Our group investigates the mechanisms of signal transduction and inducible gene expression in eukaryotic cells using the transcription factors NF-kB and p53 as model systems. These transcription factors are important regulators of the immune response and cell proliferation and are thus found to be dysregulated in a variety of ailments ranging from cancer to cardiovascular diseases. We are always interested in applications of prospective PhD students or postdocs who are willing to join a hard-working and competitive team with a friendly atmosphere.

1) The first focus of our research is centered on NF-kB. This transcription factor contributes to the mounting of an effective immune response, but is also involved in the regulation of cell proliferation and apoptosis. The implication of NF-kB in central biological processes and its extraordinary connectivity to other signaling pathways raise a need for highly controlled regulation of NF-kB activity at several levels. While all NF-kB activation pathways share a central and critical proteasome-mediated step that leads to the degradation of inhibitory proteins and the release of DNA-binding subunits, there is evidence for a downstream level of NF-kB regulation that employs several mechanisms. These include promoter-specific exchange of dimers and modification of the transactivating p65 subunit by phosphorylation, acetylation, ubiquitination, or prolyl isomerization. The signaling pathways and enzymes controlling this second level of regulation and their potential use as therapeutic targets for the treatment of NF-kB-associated pathologies are studied in our lab. We are also studying the IKK related kinase IKKi/IKKe, which is important for the expression of selective NF-kB target genes by mechanisms which are poorly understood. We are thus in the search for new substrates and activation/inactivation pathways for this kinase.

2) The second project deals with the human serine/threonine kinase HIPK2 (homeodomain-interacting protein kinase 2). HIPK2 co-localizes and interacts with p53 and CBP within PML nuclear bodies. DNA damaging agents activate HIPK2 which in turn phosphorylates a variety of substrates including the tumor suppressor p53 at serine 46. Accordingly, the kinase function of HIPK2 mediates increased expression of p53 target genes and enhanced cell death. We are currently characterizing novel HIPK2 interactors that we found in a Y2H screen. Target genes for this regulatory kinase are identified by hybridization of DNA arrays. The role of HIPK2 in human cancers and its importance for cell proliferation is a further research goal. In addition to its function in regulating the cell cycle and apoptosis, HIPK2 is also involved in organizing transcriptional repression. HIPK2-mediated reorganisation of distinct chromatin regions is important for perpetuation of the transcriptionally repressed state. Accordingly, under certain conditions such as hypoxia, HIPK2 is eliminated from the repressed promoters, thus allowing for full gene induction.