Journal ArticleDOI
Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression.
TLDR
Understanding oxygen and tissue-specific regulation of EPO production is of high relevance for physiology and might be useful for new therapies to treat human diseases.Abstract:
Hypoxia-inducible expression of the gene encoding for the glycoprotein hormone erythropoietin (EPO) is the paradigm of oxygen-regulated gene expression. EPO is the main regulator of red blood cell production and more than 100 years of research on the regulation of EPO production have led to the identification of a widespread cellular oxygen sensing mechanism. Central to this signaling cascade is the transcription factor complex hypoxia-inducible factor-1 (HIF-1). Meanwhile, it is known that HIF-1 controls more than 50 oxygen-dependent genes and is now recognized as the main regulator of oxygen homoeostasis in the body. In addition to hypoxic induction, expression of the EPO gene is tightly regulated in a tissue-specific manner. During ontogeny, production of EPO required for erythropoiesis is switched from the fetal liver to the kidneys. Here EPO is mainly synthesized in adulthood. Production of EPO has also been found in organs where it has nonerythropoietic functions: EPO is important for development of the brain and is neuroprotective, whereas it stimulates angiogenesis in the reproductive tract and possibly in other organs. Understanding oxygen and tissue-specific regulation of EPO production is of high relevance for physiology. Moreover, this knowledge might be useful for new therapies to treat human diseases.read more
Citations
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Journal ArticleDOI
Hypoxia inducible factors and the response to hypoxic stress
TL;DR: In mammals, the primary transcriptional response to hypoxic stress is mediated by the hypoxia-inducible factors, and the HIFα subunits are intricately responsive to numerous other factors, including factor-inhibiting HIF1α, sirtuins, and metabolites.
Journal ArticleDOI
Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients
TL;DR: Results from clinical studies of a number of HIF prolyl hydroxylase inhibitors are increasingly available and provide support for the continued evaluation of the risk-benefit ratio of this novel therapeutic approach to the treatment of anemia in CKD.
Journal ArticleDOI
The causes of porotic hyperostosis and cribra orbitalia: a reappraisal of the iron-deficiency-anemia hypothesis.
TL;DR: Several lines of evidence suggest that the accelerated loss and compensatory over-production of red blood cells seen in hemolytic and megaloblastic anemias is the most likely proximate cause of porotic hyperostosis.
Journal ArticleDOI
Hypoxia-inducible factor–2 (HIF-2) regulates hepatic erythropoietin in vivo
Erinn B. Rankin,Mangatt P. Biju,Qingdu Liu,Travis L. Unger,Jennifer Rha,Randall S. Johnson,M. Celeste Simon,Brian Keith,Volker H. Haase +8 more
TL;DR: Conditional inactivation of Hif-2alpha in pVHL-deficient mice suppressed hepatic Epo and the development of polycythemia is shown, providing genetic evidence that HIF-1 and H IF-2 have distinct roles in the regulation of hypoxia-inducible genes and that EPO is preferentially regulated by HIFs in the liver.
Journal ArticleDOI
Erythropoietin after a century of research: younger than ever.
TL;DR: The demonstration of Epo‐R in non‐haematopoietic tissues indicates that Epo is a pleiotropic viability and growth factor, and the neuroprotective and cardioprotective potentials ofEpo are reviewed with a focus on clinical research.
References
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Journal ArticleDOI
Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension
TL;DR: Hypoxia-inducible factor 1 (HIF-1) is found in mammalian cells cultured under reduced O2 tension and is necessary for transcriptional activation mediated by the erythropoietin gene enhancer in hypoxic cells.
Journal ArticleDOI
Targeting of HIF-alpha to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation
Panu Jaakkola,David R. Mole,Ya-Min Tian,Michael I. Wilson,Janine Gielbert,Simon J. Gaskell,Alex von Kriegsheim,Holger F. Hebestreit,Mridul Mukherji,Christopher J. Schofield,Patrick H. Maxwell,Christopher W. Pugh,Peter J. Ratcliffe +12 more
TL;DR: 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).
Journal ArticleDOI
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Patrick H. Maxwell,Michael S. Wiesener,Gin-Wen Chang,Steven C. Clifford,Emma C. Vaux,Matthew Edward Cockman,Charles C. Wykoff,Christopher W. Pugh,Eamonn R. Maher,Peter J. Ratcliffe,Peter J. Ratcliffe +10 more
TL;DR: 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.
Journal ArticleDOI
HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing
Mircea Ivan,Keiichi Kondo,Haifeng Yang,William Y. Kim,Jennifer Valiando,Michael Ohh,Adrian Salic,John M. Asara,William S. Lane,William G. Kaelin,William G. Kaelin +10 more
TL;DR: 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.
Journal ArticleDOI
C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation.
Andrew C. R Epstein,Jonathan M. Gleadle,Luke A. McNeill,Kirsty S. Hewitson,J F O'Rourke,David R. Mole,Mridul Mukherji,Eric Metzen,Michael A Wilson,Anu Dhanda,Ya-Min Tian,Norma Masson,Donald L. Hamilton,Panu Jaakkola,Robert Barstead,Jonathan Hodgkin,Patrick H. Maxwell,Christopher W. Pugh,Christopher J. Schofield,Peter J. Ratcliffe +19 more
TL;DR: Direct modulation of recombinant enzyme activity by graded hypoxia, iron chelation, and cobaltous ions mirrors the characteristics of HIF induction in vivo, fulfilling requirements for these enzymes being oxygen sensors that regulate HIF.
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