title: Analysis and verification of the HMGB1 signaling pathway.
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.
authors.affiliation: Computer Science Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA. haijung@cs.cmu.edu
authors.forename: Haijun
authors.initials: H
authors.lastname: Gong
authors.forename: Paolo
authors.initials: P
authors.lastname: Zuliani
authors.forename: Anvesh
authors.initials: A
authors.lastname: Komuravelli
authors.forename: James R
authors.initials: JR
authors.lastname: Faeder
authors.forename: Edmund M
authors.initials: EM
authors.lastname: Clarke
mesh_terms: D017209:Apoptosis; D049109:Cell Proliferation; D003198:Computer Simulation; D015972:Gene Expression Regulation, Neoplastic; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000503:physiopathology; D015513:Oncogene Proteins / Q000235:genetics; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D024243:HMGB1 Protein; D015513:Oncogene Proteins; D025521:Tumor Suppressor Proteins