Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis

Research output: Contribution to journalArticle

Abstract

Red blood cells deliver O2 from the lungs to every cell in the human body. Reduced tissue oxygenation triggers increased production of erythropoietin by hypoxia-inducible factor 1 (HIF-1), which is a transcriptional activator composed of an O2-regulated α subunit and a constitutively expressed β subunit. Hydroxylation of HIF-1α or HIF-2α by the asparaginyl hydroxylase FIH-1 blocks coactivator binding and transactivation. Hydroxylation of HIF-1α or HIF-2α by the prolyl hydroxylase PHD2 is required for binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation. Mutations in the genes encoding VHL, PHD2, and HIF-2α have been identified in patients with familial erythrocytosis. Patients with Chuvash polycythemia, who are homozygous for a missense mutation in the VHL gene, have multisystem pathology attributable to dysregulated oxygen homeostasis. Intense efforts are under way to identify small molecule hydroxylase inhibitors that can be administered chronically to selectively induce erythropoiesis without undesirable side effects.

Original languageEnglish (US)
Pages (from-to)2015-2019
Number of pages5
JournalBlood
Volume114
Issue number10
DOIs
StatePublished - 2009

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Hypoxia-Inducible Factor 1
Erythropoiesis
Hydroxylation
Oxygen
Mixed Function Oxygenases
Prolyl Hydroxylases
Polycythemia
Proteins
Gene encoding
Oxygenation
Ubiquitination
Pathology
Missense Mutation
Erythropoietin
Human Body
Transcriptional Activation
Homeostasis
Blood
Erythrocytes
Cells

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis. / Semenza, Gregg L.

In: Blood, Vol. 114, No. 10, 2009, p. 2015-2019.

Research output: Contribution to journalArticle

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