Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins.
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) alpha subunits for polyubiquitination and proteasomal degradation by oxygen-dependent prolyl hydroxylation. Here we show that different PHD isoforms differentially regulate HIF-alpha 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-2alpha, which is known to activate Epo expression, accumulated in the liver. In adult mice deficient for PHD2, the prototypic Epo transcriptional activator HIF-1alpha accumulated in both the kidney and liver. Elevated HIF-1alpha 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-2alpha/Epo pathway, whereas PHD2 deficiency leads to erythrocytosis by activating the renal Epo pathway.
Takeda
Kotaro
K
Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030-3501, USA.
Aguila
Hector L
HL
Parikh
Nehal S
NS
Li
Xiping
X
Lamothe
Katie
K
Duan
Li-Juan
LJ
Takeda
Hiromi
H
Lee
Frank S
FS
Fong
Guo-Hua
GH
D000375:Aging / Q000502:physiology*; D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004920:Erythropoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000201:enzymology; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; C522721:PHD1 protein, mouse; C522722:PHD3 protein, mouse; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases