The Molecular Cancer Research Group performs basic research within the research areas autophagy, cell signaling and regulation of transcription. Specific protein-protein interactions and their functional consequences are being addressed in all projects using a set of biochemical-, cell biological- and immunological tools. Bioimaging and proteomics are important in the research strategy of the group. The pathways and proteins we study act in autophagy, cell proliferation control, anti-apoptotic signaling and establishment and maintenance of cell- and tissue polarity. These processes are deregulated in cancer development. The insight that basic research can provide into the normal regulation versus the dysregulation occurring in cancer cells is vital for identification of potential drug targets and subsequent development of future treatment rationales and strategies. Via studies of the atypical Protein Kinase C (aPKC) isozymes, iota and zeta, we have focused on detailed analyses of one of their scaffold proteins, p62/SQSTM1. Our results so far suggest that the p62 protein is a key player in selective autophagy of ubiquitinated protein aggregates. We have now also implicated another protein, NBR1 in selective autophagy of ubiqutinated substrates. Protein degradation in eukaryotic cells is carried out either by the proteasome or by autophagy. In autophagy a crescent-like double mebrane called the isolation membrane forms and enwraps part of the cytoplasm including both soluble components and damaged organelles, like mitochodria. When the isolation mebrane closes on itself an autophagosome is formed. Autophagosomes subsequently fuse with lysosomes where their contents are degraded. Recent research has highlighted that dysregulation or impairment of autophagy may have strong impact on cancer, neurodegenerative diseases such as Alzheimer’s and Parkinson’s, infections and immune responses. Autophagy is basically a process whereby the cell can salvage nutrients during starvation and also dispose of toxic waste such as protein aggregates and damaged organelles. It has been thought of as a bulk degradation process but recent results from our group and others suggest that some proteins, like p62 and NBR1, act as cargo recptors for autophagic degradation of ubiqutinated substrates.
An important role for iotaPKC as an oncogene in human cancer was recently established and the aPKCs are central components protein complexes regualting cell polarity processes. In our group we also study proteins that we have found by yeast two-hybrid screens to interact with aPKCs in order to determine if these interaction partners are substrates or adapter/scaffold proteins or both. A challenge is then to unravel the biological roles of the interactions that we verify.
From the early nineties we have studied some members of the Pax family of organogenetic transcription factors. We have focused mostly on Pax6 which is responsible for proper development of the eyes, part of the brain and some of the endocrine cells of the pancreas. Current projects involve identification and analyses of novel interaction partners for Pax6 as well as studies of the dynamic movements of Pax family proteins in the nuclei of live cells. A major finding of ours is that the Pax proteins use also their DNA binding domains as protein-protein interactions, both intra- and intermolecularly.
We also study a large nuclear protein, called SPBP, that we have shown acts as a chromatin-binding cofactor in regulation of transcription mediated by different transcription factors.