Nguyen, Lan K., Cavadas, Miguel A.S., Scholz, Carsten C., Fitzpatrick, Susan F., Bruning, Ulrike, Cummins, Eoin P., Tambuwala, Murtaza M., Manresa, Mario C., Kholodenko, Boris N., Taylor, Cormac T. and Cheong, Alex (2013). A dynamic model of the hypoxia-inducible factor 1α (HIF-1α) network. Journal of Cell Science, 126 (6), pp. 1454-1463.
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-1a 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-1a 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-1a transcriptional activity, but paradoxically decreases HIF-1a 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-1a to proteosomal degradation. Thus, through in vitro experimental data and in silico predictions, we provide a comprehensive model of the dynamic regulation of HIF-1a transcriptional activity by hydroxylases and use its predictive and adaptive properties to explain counter-intuitive biological observations.
Publication DOI: | https://doi.org/10.1242/jcs.119974 |
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Divisions: | College of Health & Life Sciences > Aston Pharmacy School College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine |
Additional Information: | © 2013. Published by The Company of Biologists Ltd. Non-commercial use Correction: Nguyen, L. K., Cavadas, M. A. S., Scholz, C. C., Fitzpatrick, S. F., Bruning, U., Cummins, E. P., ... Cheong, A. (2015). A dynamic model of the hypoxia-inducible factor 1a (HIF-1a) network. Journal of cell science, 128(2), 422. 10.1242/jcs.167304 |
Uncontrolled Keywords: | hypoxia,HIF,FIH,hydroxylase,mathematical model |
Publication ISSN: | 1477-9137 |
Last Modified: | 05 Aug 2024 12:15 |
Date Deposited: | 30 Sep 2013 09:30 |
Full Text Link: | |
Related URLs: |
http://jcs.biol ... tent/126/6/1454
(Publisher URL) http://jcs.biol ... ntent/128/2/422 (Publisher URL) |
PURE Output Type: | Article |
Published Date: | 2013-03-15 |
Published Online Date: | 2013-02-06 |
Authors: |
Nguyen, Lan K.
Cavadas, Miguel A.S. Scholz, Carsten C. Fitzpatrick, Susan F. Bruning, Ulrike Cummins, Eoin P. Tambuwala, Murtaza M. Manresa, Mario C. Kholodenko, Boris N. Taylor, Cormac T. Cheong, Alex ( ![]() |