Projektgruppe
Systemtoxikologie [SysTox]

SignalTox

Nachwuchsgruppe Reif

Background

In recent years it has become obvious that epithelial cells respond with specific signalling to cellular stress, such as hypoxia, nutrient deprivation and in particular to toxic substances. These stress situations lead to cell fate decisions which programme the cell for apoptosis, survival, activate repair mechanisms, proliferation or even malignant transformation. Persistent stress can initiate first steps of serious diseases like chronic inflammation and cancer. The final effect of the stress response depends on the extent of the stress exposure, the addressed pathways and on the key proteins of its processing. The basic principles of signalling pathway activation, the following protein expression and protein activation are currently under intensive investigation. However, little is known about the interfaces of the stress stimuli and the resulting activation of signalling mechanisms.

Aims

The aim of our project is to identify interfaces of toxic substances and cellular targets of the early signalling networks in order to understand certain activation states and the way they contribute to cell fate decisions and pathologic effects. We are interested in mechanisms of stress signalling induction, in particular for receptor tyrosine kinases. Further on, we try to understand in which way nuclear translocation of receptor tyrosine kinases, as a consequence to cellular stress, influences cell function. Deeper understanding of early stress effects in terms of signalling alterations would make it easier to screen for substance toxicity. Therefore, our specific aims are:

• To identify key players of stress response in important signalling pathways.
• To find genes regulated directly by receptor tyrosine kinases and their effect on gene transcription.
• To investigate the cellular response in terms of proliferation, apoptosis, cell survival and stress susceptibility in relation to nuclear translocation of receptor tyrosine kinases.
• To study the relevance of the newly characterised mechanisms for toxicity of compounds relevant in the occupational context.

Current techniques

We are investigating molecular and cellular responses on stress treatment both in vitro and in vivo. Our recent research covers state of the art tools in biochemistry, molecular biology, cell biology and toxicology. In particular we established translocation assays for membrane bound proteins, pull-down experiments, protease cleavage assays and cell proliferation analysis.

Selected papers

• Aurich, I, L P Mueller, H Aurich, J Luetzkendorf, K Tisljar, M M Dollinger, W Schormann, J Walldorf, J G Hengstler, W E Fleig, B Christ (2007). Functional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers: Gut 56(3),405-15
• Brulport M, W Schormann, A Bauer , M Hermes, C Elsner , FJ Hammersen, W Beerheide, D Spitkovsky, W Härtig, A Nussler, LC Horn, J Edelmann, O Pelz-Ackermann, J Petersen, M Kamprad, M von Mach, A Lupp, H Zulewski, JG Hengstler (2007). Fate of extrahepatic human stem and precursor cells after transplantation into mouse livers. Hepatology 46(3):861-70
• von Mach MA, JG Hengstler, M Brulport, M Eberhardt, W Schormann, M Hermes, D Prawitt, B Zabel, J Grosche, A Reichenbach, B Müller, LS Weilemann, H Zulewski (2004). In vitro cultured islet-derived progenitor cells of human origin express human albumin in severe combined immunodeficiency mouse liver in vivo. StemCells 22(7):1134-41
• Reif R, S Sales, S Hettwer, B Dreier, C Gisler, J Wölfel, D Lüscher, A Zurlinden, A Stephan, S Ahmed, A Baici, B Ledermann, B Kunz, P Sonderegger (2007). Specific cleavage of agrin by neurotrypsin, a synaptic protease linked to mental retardation. FASEBJ 21(13):3468-78.
• Tanner, B, D Hasenclever, K Stern, W Schormann, M Bezler, M Hermes, M Brulport, A Bauer, I B Schiffer, S Gebhard, M Schmidt, E Steiner, J Sehouli, J Edelmann, J Lauter, R Lessig, K Krishnamurthi, A Ullrich, J G Hengstler (2006). ErbB-3 predicts survival in ovarian cancer: JClinOncol 24(26):4317-4323.