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Experimental Research

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Research Topics

1. Signal transduction after genotoxic stress

Despite recent advances, tumors are still life-threatening diseases. The three main treatment modalities are surgery, chemotherapy and radiation therapy. In a number of malignant tumor types, especially childhood tumors, healing rates of over 90 % can be achieved. In those patients, it is of special importance to keep possible late effects of treatment (e.g. radiation late effects) as low as possible.

Our lab is interested in signal transduction pathways that are of potential importance for the generation and the treatment of malignant tumors, especially pathways that are responsible for survival, proliferation, differentiation and stress response of tumor cells. We are focusing at growth factor signal transduction pathways and their nuclear end-points, the transcription factors such as AP-1, NF-kappaB, Sp1 and c-Myc. We are interested in differences between normal and tumor cells in their reaction to cellular stress such as irradiation and chemotherapy and the signal transduction pathways involved. For these experiments, we use cell lines, histological tumor samples and genetic models.

In earlier work on chronic radiation damage, we found that several transcription factors, such as AP-1 [1], Sp1 [2] and c-Myc are inactivated whereas the DNA binding activity of NF-kappaB is induced [3]. These changes have consequences for important basic cellular processes such as proliferation, regeneration, differentiation, and the regulation of inflammatory processes (see scheme below). Further research work will deal with the molecular mechanisms of those changes.

The aim of our wok is to improve our knowledge on tumor biology and to improve the tumor treatment.

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2. Mutations in the c-Ret gene: implications for signal transduction and cell behavior

C-Ret is a transmembrane tyrosine kinase which associates with GDNF-family receptors (GFRs) to form complete receptors for GDNF (glial cell line derived neurotrophic factor) and other GDNF-family ligand (GFLs). C-Ret plays a role in migration, differentiation and proliferation of neural crest derived cells. A diminished function or lower expression of c-Ret leads to reduced migration of enteric neural cells which causes Hirschsprungs disease. An increased activity of c-Ret leads to multiple endocrine neoplasias, type 2 (MEN2-syndrome). In this project, the role of specific mutations of the c-Ret protooncogene is examined with respect to cell survival, proliferation and migration. This should lead to a better understanding of the function of c-Ret and its role in the pathogenesis of Hirschsprungs disease.

3. Role of IkappaBgamma in the signal transduction of mast cells

Mast cells are important effector cells in the immune response, especially in allergic and autoimmune reactions like asthma and rheumatoid arthritis (RA). In addition, they are effector cells in the tissue response to ionizing irradiation and occur as autonomously growing cells in tumors such as mastocytomas. The transcription factor NF-kappaB plays an important role in the regulation of the immune response. As such, it is necessary for the activation of mast cells. Our own work has shown that mast cells are among the few cell types in the body that express IkappaBgamma, an inhibitor of NF-kappaB signaling, but not p50 which is produced from the same precursor molecule p105. This suggests that in mast cells, IkappaBgamma is not generated from p105 which is supported by our RT-PCR results. On the basis of those special features this project aims at elucidating the role of IkappaBgamma for the NF-kappaB signaling in mast cells. In particular, it will be analyzed how IkappaBgamma is generated in mast cells, which role IkappaBgamma plays in the activation of mast cells and the activity of NF-kappaB and on the general cDNA expression pattern. These experiments should reveal new insights into the biology of mast cells and facilitate the search for new specific therapeutic modalities for mast cell diseases.

References:

 [1] M.G. Haase, A. Klawitter, A. Bierhaus, K.K. Yokoyama, M. Kasper, P. Geyer, M. Baumann, G.B. Baretton, Inactivation of AP1 proteins by a nuclear serine protease precedes the onset of radiation-induced fibrosing alveolitis, Radiat Res 169 (2008) 531-542.

[2] M. Haase, P. Geyer, S. Appold, D. Schuh, M. Kasper, M. Muller, Down-regulation of Sp1 DNA binding activity in the process of radiation-induced pulmonary fibrosis, Int J Radiat Biol 76 (2000) 487-492.

[3] M.G. Haase, A. Klawitter, P. Geyer, H. Alheit, M. Baumann, T.M. Kriegel, M. Kasper, G.B. Baretton, Sustained elevation of NF-kappaB DNA binding activity in radiation-induced lung damage in rats, Int J Radiat Biol 79 (2003) 863-877.