From Erythropoietin to Oxygen: Hypoxia-Inducible Factor Hydroxylases and the Hypoxia Signal Pathway

@article{Ratcliffe2002FromET,
  title={From Erythropoietin to Oxygen: Hypoxia-Inducible Factor Hydroxylases and the Hypoxia Signal Pathway},
  author={Peter J. Ratcliffe},
  journal={Blood Purification},
  year={2002},
  volume={20},
  pages={445 - 450}
}
  • P. Ratcliffe
  • Published 30 August 2002
  • Biology
  • Blood Purification
The regulation of blood red cell production by the hormone erythropoietin (Epo) provides a paradigm for control of gene expression by oxygen. Analysis of this pathway has revealed a widespread system of gene regulation based on a transcriptional complex termed hypoxia-inducible factor (HIF). Hydroxylation of specific prolyl and asparinyl residues in the α subunit of HIF by a series of non-haem iron-dependent dioxygenases has been defined as a novel mechanism of protein modification that… 

Figures from this paper

Molecular biology of erythropoietin.

Evidence suggests that rHuEPO may be a useful neuroprotective agent in relation to EPO signalling and treatment with recombinant human EPO is efficient and safe in improving the management of the anemia associated with chronic renal failure.

Thyroid hormone induces erythropoietin gene expression through augmented accumulation of hypoxia-inducible factor-1.

It is found that thyroid hormone increased Hif-1alpha protein accumulation by increasing HIF-1 alpha protein synthesis rather than attenuating its proteasomal degradation, which may contribute to the adaptive response of increased oxygen demand under hyperthyroid conditions.

Current Understanding of HIF in Renal Disease

The discovery of HIF prolyl-hydroxylases as key enzymes of oxygen sensing and HIF proteolysis offer new possibilities to therapeutically target HIF.

Fine tuning the HIF-1 'global' O2 sensor for hypobaric hypoxia in Andean high-altitude natives.

The data indicate that the DNA sequences of the genes encoding Epo (including the 3' regulatory region) and HIF-1alpha appear to be conserved, and suggest that the altered erthropoietic response in Andean natives reflects adaptations in hypoxia sensing, rather than hypoxic response, mechanisms.

Disruption of dimerization and substrate phosphorylation inhibit factor inhibiting hypoxia-inducible factor (FIH) activity.

It is shown that phosphorylation of Thr-796 prevents the hydroxylation of Asn-803 by FIH, which enhances the transcriptional response in hypoxia and implies that the homodimeric form of FIH is required for productive substrate binding.

Effect of hypoxia on the expression of iron regulatory proteins 1 and the mechanisms involved

It is suggested that HIF/HRE system was an essential link between IRP1 and hypoxia and the HRE of IRP 1 5′‐regulation regions could combine with HIF‐1 in vitro.

Hypoxia regulates the ferrous iron uptake and reactive oxygen species level via divalent metal transporter 1 (DMT1) Exon1B by hypoxia‐inducible factor‐1

A functional hypoxia‐response element (HRE) is identified at position of −327 to −323 (‐ACGTG‐) in DMT1 exon1B promoter using a combination of bioinformatics and biological approaches and implicated DMT 1 exon 1B was a target gene for HIF‐1.
...

References

SHOWING 1-10 OF 54 REFERENCES

Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein.

A model is proposed in which a ligand-dependent conformational change in a heme protein accounts for the mechanism by which hypoxia as well as cobalt and nickel stimulate the production of Epo.

Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction.

Treatment of Hep3B cells with desferrioxamine (DFX) induced HIF-1 activity and EPO RNA expression with kinetics similar to the induction of Hif-1 by hypoxia or cobalt chloride, suggesting the existence of a common Hypoxia signal-transduction pathway leading to HIF -1 induction in different cell types.

A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF

In cultured mammalian cells, inappropriate accumulation of HIF caused by forced expression of the HIF-1α subunit under normoxic conditions was attenuated by coexpression of HPH, indicating that HPH is an essential component of the pathway through which cells sense oxygen.

HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing

It is found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated, which may play a key role in mammalian oxygen sensing.

Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation

It is shown that the interaction between human pVHL and a specific domain of the HIF-1α subunit is regulated through hydroxylation of a proline residue by an enzyme the authors have termed Hif-α prolyl-hydroxylase (HIF-PH).

The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis

It is indicated that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF α-subunits, which may underlie the angiogenic phenotype of VHL-associated tumours.

Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway.

The identification of an oxygen-dependent degradation (ODD) domain within HIF-1alpha that controls its degradation by the ubiquitin-proteasome pathway is reported and may provide a means of controlling gene expression by changes in oxygen tension.

Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha.

Functional studies in a mutant cell line expressing neither HIF-1alpha nor EPAS-1 confirmed that both proteins interact with hypoxically responsive targets, but suggest target specificity with greater EPas-1 transactivation of the VEGF promoter than the LDH-A promoter.

Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL

Optimize hydrogen bonding to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues in two functionally independent regions of HIF-1α, providing a new focus for development of therapeutic agents to modulate cellular responses to hypoxia.

Activation of Hypoxia-inducible Factor-1; Definition of Regulatory Domains within the α Subunit*

A dual mechanism of activation is proposed in which the operation of an inducible activation domain is amplified by regulation of transcription factor abundance, most likely occurring through changes in protein stability.
...