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Blood, 15 March 2008, Vol. 111, No. 6, pp. 3229-3235. Prepublished online as a Blood First Edition Paper on December 4, 2007; DOI 10.1182/blood-2007-09-114561. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-09-114561v1 111/6/3229    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 Takeda, K. Articles by Fong, G.-H. PubMed PubMed Citation Articles by Takeda, K. Articles by Fong, G.-H. Related Collections Red Cells Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins Kotaro Takeda1, Hector L. Aguila2, Nehal S. Parikh3, Xiping Li4, Katie Lamothe2, Li-Juan Duan1, Hiromi Takeda1, Frank S. Lee4, and Guo-Hua Fong1 1 Center for Vascular Biology, Department of Cell Biology, 2 Department of Immunology, University of Connecticut Health Center, Farmington; 3 Division of Hematology and Oncology, Connecticut Children's Medical Center, Hartford; 4 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia Polycythemia is often associated with erythropoietin (EPO) overexpression and defective oxygen sensing. In normal cells, intracellular oxygen concentrations are directly sensed by prolyl hydroxylase domain (PHD)–containing proteins, which tag hypoxia-inducible factor (HIF) subunits for polyubiquitination and proteasomal degradation by oxygen-dependent prolyl hydroxylation. Here we show that different PHD isoforms differentially regulate HIF- stability in the adult liver and kidney and suppress Epo expression and erythropoiesis through distinct mechanisms. Although Phd1–/– or Phd3–/– mice had no apparent defects, double knockout of Phd1 and Phd3 led to moderate erythrocytosis. HIF-2, which is known to activate Epo expression, accumulated in the liver. In adult mice deficient for PHD2, the prototypic Epo transcriptional activator HIF-1 accumulated in both the kidney and liver. Elevated HIF-1 levels were associated with dramatically increased concentrations of both Epo mRNA in the kidney and Epo protein in the serum, which led to severe erythrocytosis. In contrast, heterozygous mutation of Phd2 had no detectable effects on blood homeostasis. These findings suggest that PHD1/3 double deficiency leads to erythrocytosis partly by activating the hepatic HIF-2/Epo pathway, whereas PHD2 deficiency leads to erythrocytosis by activating the renal Epo pathway. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: PHDs in adult life: not simple, not redundant Eric Metzen Blood 2008 111: 2947-2948. [Full Text] [PDF]

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