English

Abstract

Introduction Hypoxia-inducible factor is a key transcriptional factor involved in the cellular response to low levels of oxygen, hypoxia. Moreover, hypoxiainducible factor has been recently associated with a role in inflammation and immunity. Importantly, hypoxiainducible factor is regulated by the major inflammatory responsive transcription factor, nuclear factor-κB. These two major pathways have been intimately linked. On one hand, they share a number of common target genes; on the other hand, physical interactions between hypoxiainducible factor subunits and nuclear factor-κB have been observed. Even though the role of nuclear factor-κB over hypoxia-inducible factor is fairly well-known, the involvement of hypoxia-inducible factor over the nuclear factor-κB pathway is not. Given the overlap between these pathways, it would not be surprising to find a functional involvement of hypoxiainducible factor in processes where nuclear factor-κB is involved. In this review, we will describe the communalities between hypoxia-inducible factor and nuclear factor-κB pathways, highlighting the crosstalk that occurs in a variety of conditions. Conclusion Taken together all the communalities between hypoxia-inducible factor and nuclear factor-κB pathways, there is no doubt that a crosstalk occurs, which can potentially bring new insights for therapeutic intervention in situations of disease such as cancer, stroke or rheumatoid arthritis. Introduction Oxygen is essential for multicellular organisms. As such, being able to respond to variations in oxygen availability is a requirement for the survival and homoeostasis of the organism. Sensing and responding appropriately to oxygen changes is important for a variety of important physiological processes, which include high altitude living, intense exercise and embryo development. However, lowering of the oxygen concentration or availability (hypoxia) is part and/or contributes to a number of human pathologies, such as cancer, stroke/infarction, diabetes and ageing1–2. Understanding the molecular mechanisms controlling the cellular response to hypoxia is, therefore, of great importance. One master regulator of the cellular response to oxygen changes is the family of transcription factors, hypoxia-inducible factor (HIF). However, HIF activity has been associated with additional stimuli that do not involve changes in oxygen, such as infection and inflammation3. These findings led to the discovery that HIF is controlled by a transcription factor, mostly involved in immune responses, nuclear factorκB (NF-κB). In this review, we will highlight the shared features of these transcription factors, from activating stimulus to common targets. Discussion The authors have referenced some of their own studies in this review. The protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed. HIF pathway At the molecular level, the cellular response to hypoxia relies on HIF. HIF was first identified in 1995 together with hypoxia response element (HRE, 5ʹ-RCGTG-3ʹ) of the erythropoietin gene (EPO). Further studies revealed that HIF is actually a heterodimeric complex comprising an αand a β-subunit, which exist as a series of isoforms: -1α, -2α, and 3α. HIF-1α is constitutively expressed, while HIF-2α and HIF-3α expression is restricted to a subset of tissues. Even though HIF-1β expression and protein are not dependent on oxygen changes, HIF-α subunits are extremely labile at normal oxygen levels. This occurs mostly at the protein level, with HIF-α half-life being very short (~ 5 min), while transcription changes in response to oxygen have not been widely reported thus far. The activity of the complex HIF-1α– HIF-1β is determined by the stabilisation of the α subunit during hypoxia. In the presence of oxygen (normoxia), HIF-α is regulated by a class of dioxygenases called prolyl hydroxylases (PHDs), of which four isoforms have been identified so far (PHD1, PHD2, PHD3 and PHD4). These proteins use iron, 2-oxoglutarate, ascorbate and molecular oxygen as co-factors to catalyse the hydroxylation of HIF-α. The hydroxylation of specific prolyl residues promotes the interaction of HIF with von Hippel-Lindauprotein (VHL) containing E3 ligase complex, which mediates proteasomalmediated * Corresponding author Email: s.rocha@dundee.ac.uk Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow street, DD1 5EH, United Kingdom