that a close collaboration of protein synthesis and degradation machineries takes place to sustain it (Vabulas and Hartl, 2005). We are investigating the molecular details of this collaboration with the aim of identifying new targets for increased oncogene clearance in tumor cells.
III. We are investigating proteome stability, especially how cellular architecture is sustained under different physical and chemical insults relevant for tumor progression, such as acidosis or oxidative damage. Using de novo designed amyloid proteins we uncovered how aggregation results in the loss of a distinct set of polypeptides (Olzscha et al, 2011). Coaggregation of a substantial number of proteins with diverse functions inevitably leads to multifocal deficits and the collapse of the cellular protein network. In search of novel therapeutic strategies to prevent (for neurodegeneration prevention) or enhance (for tumor therapy) this cellular break-down, we want to understand the quantitative details of the bystander protein coaggregation. To this end, we use cell biological, biophysical and proteomic techniques; to identify and access relevant biological material for these investigations we are creating molecular chaperone-BAC-modified transgenic mice strains.