FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor.

By D. Lando, D. Peet, J. Gorman, Dean A Whelan, M. Whitelaw, R. Bruick. Genes & Development, 2002

1,611 citations recorded by the source corpus.

Mammalian cells adapt to hypoxic conditions through a transcriptional response pathway mediated by the hypoxia-inducible factor, HIF. HIF transcriptional activity is suppressed under normoxic conditions by hydroxylation of an asparagine residue within its C-terminal transactivation domain, blocking association with coactivators. Here we show that the protein FIH-1, previously shown to interact with HIF, is an asparaginyl hydroxylase. Like known hydroxylase enzymes, FIH-1 is an Fe(II)-dependent enzyme that uses molecular O(2) to modify its substrate. Together with the recently discovered prolyl hydroxylases that regulate HIF stability, this class of oxygen-dependent enzymes comprises critical regulatory components of the hypoxic response pathway.

Subfields: Cancer Research, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/fd6faa2194e9ab377a593a77b17cc8f9e21f4f68

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In Cancer Research

1. G. Semenza
2. C. V. Dang
3. M. C. Simon
4. J. Pouysségur
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8. M. Brahimi-Horn

In Genetics

1. G. Semenza
2. C. V. Dang
3. M. C. Simon
4. J. Espinosa
5. V. L. Dengler
6. M. Galbraith
7. Richard J. Johnson
8. J. Pouysségur

In Molecular Biology

1. G. Semenza
2. C. V. Dang
3. M. C. Simon
4. J. Pouysségur
5. J. Chiche
6. P. Ratcliffe
7. Yi Zhang
8. Jung-whan Kim

Citations in the corpus

• Hypoxia signalling in cancer and approaches to enforce tumour regression (2006, background): “The second type of oxygen sensor controlling the hypoxic response is an asparaginyl hydroxylase, referred to as factor inhibiting HIF-1 (FIH”
• Oxygen sensing by HIF hydroxylases (2004, background): “Like prolyl hydroxylation, HIF asparaginyl hydroxylation is also catalysed by a member of the 2-oxoglutarate-dependent-oxygenase superfamily, but one that is significantly different in sequence to the PHD”
• ADAPTIVE AND MALADAPTIVE CARDIORESPIRATORY RESPONSES TO CONTINUOUS AND INTERMITTENT HYPOXIA MEDIATED BY HYPOXIA-INDUCIBLE FACTORS 1 AND 2 (2012, neutral): “FIH-1 is the asparaginyl hydroxylase (180).”
• HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. (2007, positive): “The interaction of HIF-1 a with the coactivators CBP and p300 is blocked by O 2 -dependent aspar-aginyl hydroxylation mediated by FIH-1 (Lando et al., 2002).”
• Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. (2016, methodology): “To this end, ENMD-1198 has been selected as a lead analog (LaVallee et al., 2008) and has been tested in a phase I dose-escalation study in advanced cancer patients (Zhou et al., 2011).”
• The N-Terminal Transactivation Domain Confers Target Gene Specificity of Hypoxia-inducible Factors HIF-1α and HIF-2α (2007, background): “4528 © 2007 by The American Society for Cell Biology transcriptional activity of both C-TADs is regulated by “factor inhibiting HIF” (FIH)-mediated hydroxylation of a conserved asparagine amino acid that blocks the recruitment of transcriptional coactivators p300 and CBP (Ema et al., 1997; Flamme et”
• Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases (2011, positive): “In addition to PHDs, the stability and steady-state levels of HIF-1a protein are also regulated by FIH-1 (factor inhibiting HIF-1a) (Lando et al., 2002; Mahon et al., 2001), an asparaginyl hydrogenase whose activity is dependent on a-KG and could therefore also be affected by reduced function of IDH”
• Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. (2010, background): “C-TAD recruits p300/ CBP to facilitate transcription, which is inhibited by FIH in normoxia (Lando et al., 2002).”
• Redox Regulation of Cell Survival (2008, positive): “Under normoxia, FIH-1 hydroxylates an N-terminal asparagines residue and renders HIF inactive by preventing the binding between HIF and its coactivators (175).”
• Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium. (2008, background): “asparagine 803 hydroxylation, which allows for complex formation between HIF-1α and the CBP and p300 transcriptional co-activators, regulates transactivation of HIF-dependent genes (49,50).”