HIF Prolyl Hydroxylase 1: A Key Regulator of HIF1A Levels

Tue, 09/17/2013 - 08:06

Hypoxia inducible factors (HIFs) are transcription factors that regulate the cellular response to decreases in oxygen levels. Under conditions of hypoxia HIFs activate the transcription of a diverse range of genes, resulting in increased oxygen delivery to the cell or metabolic adaptation.

Like all transcription factors, HIFs require careful regulation. This is mediated by post-translational modifications including phosphorylation, acetylation and hydroxylation. Prolyl hydroxylation is one of the most well studied regulators of HIF levels; this is catalysed by a family of proteins known as the HIF prolyl hydroxylases.

Three mammalian HIF prolyl hydroxylases have been identified (1).  HIF prolyl hydroxylase 1 (also known as PHD1, EGL nine homolog 2, HPH-1) is constitutively expressed, and is pre-dominantly localised to the nucleus where it plays a pivotal role in targeting HIF1A for proteasomal degradation (2). Under normoxic conditions HIF1A is continuously transcribed and translated, and is subsequently hydroxylated by HIF prolyl hydroxylase 1 on at least one of two conserved proline residues (Pro402 and Pro564) found in each of the oxygen-dependent degradation domains. This hydroxylation allows HIF1A to bind to the von Hippel-Lindau (VHL) tumour suppressor protein, which is a recognition component of the E3 ubiquitin ligase complex. Ubiquitination of HIF1A at three of its lysine residues targets it to the 26S proteasome for degradation (3). The half-life of HIF1A under conditions of normoxia is less than 5 minutes (2). Under hypoxic conditions HIF prolyl hydroxylase 1 does not hydroxylate HIF1A, and this enables HIF1A to regulate gene expression upon translocation to the nucleus.

Western Blot: HIF Prolyl Hydroxylase 1 Antibody Western Blot: HIF Prolyl Hydroxylase 1 Antibody

Schodel et al have used HIF prolyl hydroxylase antibodies to evaluate levels of the three HIF prolyl hydroxlase proteins in different cell populations from rat kidney by Western blotting; higher levels of all three proteins were found in cells with physiologically low oxygen tensions (4). Peurala et al have assessed expression levels of the HIF prolyl hydroxylases and HIF1A / HIF2A by immunohistochemical staining of samples from patients with invasive ductal breast carcinoma; HIF prolyl hydroxylase 1 expression was shown to correlate with increased levels of cellular proliferation (5).

HIF prolyl hydroxylase inhibitors are being developed as potential therapeutics for cancer, anaemia and chronic kidney disease amongst other conditions, and HIF prolyl hydroxylase inhibition is a growing research area.

  1. PMID: 15304631
  2. PMID: 22415525
  3. PMID: 22562152
  4. PMID: 19349364
  5. PMID: 21877141

Novus Biologicals offers various HIF Prolyl Hydroxylase 1 reagents for your research needs including:

Written by Emma Easthope

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