Hypoxia, a condition characterized by inadequate oxygen supply to tissues, triggers a series of adaptive responses aimed at maintaining cellular survival and function. Central to the response to hypoxia is the hypoxia-inducible factor (HIF) family of transcription factors. HIFs consist of an oxygen-sensitive alpha subunit (HIF-α) and a constitutively expressed beta subunit (HIF-β). Under normoxia (normal oxygen levels), HIF-α is hydroxylated by prolyl hydroxylase enzymes (PHDs), leading to its degradation. Here, hydroxylated proline residues on HIF-α are first recognized by the Von Hippel-Lindau (VHL) protein which acts as a substrate recognition component of an E3 ubiquitin ligase complex targeting HIF-α for ubiquitination and subsequent degradation by the proteasome. Prolyl hydroxylase domain (PHD) enzymes, specifically prolyl hydroxylases (PHD1, PHD2, and PHD3), use molecular oxygen and cofactors (iron and ascorbate) to catalyse the hydroxylation of proline residues within the oxygen-dependent degradation domain (ODD) of HIF-α. Thus, reduced oxygen availability hinders HIF hydroxylation, leading to HIF-α accumulation and translocation into the nucleus. In the nucleus, HIF-α forms a complex with HIF-β and additional coactivators. This complex binds to hypoxia-response elements (HREs) in the promoters of target genes, activating their transcription. HIF-regulated genes encode proteins involved in various adaptive responses. For example, hypoxia induces the expression of vascular endothelial growth factor (VEGF) and angiopoietin 2, promoting angiogenesis (new blood vessel formation) to enhance oxygen delivery. HIF also increases the production of erythropoietin (EPO), a hormone that stimulates red blood cell production in the bone marrow, increasing oxygen-carrying capacity. To promote energy production, HIFs enhance the expression of glycolytic enzymes, promoting anaerobic metabolism. This adaptation generates energy without relying on oxygen-dependent processes like oxidative phosphorylation. HIF can also modulate the expression of members of the Bcl-2 family of proteins, which play a critical role in regulating the intrinsic apoptotic pathway, and the survival factor IGF-1, aiding cell survival in low-oxygen conditions. Finally, HIFs influence metabolic pathways, promoting the utilization of alternative energy sources, such as glutamine metabolism, to sustain cellular function. HIF signalling also interacts with other signalling pathways. For instance, AKT activation can stabilize HIF-1α by inhibiting its prolyl hydroxylation, allowing it to accumulate even in normoxic conditions. Furthermore, HIFs interact with inflammation-related pathways, influencing immune responses and tissue repair. NF-κB activation, typically triggered by inflammatory stimuli, can impact HIF-1α stability. In some cases, NF-κB activation can stabilize HIF-1α by inhibiting its degradation through mechanisms involving the inhibitor of κB (IκB) kinase complex. Whilst hypoxia adaptation via HIF-regulated changes in gene expression is essential for survival under low oxygen conditions, its dysregulation can also contribute to various diseases. Chronic HIF activation, seen in solid tumours, can promote angiogenesis, tumour growth, and metastasis, whilst in cardiovascular diseases, hypoxia-driven vascular remodelling can also lead to adverse outcomes. Finally, aside from HIF, the AMP-Activated Protein Kinase (AMPK) an energy-sensing enzyme that is generally activated under conditions of cellular energy stress, is also activated during hypoxia. AMPK helps maintain energy balance by promoting ATP production whilst inhibiting energy-consuming processes, influencing gene expression and cellular metabolism. We offer a comprehensive product range of research reagents for investigating hypoxia, including CD73 antibodies, Carbonic Anhydrase IX antibodies, ADFP antibodies, HIF-1 alpha ELISA Kits, and Visfatin ELISA Kits. Explore our full hypoxia product range below and discover more, for less. Alternatively, you can explore our Associated Proteins product range.