title: A dynamic model of the hypoxia-inducible factor 1α (HIF-1α) network.
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.
authors: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
authors: Lan K
authors: LK
authors: Nguyen
authors: Miguel A S
authors: MA
authors: Cavadas
authors: Carsten C
authors: CC
authors: Scholz
authors: Susan F
authors: SF
authors: Fitzpatrick
authors: Ulrike
authors: U
authors: Bruning
authors: Eoin P
authors: EP
authors: Cummins
authors: Murtaza M
authors: MM
authors: Tambuwala
authors: Mario C
authors: MC
authors: Manresa
authors: Boris N
authors: BN
authors: Kholodenko
authors: Cormac T
authors: CT
authors: Taylor
authors: Alex
authors: A
authors: Cheong
mesh_terms: D019295:Computational Biology; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; D046988:Proteasome Endopeptidase Complex; D010100:Oxygen
keywords: FIH; HIF; Hydroxylase; Hypoxia; Mathematical model