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occurs in: http://identifiers.org/taxonomy/9606
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name: Schmierer2010_FIH_Ankyrins
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is described by: http://identifiers.org/pubmed/20955552
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is version of: GO:0001666
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notes: This a model from the article: Hypoxia-dependent sequestration of an oxygen sensor by a widespread structural motif can shape the hypoxic response - a predictive kinetic model Bernhard Schmierer, Béla Novák1 and Christopher J Schofield BMC Systems Biology 2010, 4:139 20955552 , Abstract: Background The activity of the heterodimeric transcription factor hypoxia inducible factor (HIF) is regulated by the post-translational, oxygen-dependent hydroxylation of its α-subunit by members of the prolyl hydroxylase domain (PHD or EGLN)-family and by factor inhibiting HIF (FIH). PHD-dependent hydroxylation targets HIFα for rapid proteasomal degradation; FIH-catalysed asparaginyl-hydroxylation of the C-terminal transactivation domain (CAD) of HIFα suppresses the CAD-dependent subset of the extensive transcriptional responses induced by HIF. FIH can also hydroxylate ankyrin-repeat domain (ARD) proteins, a large group of proteins which are functionally unrelated but share common structural features. Competition by ARD proteins for FIH is hypothesised to affect FIH activity towards HIFα; however the extent of this competition and its effect on the HIF-dependent hypoxic response are unknown. Results To analyse if and in which way the FIH/ARD protein interaction affects HIF-activity, we created a rate equation model. Our model predicts that an oxygen-regulated sequestration of FIH by ARD proteins significantly shapes the input/output characteristics of the HIF system. The FIH/ARD protein interaction is predicted to create an oxygen threshold for HIFα CAD-hydroxylation and to significantly sharpen the signal/response curves, which not only focuses HIFα CAD-hydroxylation into a defined range of oxygen tensions, but also makes the response ultrasensitive to varying oxygen tensions. Our model further suggests that the hydroxylation status of the ARD protein pool can encode the strength and the duration of a hypoxic episode, which may allow cells to memorise these features for a certain …
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curated: true
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name: vPH H
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W3 CDTF: Tue Aug 17 15:11:32 BST 2010

W3 CDTF: Mon Jan 17 16:04:56 GMT 2011

ORG:
  orgname: EMBL-EBI
n:
  given: Vijayalakshmi
  family: Chelliah

ORG:
  orgname: Developmental Signalling Lab, Cancer Research UK London Research Institute
n:
  given: Bernhard
  family: Schmierer