title: Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling.
abstract: Hypoxia is a common micro-environmental stress which is experienced by cells during a range of physiologic and pathophysiologic processes. The identification of the hypoxia-inducible factor (HIF) as the master regulator of the transcriptional response to hypoxia transformed our understanding of the mechanism underpinning the hypoxic response at the molecular level and identified HIF as a potentially important new therapeutic target. It has recently become clear that multiple levels of regulatory control exert influence on the HIF pathway giving the response a complex and dynamic activity profile. These include positive and negative feedback loops within the HIF pathway as well as multiple levels of crosstalk with other signaling pathways. The emerging model reflects a multi-level regulatory network that affects multiple aspects of the physiologic response to hypoxia including proliferation, apoptosis, and differentiation. Understanding the interplay between the molecular mechanisms involved in the dynamic regulation of the HIF pathway at a systems level is critically important in defining new appropriate therapeutic targets for human diseases including ischemia, cancer, and chronic inflammation. Here, we review our current knowledge of the regulatory circuits which exert influence over the HIF response and give examples of in silico model-based predictions of the dynamic behaviour of this system.
authors.affiliation: Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. zsolt.fabian@ucd.ie.
authors.forename: Zsolt
authors.identifier: http://orcid.org/0000-0002-4973-9872
authors.initials: Z
authors.lastname: Fábián
authors.affiliation: Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.|Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Cormac T
authors.initials: CT
authors.lastname: Taylor
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland. lan.k.nguyen@monash.edu.|Department of Biochemistry and Molecular Biology, School of Biomedical Sciences and Biomedical Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia. lan.k.nguyen@monash.edu.
authors.forename: Lan K
authors.initials: LK
authors.lastname: Nguyen
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D064828:Prolyl Hydroxylases / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D049490:Systems Biology / Q000379:methods
chemical_list: D002352:Carrier Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D035683:MicroRNAs; D016328:NF-kappa B; D064828:Prolyl Hydroxylases
keywords: Hypoxia; Inflammation; Keywords; Mathematical model; Signal transduction
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