2001
DOI: 10.1126/science.1066373
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A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF

Abstract: Mammalian cells respond to changes in oxygen availability through a conserved pathway that is regulated by the hypoxia-inducible factor (HIF). The alpha subunit of HIF is targeted for degradation under normoxic conditions by a ubiquitin-ligase complex that recognizes a hydroxylated proline residue in HIF. We identified a conserved family of HIF prolyl hydoxylase (HPH) enzymes that appear to be responsible for this posttranslational modification. In cultured mammalian cells, inappropriate accumulation of HIF ca… Show more

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Cited by 2,320 publications
(1,873 citation statements)
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References 27 publications
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“…Hypoxia-inducible factor PHDs hydroxylate the two specific proline residues pro 402 or pro 564 (amino-acid positions designated in humans) within the oxygen degradation domain (ODD) of HIF-1a (Bruick and McKnight, 2001;Kaelin and Ratcliffe, 2008). Hydroxylation of HIF-1a allows it to bind to the VHL (Von Hippel Lindau) tumor suppressor protein that acts as a recognition component of E3 ubiquitin ligase complex.…”
Section: Hypoxia-inducible Factor Family Transcription Factorsmentioning
confidence: 99%
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“…Hypoxia-inducible factor PHDs hydroxylate the two specific proline residues pro 402 or pro 564 (amino-acid positions designated in humans) within the oxygen degradation domain (ODD) of HIF-1a (Bruick and McKnight, 2001;Kaelin and Ratcliffe, 2008). Hydroxylation of HIF-1a allows it to bind to the VHL (Von Hippel Lindau) tumor suppressor protein that acts as a recognition component of E3 ubiquitin ligase complex.…”
Section: Hypoxia-inducible Factor Family Transcription Factorsmentioning
confidence: 99%
“…Hypoxia-inducible factor prolyl hydroxylase domain enzymes regulate many substrates in the adaptive hypoxic response Prolyl hydroxylation is the most well-studied regulator for HIF levels and is catalyzed by nonheme iron dioxygenases known as the HIF PHDs (Bruick and McKnight, 2001). In addition to iron, HIF PHD's also require 2-oxoglutarate.…”
Section: Hypoxia-inducible Factor Family Transcription Factorsmentioning
confidence: 99%
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“…The HIF prolyl-4-hydroxylase domain proteins, PHD1, 2 and 3 are responsible for normoxic HIF-a proteolysis. Prolyl-4-hydroxylation is necessary for the interaction with the von Hippel-Lindau tumor suppressor protein (pVHL) that mediates HIF-a degradation (Maxwell et al, 1999;Bruick and McKnight, 2001;Epstein et al, 2001;Jaakkola et al, 2001;Ivan et al, 2002).…”
Section: Introductionmentioning
confidence: 99%
“…This interaction induces the ubiquitination of HIF-α, wherein HIF-α becomes targeted for degradation by the proteasome. HIF-α proline hydroxylation is carried out by three enzymes (EGLN1, EGLN2 or EGLN3) that require oxygen, iron and 2-oxoglutarate (Bruick et al, 2001;Epstein et al, 2001) which have been proposed to function as oxygen sensors that directly regulate HIF-1α stability.…”
Section: Introductionmentioning
confidence: 99%