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   Science 2001 Apr 20;292(5516):468-72
   
Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by
O2-regulated prolyl hydroxylation.

    Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim
    Av, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe
    PJ
    
   The Henry Wellcome Building of Genomic Medicine, University of Oxford,
   Roosevelt Drive, Oxford OX3 7BN, UK.
   
   Hypoxia-inducible factor (HIF) is a transcriptional complex that plays
   a central role in the regulation of gene expression by oxygen. In
   oxygenated and iron replete cells, HIF-alpha subunits are rapidly
   destroyed by a mechanism that involves ubiquitylation by the von
   Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. This process
   is suppressed by hypoxia and iron chelation, allowing transcriptional
   activation. Here we show that the interaction between human pVHL and a
   specific domain of the HIF-1alpha subunit is regulated through
   hydroxylation of a proline residue (HIF-1alpha P564) by an enzyme we
   have termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute
   requirement for dioxygen as a cosubstrate and iron as cofactor
   suggests that HIF-PH functions directly as a cellular oxygen sensor.
   
   PMID: 11292861, UI: 21214630
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   Nature 1999 May 20;399(6733):271-5
   
The tumour suppressor protein VHL targets hypoxia-inducible factors for
oxygen-dependent proteolysis.

    Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff
    CC, Pugh CW, Maher ER, Ratcliffe PJ
    
   Wellcome Trust Centre for Human Genetics, Oxford, UK.
   
   Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular
   responses to hypoxia, including the regulation of genes involved in
   energy metabolism, angiogenesis and apoptosis. The alpha subunits of
   HIF are rapidly degraded by the proteasome under normal conditions,
   but are stabilized by hypoxia. Cobaltous ions or iron chelators mimic
   hypoxia, indicating that the stimuli may interact through effects on a
   ferroprotein oxygen sensor. Here we demonstrate a critical role for
   the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL in
   HIF-1 regulation. In VHL-defective cells, HIF alpha-subunits are
   constitutively stabilized and HIF-1 is activated. Re-expression of
   pVHL restored oxygen-dependent instability. pVHL and HIF
   alpha-subunits co-immunoprecipitate, and pVHL is present in the
   hypoxic HIF-1 DNA-binding complex. In cells exposed to iron chelation
   or cobaltous ions, HIF-1 is dissociated from pVHL. These findings
   indicate that the interaction between HIF-1 and pVHL is iron
   dependent, and that it is necessary for the oxygen-dependent
   degradation of HIF alpha-subunits. Thus, constitutive HIF-1 activation
   may underlie the angiogenic phenotype of VHL-associated tumours. The
   pVHL/HIF-1 interaction provides a new focus for understanding cellular
   oxygen sensing.
   
   PMID: 10353251, UI: 99279691
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