title: Logical network of genotoxic stress-induced NF-κB signal transduction predicts putative target structures for therapeutic intervention strategies.
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.
authors.affiliation: Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Poltz
authors.forename: Raimo
authors.initials: R
authors.lastname: Franke
authors.forename: Katrin
authors.initials: K
authors.lastname: Schweitzer
authors.forename: Steffen
authors.initials: S
authors.lastname: Klamt
authors.forename: Ernst-Dieter
authors.initials: ED
authors.lastname: Gilles
authors.forename: Michael
authors.initials: M
authors.lastname: Naumann