Type

Journal Article

Authors

Alex Cheong
Cormac T. Taylor
Boris N. Kholodenko
Mario C Manresa
Murtaza M. Tambuwala
Eoin P. Cummins
Carsten C. Scholz
Miguel A. S. Cavadas
Ulrike Bruning
Lan K. Nguyen
and 1 others

Subjects

Biology

Topics
rna small interfering fih signal transduction genetics proteasome endopeptidase complex hif1a protein human metabolism hypoxia inducible factor 1 low oxygen tension transcriptional activation proteolysis mixed function oxygenases hif 1 experimental data repressor proteins hydroxylase pharmacology hek293 cells network topology computational biology hypoxia inducible factor 1 alpha subunit hypoxia hypoxia inducible factor hif hif protein stability dynamic model oxygen models biological hif1an protein human humans mathematical model antagonists inhibitors

A dynamic model of the hypoxia-inducible factor 1 (HIF-1α) network (2013)

Abstract 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.
Collections Ireland -> University College Dublin -> Systems Biology Ireland
Ireland -> University College Dublin -> Institutes and Centres
Ireland -> University College Dublin -> SBI Research Collection

Full list of authors on original publication

Alex Cheong, Cormac T. Taylor, Boris N. Kholodenko, Mario C Manresa, Murtaza M. Tambuwala, Eoin P. Cummins, Carsten C. Scholz, Miguel A. S. Cavadas, Ulrike Bruning, Lan K. Nguyen and 1 others

Experts in our system

1
Alex Cheong
University College Dublin
Total Publications: 18
 
2
Cormac T. Taylor
University College Dublin
Total Publications: 110
 
3
Boris N. Kholodenko
University College Dublin
Total Publications: 82
 
4
Mario C Manresa
University College Dublin
Total Publications: 8
 
5
Murtaza M. Tambuwala
University College Dublin
Total Publications: 12
 
6
Eoin P. Cummins
University College Dublin
Total Publications: 53
 
7
Carsten C Scholz
University College Dublin
Total Publications: 21
 
8
Miguel A S Cavadas
University College Dublin
Total Publications: 13
 
9
Ulrike Bruning
University College Dublin
Total Publications: 10
 
10
Lan K Nguyen
University College Dublin
Total Publications: 33