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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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Schematic view of HMGB1 signal transduction. Blue nodes represent tumor suppressor proteins; red nodes represent oncoproteins/lipids; brown node represents protein complex formed by oncoprotein E2F and tumor suppressor protein RB. Solid lines with arrows denote protein transcription, degradation or changes of molecular species; dashed lines with arrows denote activation processes.
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Figure 1: Schematic view of HMGB1 signal transduction. Blue nodes represent tumor suppressor proteins; red nodes represent oncoproteins/lipids; brown node represents protein complex formed by oncoprotein E2F and tumor suppressor protein RB. Solid lines with arrows denote protein transcription, degradation or changes of molecular species; dashed lines with arrows denote activation processes.

Mentions: Our HMGB1 signaling pathway model is illustrated in Fig. 1. It includes 31 molecular species (6 tumor suppressor proteins), 59 chemical reactions, and three different signaling pathways activated by HMGB1: the RAS-ERK, Rb-E2F and p53-MDM2 pathways. Since the interaction between HMGB1 and its receptors TLR and RAGE is not clear at the mechanistic level, RAGE is used to represent all the receptors in our model in order to reduce the number of unknown parameters. We now briefly discuss the three pathways and their crosstalk. We denote activation (or promotion) by →, while inhibition (or repression) is denoted by ⊣.


Analysis and verification of the HMGB1 signaling pathway.

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

Schematic view of HMGB1 signal transduction. Blue nodes represent tumor suppressor proteins; red nodes represent oncoproteins/lipids; brown node represents protein complex formed by oncoprotein E2F and tumor suppressor protein RB. Solid lines with arrows denote protein transcription, degradation or changes of molecular species; dashed lines with arrows denote activation processes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Schematic view of HMGB1 signal transduction. Blue nodes represent tumor suppressor proteins; red nodes represent oncoproteins/lipids; brown node represents protein complex formed by oncoprotein E2F and tumor suppressor protein RB. Solid lines with arrows denote protein transcription, degradation or changes of molecular species; dashed lines with arrows denote activation processes.
Mentions: Our HMGB1 signaling pathway model is illustrated in Fig. 1. It includes 31 molecular species (6 tumor suppressor proteins), 59 chemical reactions, and three different signaling pathways activated by HMGB1: the RAS-ERK, Rb-E2F and p53-MDM2 pathways. Since the interaction between HMGB1 and its receptors TLR and RAGE is not clear at the mechanistic level, RAGE is used to represent all the receptors in our model in order to reduce the number of unknown parameters. We now briefly discuss the three pathways and their crosstalk. We denote activation (or promotion) by →, while inhibition (or repression) is denoted by ⊣.

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