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Analysis and verification of the HMGB1 signaling pathway.

Gong H, Zuliani P, Komuravelli A, Faeder JR, Clarke EM - BMC Bioinformatics (2010)

Bottom Line: Recent studies have found that overexpression of the High-mobility group box-1 (HMGB1) protein, in conjunction with its receptors for advanced glycation end products (RAGEs) and toll-like receptors (TLRs), is associated with proliferation of various cancer types, including that of the breast and pancreatic.Discrete, stochastic simulations show that p53 and MDM2 oscillations continue even after 10 hours, as observed by experiments.This property is not exhibited by the deterministic ODE simulation, for the chosen parameters.

View Article: PubMed Central - HTML - PubMed

Affiliation: Computer Science Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA. haijung@cs.cmu.edu

ABSTRACT

Background: Recent studies have found that overexpression of the High-mobility group box-1 (HMGB1) protein, in conjunction with its receptors for advanced glycation end products (RAGEs) and toll-like receptors (TLRs), is associated with proliferation of various cancer types, including that of the breast and pancreatic.

Results: We have developed a rule-based model of crosstalk between the HMGB1 signaling pathway and other key cancer signaling pathways. The model has been simulated using both ordinary differential equations (ODEs) and discrete stochastic simulation. We have applied an automated verification technique, Statistical Model Checking, to validate interesting temporal properties of our model.

Conclusions: Our simulations show that, if HMGB1 is overexpressed, then the oncoproteins CyclinD/E, which regulate cell proliferation, are overexpressed, while tumor suppressor proteins that regulate cell apoptosis (programmed cell death), such as p53, are repressed. Discrete, stochastic simulations show that p53 and MDM2 oscillations continue even after 10 hours, as observed by experiments. This property is not exhibited by the deterministic ODE simulation, for the chosen parameters. Moreover, the models also predict that mutations of RAS, ARF and P21 in the context of HMGB1 signaling can influence the cancer cell's fate - apoptosis or survival - through the crosstalk of different pathways.

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HMGB1 baseline simulation. Number of p53, MDM2p (A, C), CyclinD/E (B, D) molecules versus time for baseline simulations with SSA (A-B) and ODE (C-D) models.
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Figure 3: HMGB1 baseline simulation. Number of p53, MDM2p (A, C), CyclinD/E (B, D) molecules versus time for baseline simulations with SSA (A-B) and ODE (C-D) models.

Mentions: The baseline stochastic simulations in Fig. 3A demonstrate that the expression levels of p53 and MDM2p oscillate even after 10 hours, when the cell enters the S phase (recall that cells usually remain in phase G1 for about 10 hours before moving to the S phase). However, oscillations are strongly damped in the ODE simulations (Fig. 3C) when the cell proceeds to the S phase, approximately after 10 hours. The stochastic simulation model is thus more consistent with the experimental results of Geva-Zatorsky et al. [52]. In that experiment the authors measured the dynamics of p53 and MDM2p in human breast cancer cells damaged by γ radiation. It was observed that the oscillations of p53 and MDM2p expression levels can last more than 72 hours after irradiation.


Analysis and verification of the HMGB1 signaling pathway.

Gong H, Zuliani P, Komuravelli A, Faeder JR, Clarke EM - BMC Bioinformatics (2010)

HMGB1 baseline simulation. Number of p53, MDM2p (A, C), CyclinD/E (B, D) molecules versus time for baseline simulations with SSA (A-B) and ODE (C-D) models.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2957678&req=5

Figure 3: HMGB1 baseline simulation. Number of p53, MDM2p (A, C), CyclinD/E (B, D) molecules versus time for baseline simulations with SSA (A-B) and ODE (C-D) models.
Mentions: The baseline stochastic simulations in Fig. 3A demonstrate that the expression levels of p53 and MDM2p oscillate even after 10 hours, when the cell enters the S phase (recall that cells usually remain in phase G1 for about 10 hours before moving to the S phase). However, oscillations are strongly damped in the ODE simulations (Fig. 3C) when the cell proceeds to the S phase, approximately after 10 hours. The stochastic simulation model is thus more consistent with the experimental results of Geva-Zatorsky et al. [52]. In that experiment the authors measured the dynamics of p53 and MDM2p in human breast cancer cells damaged by γ radiation. It was observed that the oscillations of p53 and MDM2p expression levels can last more than 72 hours after irradiation.

Bottom Line: Recent studies have found that overexpression of the High-mobility group box-1 (HMGB1) protein, in conjunction with its receptors for advanced glycation end products (RAGEs) and toll-like receptors (TLRs), is associated with proliferation of various cancer types, including that of the breast and pancreatic.Discrete, stochastic simulations show that p53 and MDM2 oscillations continue even after 10 hours, as observed by experiments.This property is not exhibited by the deterministic ODE simulation, for the chosen parameters.

View Article: PubMed Central - HTML - PubMed

Affiliation: Computer Science Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA. haijung@cs.cmu.edu

ABSTRACT

Background: Recent studies have found that overexpression of the High-mobility group box-1 (HMGB1) protein, in conjunction with its receptors for advanced glycation end products (RAGEs) and toll-like receptors (TLRs), is associated with proliferation of various cancer types, including that of the breast and pancreatic.

Results: We have developed a rule-based model of crosstalk between the HMGB1 signaling pathway and other key cancer signaling pathways. The model has been simulated using both ordinary differential equations (ODEs) and discrete stochastic simulation. We have applied an automated verification technique, Statistical Model Checking, to validate interesting temporal properties of our model.

Conclusions: Our simulations show that, if HMGB1 is overexpressed, then the oncoproteins CyclinD/E, which regulate cell proliferation, are overexpressed, while tumor suppressor proteins that regulate cell apoptosis (programmed cell death), such as p53, are repressed. Discrete, stochastic simulations show that p53 and MDM2 oscillations continue even after 10 hours, as observed by experiments. This property is not exhibited by the deterministic ODE simulation, for the chosen parameters. Moreover, the models also predict that mutations of RAS, ARF and P21 in the context of HMGB1 signaling can influence the cancer cell's fate - apoptosis or survival - through the crosstalk of different pathways.

Show MeSH
Related in: MedlinePlus