Nguyen2013 - Dynamic model of HIF regulation in hypoxia

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Model Identifier
MODEL1912100004
Short description 
Its a mathematcial model explaining regulation of HIF via FIH and oxygen. Model is further validated by Experimental data and various hypothesis has been tested on the same.
Format
SBML (L2V4)
Related Publication
  • A dynamic model of the hypoxia-inducible factor 1α (HIF-1α) network.
  • Nguyen LK, Cavadas MA, Scholz CC, Fitzpatrick SF, Bruning U, Cummins EP, Tambuwala MM, Manresa MC, Kholodenko BN, Taylor CT, Cheong A
  • Journal of cell science , 3/ 2013 , Volume 126 , Issue Pt 6 , pages: 1454-1463 , PubMed ID: 23390316
  • Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
  • Activation of the hypoxia-inducible factor (HIF) pathway is a critical step in the transcriptional response to hypoxia. Although many of the key proteins involved have been characterised, the dynamics of their interactions in generating this response remain unclear. In the present study, we have generated a comprehensive mathematical model of the HIF-1α pathway based on core validated components and dynamic experimental data, and confirm the previously described connections within the predicted network topology. Our model confirms previous work demonstrating that the steps leading to optimal HIF-1α transcriptional activity require sequential inhibition of both prolyl- and asparaginyl-hydroxylases. We predict from our model (and confirm experimentally) that there is residual activity of the asparaginyl-hydroxylase FIH (factor inhibiting HIF) at low oxygen tension. Furthermore, silencing FIH under conditions where prolyl-hydroxylases are inhibited results in increased HIF-1α transcriptional activity, but paradoxically decreases HIF-1α stability. Using a core module of the HIF network and mathematical proof supported by experimental data, we propose that asparaginyl hydroxylation confers a degree of resistance upon HIF-1α to proteosomal degradation. Thus, through in vitro experimental data and in silico predictions, we provide a comprehensive model of the dynamic regulation of HIF-1α transcriptional activity by hydroxylases and use its predictive and adaptive properties to explain counter-intuitive biological observations.
Contributors
Submitter of the first revision: Krishna Kumar Tiwari
Submitter of this revision: Krishna Kumar Tiwari
Modellers: Krishna Kumar Tiwari

Metadata information

hasTaxon (1 statement)
Taxonomy Homo sapiens

hasProperty (1 statement)
Mathematical Modelling Ontology Ordinary differential equation model

Curation status
Non-curated
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Model files
Nguyen2013_HIF.xml SBML L2V4 model file for Nguyen2013 198.59 KB Preview | Download

Additional files
Nguyen2013_HIF.cps COPASI 4.27 (build217) model for Nguyen2013 227.52 KB Preview | Download
Nguyen2013_HIF.sedml SEDML file for Nguyen2013 25.93 KB Preview | Download

  • Model originally submitted by : Krishna Kumar Tiwari
  • Submitted: Dec 10, 2019 4:30:15 PM
  • Last Modified: Dec 10, 2019 4:30:15 PM
Revisions
  • Version: 1 public model Download this version
    • Submitted on: Dec 10, 2019 4:30:15 PM
    • Submitted by: Krishna Kumar Tiwari
    • With comment: Import of Nguyen2013 - Dynamic model of HIF regulation in hypoxia