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Hypoxia Inducible Factor 1 alpha (HIF-1alpha) was discovered in the early nineties as the transcription factor responsible for the induction of the erythropoietin gene in response to low oxygen availability . Subsequent individual gene studies  revealed that HIF1-alpha is the major transcription factor controlling the gene expression programme that is activated when cellular oxygen demand exceed its supply, a condition known as hypoxia. HIF1-alpha belongs to the basic helix-loop-helix (bHLH) class of transcription factors and binds DNA as an heterodimer together with another bHLH member, the protein ARNT . In spite of ARNT being an essential component of the functional HIF transcription factor complex, the oxygen sensitivity is mediated by HIF1-alpha only. Oxygen regulates both HIF-1alpha protein half-life  and transactivation potential . In the presence of oxygen, HIF1-alpha binds to the protein pVHL which forms part of an E3 ubiquitin ligase complex that targets HIF1-alpha for proteasomal degradation . Importantly, the interaction between HIF1-alpha and VHL is strictly dependent on the hydroxylation of specific proline residues in HIF1-alpha  and this post-translational modification is only present under normoxic conditions since the enzymes responsible for it (termed EGLNs or PHDs) require molecular oxygen as cosubstrate for the hydroxylation reaction . Thus, under reduced oxygen availability, the activity of the EGLNs enzymes is compromised and, as a consequence, HIF1-alpha avoids hydroxylation and escapes degradation. A similar mechanism, involving the oxygen-dependent interaction between HIF1A and the p300/CBP , accounts for the enhanced transactivation potential of HIF1-alpha during hypoxia. The resulting net effect is the induction of a large number of genes  that mediate the cellular and systemic adaptations to hypoxia. Among these HIF-mediated adaptive responses is the aforementioned induction of erythropoiesis  that, together with the induccion of angiogenesis  and the regulation of iron homeostasis  aims to enhance oxygen delivery to hypoxic tissues. On the other hand, HIF1A promotes an extensive reprogramming of the metabolic networks that results in a reduction of the cellular oxygen consumption rate while maintaining ATP production . Interestingly, the link between HIF1-alpha and metabolism seems to be bidirectional as HIF regulates targets involved in these processes and, at the same time, metabolic intermediates  and electron transport chain-derived ROS  induce HIF activity by inhibiting the EGLNs. Thus there is a profound connection between the HIF pathway and cellular metabolism. The central role of HIF1A in the adaptation to hypoxia is highlighted by the conservation of the HIF pathway in metazoans  and inability of HIF1A-deficient animals to adapt to hypoxia . Finally, tissue hypoxia is a common feature in the progression of a variety of pathologies including cardiovascular and respiratory diseases, inflammation and cancer among others . Thus, given the central role of the HIF pathway in the response to reduced oxygenation, it constitutes an attractive target for the development of novel approaches to treat these prevalent diseases.
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FIGURE 1 HIF1-alpha structure and model of the regulation of HIF by oxygen
A. Diagram depicting HIF1-alpha structure. BHLH, basic Helix-Loop-Helix; ODDD, Oxygen-dependent degradation domain; PAS, Per-ARNT-Sim domain; TAD, Transactivation domain. P402 and P564 represent the position of the proline residues that became hydroxylated in the presence of oxygen. N803, represent the position of the Asparagine residue whose hydroxylation under normoxia interferes with p300/CBP binding.
B. In the presence of oxygen the dioxigenases EGLN and FIH catalyze the hydroxylation of HIF1-alpha Pro402/Pro564 and Asn803 residues respectively. The hydroxylation of the prolines allows the binding of pVHL that, being part of an E3-ubiquitin ligase complex, targets HIF for proteasomal degradation. As a consequence of this reactions, normoxic level of HIF1-alpha are extremely low. On the other hand, Asn803 hydroxylation prevents the binding of p300/CBP to the CTAD blunting its transcriptional activity. Under limiting oxygen conditions, the catalytic activity of EGLNs (PHDs) and FIH is compromised so HIF1-alpha escapes degradation and accumulates in the cell nuclei where it forms a complex with ARNT, p300/CBP at the RCGTC motifs in the regulatory regions of target genes. A non-comprehensive list of target genes it shown to illustrate the major role of HIF in the response to hypoxia through metabolic reprogramming and restoration of oxygen delivery.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.
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