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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.
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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.
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