Logical network of genotoxic stress-induced NF-kappaB signal transduction predicts putative target structures for therapeutic intervention strategies

Original Research

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Authors: Rainer Poltz, Raimo Franke, Katrin Schweitzer, et al

Published Date December 2009 Volume 2009:2 Pages 125 - 138

DOI: http://dx.doi.org/10.2147/AABC.S8211

Rainer Poltz¹, Raimo Franke^1,#, Katrin Schweitzer¹, Steffen Klamt², Ernst-Dieter Gilles², Michael Naumann¹

¹Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, Germany; ²Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany; ^#Present address: Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany

Abstract: Genotoxic stress is induced by a broad range of DNA-damaging agents and could lead to a variety of human diseases including cancer. DNA damage is also therapeutically induced for cancer treatment with the aim to eliminate tumor cells. However, the effectiveness of radio- and chemotherapy is strongly hampered by tumor cell resistance. A major reason for radio- and chemotherapeutic resistances is the simultaneous activation of cell survival pathways resulting in the activation of the transcription factor nuclear factor-kappa B (NF-κB). Here, we present a Boolean network model of the NF-κB signal transduction induced by genotoxic stress in epithelial cells. For the representation and analysis of the model, we used the formalism of logical interaction hypergraphs. Model reconstruction was based on a careful meta-analysis of published data. By calculating minimal intervention sets, we identified p53-induced protein with a death domain (PIDD), receptor-interacting protein 1 (RIP1), and protein inhibitor of activated STAT y (PIASy) as putative therapeutic targets to abrogate NF-κB activation resulting in apoptosis. Targeting these structures therapeutically may potentiate the effectiveness of radio- and chemotherapy. Thus, the presented model allows a better understanding of the signal transduction in tumor cells and provides candidates as new therapeutic target structures.

Keywords: apoptosis, Boolean network, cancer therapy, DNA-damage response, NF-κB