[HTML][HTML] HIF prolyl‐hydroxylase 2 is the key oxygen sensor setting low steady‐state levels of HIF‐1α in normoxia

E Berra, E Benizri, A Ginouvès, V Volmat, D Roux… - The EMBO …, 2003 - embopress.org
E Berra, E Benizri, A Ginouvès, V Volmat, D Roux, J Pouysségur
The EMBO journal, 2003embopress.org
Hypoxia‐inducible factor (HIF), a transcriptional complex conserved from Caenorhabditis
elegans to vertebrates, plays a pivotal role in cellular adaptation to low oxygen availability.
In normoxia, the HIF‐α subunits are targeted for destruction by prolyl hydroxylation, a
specific modification that provides recognition for the E3 ubiquitin ligase complex containing
the von Hippel–Lindau tumour suppressor protein (pVHL). Three HIF prolyl‐hydroxylases
(PHD1, 2 and 3) were identified recently in mammals and shown to hydroxylate HIF‐α …
Hypoxia‐inducible factor (HIF), a transcriptional complex conserved from Caenorhabditis elegans to vertebrates, plays a pivotal role in cellular adaptation to low oxygen availability. In normoxia, the HIF‐α subunits are targeted for destruction by prolyl hydroxylation, a specific modification that provides recognition for the E3 ubiquitin ligase complex containing the von Hippel–Lindau tumour suppressor protein (pVHL). Three HIF prolyl‐hydroxylases (PHD1, 2 and 3) were identified recently in mammals and shown to hydroxylate HIF‐α subunits. Here we show that specific ‘silencing’of PHD2 with short interfering RNAs is sufficient to stabilize and activate HIF‐1α in normoxia in all the human cells investigated.‘Silencing’of PHD1 and PHD3 has no effect on the stability of HIF‐1α either in normoxia or upon re‐oxygenation of cells briefly exposed to hypoxia. We therefore conclude that, in vivo, PHDs have distinct assigned functions, PHD2 being the critical oxygen sensor setting the low steady‐state levels of HIF‐1α in normoxia. Interestingly, PHD2 is upregulated by hypoxia, providing an HIF‐1‐dependent auto‐regulatory mechanism driven by the oxygen tension.
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