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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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Related in: MedlinePlus

Dependency matrix. Interdependencies between all pairs of regulatory components in the model are displayed. The colour of a matrix element Mij defines the type of impact of a component i (left hand side) on a component j (bottom). Colour codes: dark green, strong activator; turquois green, weak activator; dark red, strong inhibitor; pink, weak inhibitor; yellow, ambivalent factor; black, no effect. ‘-P’ = phosphorylation, ‘-S’ = sumoylation, ‘-Ub’ = ubiquitinylation.
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Figure 2: Dependency matrix. Interdependencies between all pairs of regulatory components in the model are displayed. The colour of a matrix element Mij defines the type of impact of a component i (left hand side) on a component j (bottom). Colour codes: dark green, strong activator; turquois green, weak activator; dark red, strong inhibitor; pink, weak inhibitor; yellow, ambivalent factor; black, no effect. ‘-P’ = phosphorylation, ‘-S’ = sumoylation, ‘-Ub’ = ubiquitinylation.

Mentions: Network-wide causal relationships between all pairs of regulatory components are displayed in the dependency matrix (Figure 2). Two components have a causal relationship, if a sequence of adjacent components, a pathway, links them. As the large fraction of yellow matrix elements in Figure 2 illustrates, in most causal relationships between two components i and ji is an ambivalent factor for j. In other words, i has an activating as well as an inhibiting influence on another component j. Usually, the activating influence becomes operational at another time scale than the inhibiting influence. ATM for instance phosphorylates, i.e. has an activating influence on Chk2 [43] (interaction 25). However, ATM phosphorylates p53 as well [44,45] (interaction 31), leading to expression of Wip1 later (at time scale value 3) [30] (interaction 82). Wip1 in turn deactivates Chk2 by means of dephosphorylation [46] (interaction 25). Therefore, the activation of Chk2 by ATM is counteracted by the ATM-dependent deactivation of Chk2 by Wip1. Thus, ATM is an ambivalent factor for Chk2, as the yellow matrix element in Figure 2 indicates. As the high frequency of coincidences of activating and inhibiting relationships indicates, most pathways become inactivated in a later phase of the DDR. Moreover, these coincidences suggest an important role of crosstalk in the DDR.


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)

Dependency matrix. Interdependencies between all pairs of regulatory components in the model are displayed. The colour of a matrix element Mij defines the type of impact of a component i (left hand side) on a component j (bottom). Colour codes: dark green, strong activator; turquois green, weak activator; dark red, strong inhibitor; pink, weak inhibitor; yellow, ambivalent factor; black, no effect. ‘-P’ = phosphorylation, ‘-S’ = sumoylation, ‘-Ub’ = ubiquitinylation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Dependency matrix. Interdependencies between all pairs of regulatory components in the model are displayed. The colour of a matrix element Mij defines the type of impact of a component i (left hand side) on a component j (bottom). Colour codes: dark green, strong activator; turquois green, weak activator; dark red, strong inhibitor; pink, weak inhibitor; yellow, ambivalent factor; black, no effect. ‘-P’ = phosphorylation, ‘-S’ = sumoylation, ‘-Ub’ = ubiquitinylation.
Mentions: Network-wide causal relationships between all pairs of regulatory components are displayed in the dependency matrix (Figure 2). Two components have a causal relationship, if a sequence of adjacent components, a pathway, links them. As the large fraction of yellow matrix elements in Figure 2 illustrates, in most causal relationships between two components i and ji is an ambivalent factor for j. In other words, i has an activating as well as an inhibiting influence on another component j. Usually, the activating influence becomes operational at another time scale than the inhibiting influence. ATM for instance phosphorylates, i.e. has an activating influence on Chk2 [43] (interaction 25). However, ATM phosphorylates p53 as well [44,45] (interaction 31), leading to expression of Wip1 later (at time scale value 3) [30] (interaction 82). Wip1 in turn deactivates Chk2 by means of dephosphorylation [46] (interaction 25). Therefore, the activation of Chk2 by ATM is counteracted by the ATM-dependent deactivation of Chk2 by Wip1. Thus, ATM is an ambivalent factor for Chk2, as the yellow matrix element in Figure 2 indicates. As the high frequency of coincidences of activating and inhibiting relationships indicates, most pathways become inactivated in a later phase of the DDR. Moreover, these coincidences suggest an important role of crosstalk in the DDR.

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