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Dynamics of p53 and NF-κB regulation in response to DNA damage and identification of target proteins suitable for therapeutic intervention.

Poltz R, Naumann M - BMC Syst Biol (2012)

Bottom Line: Simulating therapeutic intervention by agents causing DNA single-strand breaks (SSBs) or DNA double-strand breaks (DSBs) we identified candidate target proteins for sensitization of carcinomas to therapeutic intervention.Further, we enlightened the DDR in different genetic diseases, and by failure mode analysis we defined molecular defects putatively contributing to carcinogenesis.By logic modelling we identified candidate target proteins that could be suitable for radio- and chemotherapy, and contributes to the design of more effective therapies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Experimental Internal Medicine, Otto von Guericke University, Leipziger Str, 44, Magdeburg, 39120, Germany.

ABSTRACT

Background: The genome is continuously attacked by a variety of agents that cause DNA damage. Recognition of DNA lesions activates the cellular DNA damage response (DDR), which comprises a network of signal transduction pathways to maintain genome integrity. In response to severe DNA damage, cells undergo apoptosis to avoid transformation into tumour cells, or alternatively, the cells enter permanent cell cycle arrest, called senescence. Most tumour cells have defects in pathways leading to DNA repair or apoptosis. In addition, apoptosis could be counteracted by nuclear factor kappa B (NF-κB), the main anti-apoptotic transcription factor in the DDR. Despite the high clinical relevance, the interplay of the DDR pathways is poorly understood. For therapeutic purposes DNA damage signalling processes are induced to induce apoptosis in tumour cells. However, the efficiency of radio- and chemotherapy is strongly hampered by cell survival pathways in tumour cells. In this study logical modelling was performed to facilitate understanding of the complexity of the signal transduction networks in the DDR and to provide cancer treatment options.

Results: Our comprehensive discrete logical model provided new insights into the dynamics of the DDR in human epithelial tumours. We identified new mechanisms by which the cell regulates the dynamics of the activation of the tumour suppressor p53 and NF-κB. Simulating therapeutic intervention by agents causing DNA single-strand breaks (SSBs) or DNA double-strand breaks (DSBs) we identified candidate target proteins for sensitization of carcinomas to therapeutic intervention. Further, we enlightened the DDR in different genetic diseases, and by failure mode analysis we defined molecular defects putatively contributing to carcinogenesis.

Conclusion: By logic modelling we identified candidate target proteins that could be suitable for radio- and chemotherapy, and contributes to the design of more effective therapies.

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Feed-forward loops (FFLs) and Feedback loops (FLs) in the logical model. Coherent FFLs of type 1 with AND logic (A-E), or OR logic (F-K), respectively; coherent FFLs of type 2 with AND logic (L, M); coherent FFLs of type 3 (N-R); coherent FFLs of type 4 (S-Ä), and an incoherent FFL of type 2 (Ö). Among negative FLs (a-g), only the functional (in the logical model) are shown. Letters in circles: P = phosphorylation, S = sumoylation.
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Figure 3: Feed-forward loops (FFLs) and Feedback loops (FLs) in the logical model. Coherent FFLs of type 1 with AND logic (A-E), or OR logic (F-K), respectively; coherent FFLs of type 2 with AND logic (L, M); coherent FFLs of type 3 (N-R); coherent FFLs of type 4 (S-Ä), and an incoherent FFL of type 2 (Ö). Among negative FLs (a-g), only the functional (in the logical model) are shown. Letters in circles: P = phosphorylation, S = sumoylation.

Mentions: Feed-forward loops (FFLs) and Feedback loops (FLs) can play decisive roles in the processing of the signals, which are being transmitted in signal transduction networks. Moreover, they may profoundly influence the dynamics (temporal behaviour) of a signal transduction network [47]. For these reasons, we identified FFLs (Figure 3). They appear in two groups, those with ‘AND gates’ and those with ‘OR gates’. For example, ‘AND gated’ is the activation of sumoylated and phosphorylated IKKϵ (IKKϵ-S-P) by IKKϵ-P and PML-P (Figure 3A), as IKKϵ-S-P activation requires both proteins, i.e. IKKϵ-P AND PML-P. ‘OR gated’ is for instance the activation of p53-P by either ATM-P or Chk2-P (Figure 3F), as either ATM-P OR Chk2-P phosphorylates p53.


Dynamics of p53 and NF-κB regulation in response to DNA damage and identification of target proteins suitable for therapeutic intervention.

Poltz R, Naumann M - BMC Syst Biol (2012)

Feed-forward loops (FFLs) and Feedback loops (FLs) in the logical model. Coherent FFLs of type 1 with AND logic (A-E), or OR logic (F-K), respectively; coherent FFLs of type 2 with AND logic (L, M); coherent FFLs of type 3 (N-R); coherent FFLs of type 4 (S-Ä), and an incoherent FFL of type 2 (Ö). Among negative FLs (a-g), only the functional (in the logical model) are shown. Letters in circles: P = phosphorylation, S = sumoylation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3473366&req=5

Figure 3: Feed-forward loops (FFLs) and Feedback loops (FLs) in the logical model. Coherent FFLs of type 1 with AND logic (A-E), or OR logic (F-K), respectively; coherent FFLs of type 2 with AND logic (L, M); coherent FFLs of type 3 (N-R); coherent FFLs of type 4 (S-Ä), and an incoherent FFL of type 2 (Ö). Among negative FLs (a-g), only the functional (in the logical model) are shown. Letters in circles: P = phosphorylation, S = sumoylation.
Mentions: Feed-forward loops (FFLs) and Feedback loops (FLs) can play decisive roles in the processing of the signals, which are being transmitted in signal transduction networks. Moreover, they may profoundly influence the dynamics (temporal behaviour) of a signal transduction network [47]. For these reasons, we identified FFLs (Figure 3). They appear in two groups, those with ‘AND gates’ and those with ‘OR gates’. For example, ‘AND gated’ is the activation of sumoylated and phosphorylated IKKϵ (IKKϵ-S-P) by IKKϵ-P and PML-P (Figure 3A), as IKKϵ-S-P activation requires both proteins, i.e. IKKϵ-P AND PML-P. ‘OR gated’ is for instance the activation of p53-P by either ATM-P or Chk2-P (Figure 3F), as either ATM-P OR Chk2-P phosphorylates p53.

Bottom Line: Simulating therapeutic intervention by agents causing DNA single-strand breaks (SSBs) or DNA double-strand breaks (DSBs) we identified candidate target proteins for sensitization of carcinomas to therapeutic intervention.Further, we enlightened the DDR in different genetic diseases, and by failure mode analysis we defined molecular defects putatively contributing to carcinogenesis.By logic modelling we identified candidate target proteins that could be suitable for radio- and chemotherapy, and contributes to the design of more effective therapies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Experimental Internal Medicine, Otto von Guericke University, Leipziger Str, 44, Magdeburg, 39120, Germany.

ABSTRACT

Background: The genome is continuously attacked by a variety of agents that cause DNA damage. Recognition of DNA lesions activates the cellular DNA damage response (DDR), which comprises a network of signal transduction pathways to maintain genome integrity. In response to severe DNA damage, cells undergo apoptosis to avoid transformation into tumour cells, or alternatively, the cells enter permanent cell cycle arrest, called senescence. Most tumour cells have defects in pathways leading to DNA repair or apoptosis. In addition, apoptosis could be counteracted by nuclear factor kappa B (NF-κB), the main anti-apoptotic transcription factor in the DDR. Despite the high clinical relevance, the interplay of the DDR pathways is poorly understood. For therapeutic purposes DNA damage signalling processes are induced to induce apoptosis in tumour cells. However, the efficiency of radio- and chemotherapy is strongly hampered by cell survival pathways in tumour cells. In this study logical modelling was performed to facilitate understanding of the complexity of the signal transduction networks in the DDR and to provide cancer treatment options.

Results: Our comprehensive discrete logical model provided new insights into the dynamics of the DDR in human epithelial tumours. We identified new mechanisms by which the cell regulates the dynamics of the activation of the tumour suppressor p53 and NF-κB. Simulating therapeutic intervention by agents causing DNA single-strand breaks (SSBs) or DNA double-strand breaks (DSBs) we identified candidate target proteins for sensitization of carcinomas to therapeutic intervention. Further, we enlightened the DDR in different genetic diseases, and by failure mode analysis we defined molecular defects putatively contributing to carcinogenesis.

Conclusion: By logic modelling we identified candidate target proteins that could be suitable for radio- and chemotherapy, and contributes to the design of more effective therapies.

Show MeSH
Related in: MedlinePlus