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Blood, 3 September 2009, Vol. 114, No. 10, pp. 2015-2019. Prepublished online as a Blood First Edition Paper on June 3, 2009; DOI 10.1182/blood-2009-05-189985. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2009-05-189985v1 114/10/2015    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Semenza, G. L. PubMed PubMed Citation Articles by Semenza, G. L. Related Collections Red Cells, Iron, and Erythropoiesis Review Articles Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  REVIEW ARTICLE Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis Gregg L. Semenza1 1 Vascular Program, Institute for Cell Engineering; McKusick-Nathans Institute of Genetic Medicine; and Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 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 subunit and a constitutively expressed β subunit. Hydroxylation of HIF-1 or HIF-2 by the asparaginyl hydroxylase FIH-1 blocks coactivator binding and transactivation. Hydroxylation of HIF-1 or HIF-2 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-2 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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