title: Exploring the HIFs, buts and maybes of hypoxia signalling in disease: lessons from zebrafish models.
abstract: A low level of tissue oxygen (hypoxia) is a physiological feature of a wide range of diseases, from cancer to infection. Cellular hypoxia is sensed by oxygen-sensitive hydroxylase enzymes, which regulate the protein stability of hypoxia-inducible factor α (HIF-α) transcription factors. When stabilised, HIF-α binds with its cofactors to HIF-responsive elements (HREs) in the promoters of target genes to coordinate a wide-ranging transcriptional programme in response to the hypoxic environment. This year marks the 20th anniversary of the discovery of the HIF-1α transcription factor, and in recent years the HIF-mediated hypoxia response is being increasingly recognised as an important process in determining the outcome of diseases such as cancer, inflammatory disease and bacterial infections. Animal models have shed light on the roles of HIF in disease and have uncovered intricate control mechanisms that involve multiple cell types, observations that might have been missed in simpler in vitro systems. These findings highlight the need for new whole-organism models of disease to elucidate these complex regulatory mechanisms. In this Review, we discuss recent advances in our understanding of hypoxia and HIFs in disease that have emerged from studies of zebrafish disease models. Findings from such models identify HIF as an integral player in the disease processes. They also highlight HIF pathway components and their targets as potential therapeutic targets against conditions that range from cancers to infectious disease.
authors.affiliation: Department of Infection and Immunity, Medical School, The University of Sheffield, Sheffield, S10 2RX, UK The Bateson Centre, The University of Sheffield, Sheffield, S10 2TN, UK p.elks@sheffield.ac.uk.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Elks
authors.affiliation: Department of Infection and Immunity, Medical School, The University of Sheffield, Sheffield, S10 2RX, UK The Bateson Centre, The University of Sheffield, Sheffield, S10 2TN, UK.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Renshaw
authors.affiliation: Institute of Biology, Leiden University, 2333 CC Leiden, The Netherlands.
authors.forename: Annemarie H
authors.initials: AH
authors.lastname: Meijer
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, EH16 4TJ, UK.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Walmsley
authors.affiliation: The Bateson Centre, The University of Sheffield, Sheffield, S10 2TN, UK.
authors.forename: Fredericus J
authors.initials: FJ
authors.lastname: van Eeden
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D060833:Cellular Microenvironment; D015195:Drug Design; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D023421:Models, Animal; D058990:Molecular Targeted Therapy; D010100:Oxygen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D014157:Transcription Factors; D029961:Zebrafish Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C000630526:arnt protein, zebrafish
keywords: Disease models; Hypoxia; Hypoxia-inducible factor; Zebrafish