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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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Related in: MedlinePlus

Mutations of ARF, P21 and RAS affect the cell's fate. Mutations of the tumor suppressor proteins ARF and P21, and of the oncoprotein RAS affect the cell's fate, using ODE (A-C) and stochastic (D-F) simulations. The mutations of ARF (A, D) and P21 (B, E), and RAS (C, F), which correspond to small dARF and dP21, and large dRAS values, upregulate the expression level of the oncoproteins MDM2 and CyclinD/E, and downregulate p53's expression level.
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Figure 5: Mutations of ARF, P21 and RAS affect the cell's fate. Mutations of the tumor suppressor proteins ARF and P21, and of the oncoprotein RAS affect the cell's fate, using ODE (A-C) and stochastic (D-F) simulations. The mutations of ARF (A, D) and P21 (B, E), and RAS (C, F), which correspond to small dARF and dP21, and large dRAS values, upregulate the expression level of the oncoproteins MDM2 and CyclinD/E, and downregulate p53's expression level.

Mentions: Fig. 5 shows how mutations of ARF, P21 and FBXW7, and K-RAS influence tumor suppressor and cell cycle regulatory protein levels at 10 hours in the HMGB1 signaling pathway. We use the MDM2 degradation rate driven by ARF, dARF ( in the ODE model), to describe ARF mutations. Also, we use the Cyclin degradation rate driven by P21 (dP21 for stochastic simulation, and for ODE simulation) to describe P21 and FBXW7 mutations. Large dARF and dP21 values correspond to small mutations of ARF and P21 respectively, while small dARF and dP21 values correspond to large ARF and P21 mutations in the cell.


Analysis and verification of the HMGB1 signaling pathway.

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

Mutations of ARF, P21 and RAS affect the cell's fate. Mutations of the tumor suppressor proteins ARF and P21, and of the oncoprotein RAS affect the cell's fate, using ODE (A-C) and stochastic (D-F) simulations. The mutations of ARF (A, D) and P21 (B, E), and RAS (C, F), which correspond to small dARF and dP21, and large dRAS values, upregulate the expression level of the oncoproteins MDM2 and CyclinD/E, and downregulate p53's expression level.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Mutations of ARF, P21 and RAS affect the cell's fate. Mutations of the tumor suppressor proteins ARF and P21, and of the oncoprotein RAS affect the cell's fate, using ODE (A-C) and stochastic (D-F) simulations. The mutations of ARF (A, D) and P21 (B, E), and RAS (C, F), which correspond to small dARF and dP21, and large dRAS values, upregulate the expression level of the oncoproteins MDM2 and CyclinD/E, and downregulate p53's expression level.
Mentions: Fig. 5 shows how mutations of ARF, P21 and FBXW7, and K-RAS influence tumor suppressor and cell cycle regulatory protein levels at 10 hours in the HMGB1 signaling pathway. We use the MDM2 degradation rate driven by ARF, dARF ( in the ODE model), to describe ARF mutations. Also, we use the Cyclin degradation rate driven by P21 (dP21 for stochastic simulation, and for ODE simulation) to describe P21 and FBXW7 mutations. Large dARF and dP21 values correspond to small mutations of ARF and P21 respectively, while small dARF and dP21 values correspond to large ARF and P21 mutations in the cell.

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