Der Forschungsschwerpunkt des Instituts liegt in der Identifizierung molekularer und biochemischer Mechanismen, die der Zelldifferenzierung, der Zellaktivierung und weiterer wichtiger zellulärer Funktionen zu Grunde liegen.

Role of the NF-κB system in differentiation and disease

The majority of our projects dealing with NF-κB are focused on the role of this signaling pathway in different disease entities or in distinct differentiation processes. Although NF-κB activation has been described for a plethora of disease entities, definite proof for a direct involvement of NF-κB in initiation of progression of these diseases is often missing. To unravel the contribution of NF-κB activation to various disease entities and differentiation processes we typically modulate the NF-κB signaling pathway using genetic tools. This is either done in cell lines or (in most cases) in transgenic mice. Alleles are available that allow to either activate or block the pathway. Modulation is typically done in a conditional way meaning that both spatial as well as temporal interference with the pathway can be modulated. Different aspects of this work involve the role of NF-κB in neuronal differentiations and glial cells (see also AG Baumann), in the pancreas, the heart, the endothelium and the liver. In addition, target genes regulated by NF-κB in the various organ systems/disease entities are also investigated. Given published evidence that FoxO3 is targeted by the IKK2 kinase, which is otherwise involved in the NF-κB activating pathway, we began to address the contribution of this pathway in processes known to be affected by IKK/NF-κB. Again, conditional alleles are used for studies in transgenic mice.

Dr. Bernd Baumann, Dr. Harald J. Maier, Nora Hipp, Alexander Magnutzki, Ayesha Maqbool, Sarah Gul, Heba Salem, Nina Ushmorova, Uta Manfras, Ute Leschik, Bianca Ries, Melanie Gerstenlauer

Supported by: KFO 142 - TP P5, KFO 167 – TP5, SyStaR, PCCC, Novartis Foundation, Fonds der Chemischen Industrie

Our analyses of normal lymphopoiesis deal with the components regulating octamer-dependent transcription in lymphocytes. The octamer-motif is a conserved regulatory motif that was initially identified in the promoter and enhancer regions of immunoglobulin genes, but soon found to be conserved in the regulatory regions of many other genes expressed in lymphocytes as well as other cell types. The lymphocyte-specificity is largely brought about by the transcriptional co-activator BOB.1/OBF.1 (POU2AF1). The role of this factor for lymphocyte differentiation and lymphocyte effector functions is analyzed using mouse models bearing either mutations in this gene or transgenic mice expressing conditional alleles of BOB.1/OBF.1 (see also AG Brunner). The fact that this factor is typically absent from classical Hodgkin lymphoma (cHL) cases has drawn our interest to this type of tumors. The reasons and consequences for the absence of this factor in this tumor entity is studied as well as additional levels of gene regulation in cHL as epigenetic modulation. Finally, we have established a conditional lymphoma model in mice using conditional expression of the human c-myc gene and are in the process of analyzing molecular pathways of myc-induced lymphomagenesis.

PD Dr. Cornelia Brunner, Dr. Katja Fiedler, Dr. Alexey Ushmorov, Marion Vogel, Anita Kick, Petra Weihrich

Supported by: SFB 1074, Deutsche Krebshilfe, Fonds der Chemischen Industrie