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

Nguyen, Lan K, Cavadas, Miguel AS, Scholz, Carsten C, Fitzpatrick, Susan F, Bruning, Ulrike, Cummins, Eoin P, Tambuwala, Murtaza, Manres, Mario C, Kholodenko, Boris N, Taylor, Cormac T and Cheong, Alex (2013) A dynamic model of the hypoxia-inducible factor 1 (HIF-1 ) network. Journal of Cell Science, 126 (6). p. 1454. [Journal article]

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URL: http://dx.doi.org/10.1242/jcs.119974

DOI: doi:10.1242/jcs.119974

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.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Pharmacy & Pharmaceutical Sciences
ID Code:26694
Deposited By: Dr Murtaza Tambuwala
Deposited On:21 Aug 2013 13:50
Last Modified:17 Oct 2017 16:10

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