Abstract
ABSTRACTA 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.
Highlights
Cellular and tissue hypoxia are an everyday occurrence that cells must respond to rapidly in order to avoid metabolic shutdown and consequent death
All mammals control the cellular response to low oxygen levels through regulation of the hypoxiainducible factor α (HIF-α) transcription factor family
PHDs hydroxylate HIF-α and target it for proteasomal degradation, which is facilitated by the binding of von Hippel-Lindau tumour suppressor protein
Summary
Cellular and tissue hypoxia are an everyday occurrence that cells must respond to rapidly in order to avoid metabolic shutdown and consequent death. The HIF-α subunit forms a nuclear heterodimeric complex with its constitutively stable counterpart HIF-β [or aryl hydrocarbon nuclear translocator (ARNT)] to transcribe target genes that contain a HIF-responsive element (HRE) in their regulatory regions (Huang et al, 1996; Kaelin and Ratcliffe, 2008; Semenza and Wang, 1992; Wenger, 2002) This year, 2015, marks the 20th anniversary of the identification of HIF-1α as the protein responsible for the cellular response to hypoxia, and since its discovery it has been implicated in disease (Wang and Semenza, 1995). Zebrafish Hif2αa and Hif-2αb are more closely related to each other than to their Hif-1α equivalents, both in terms of transcript expression levels and amino acid identity to human HIF-2α (56.1 and 53.7% amino acid identity, respectively; Rytkonen et al, 2014) Both have the two regulatory LXXLAP hydroxylation sites.
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