Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins
Tóm tắt
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) α subunits for polyubiquitination and proteasomal degradation by oxygen-dependent prolyl hydroxylation. Here we show that different PHD isoforms differentially regulate HIF-α 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-2α, which is known to activate Epo expression, accumulated in the liver. In adult mice deficient for PHD2, the prototypic Epo transcriptional activator HIF-1α accumulated in both the kidney and liver. Elevated HIF-1α 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-2α/Epo pathway, whereas PHD2 deficiency leads to erythrocytosis by activating the renal Epo pathway.
Tài liệu tham khảo
Stroka, 2001, HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia., FASEB J, 15, 2445, 10.1096/fj.01-0125com
Chikuma, 2000, Tissue-specific regulation of erythropoietin production in the murine kidney, brain, and uterus., Am J Physiol Endocrinol Metab, 279, E1242, 10.1152/ajpendo.2000.279.6.E1242
Cotes, 1961, Bio-assay of erythropoietin in mice made polycythaemic by exposure to air at a reduced pressure., Nature, 191, 1065, 10.1038/1911065a0
Alafi, 1956, Role of the spleen in acclimatization to hypoxia., Am J Physiol, 186, 369, 10.1152/ajplegacy.1956.186.2.369
Maran, 2004, Polycythemia and oxygen sensing., Pathol Biol (Paris), 52, 280, 10.1016/j.patbio.2004.02.006
Ang, 2002, Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia., Nat Genet, 32, 614, 10.1038/ng1019
Percy, 2003, Chuvash-type congenital polycythemia in 4 families of Asian and Western European ancestry., Blood, 102, 1097, 10.1182/blood-2002-10-3246
Pastore, 2003, Mutations in the VHL gene in sporadic apparently congenital polycythemia., Blood, 101, 1591, 10.1182/blood-2002-06-1843
Gordeuk, 2005, Congenital polycythemias/erythrocytoses., Haematologica, 90, 109
Semenza, 1991, Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene., Proc Natl Acad Sci U S A, 88, 5680, 10.1073/pnas.88.13.5680
Haase, 2006, Hypoxia-inducible factors in the kidney., Am J Physiol Renal Physiol, 291, F271, 10.1152/ajprenal.00071.2006
Percy, 2006, A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis., Proc Natl Acad Sci U S A, 103, 654, 10.1073/pnas.0508423103
Semenza, 2003, Targeting HIF-1 for cancer therapy., Nat Rev Cancer, 3, 721, 10.1038/nrc1187
Wang, 1995, Purification and characterization of hypoxia-inducible factor 1., J Biol Chem, 270, 1230, 10.1074/jbc.270.3.1230
Wiesener, 1998, Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha., Blood, 92, 2260, 10.1182/blood.V92.7.2260
Bruick, 2001, A conserved family of prolyl-4-hydroxylases that modify HIF., Science, 294, 1337, 10.1126/science.1066373
Epstein, 2001, C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation., Cell, 107, 43, 10.1016/S0092-8674(01)00507-4
Ivan, 2001, HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing., Science, 292, 464, 10.1126/science.1059817
Masson, 2001, Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation., EMBO J, 20, 5197, 10.1093/emboj/20.18.5197
O'Rourke, 1999, Oxygen-regulated and transactivating domains in endothelial PAS protein 1: comparison with hypoxia-inducible factor-1alpha., J Biol Chem, 274, 2060, 10.1074/jbc.274.4.2060
Masson, 2003, HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O(2) levels., J Cell Sci, 116, 3041, 10.1242/jcs.00655
Jaakkola, 2001, Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation., Science, 292, 468, 10.1126/science.1059796
Maxwell, 1999, The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis., Nature, 399, 271, 10.1038/20459
Ivan, 2002, Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor., Proc Natl Acad Sci U S A, 99, 13459, 10.1073/pnas.192342099
Hirsilä, 2003, Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor., J Biol Chem, 278, 30772, 10.1074/jbc.M304982200
Huang, 2002, Sequence determinants in hypoxia-inducible factor-1alpha for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3., J Biol Chem, 277, 39792, 10.1074/jbc.M206955200
Lieb, 2002, Mammalian EGLN genes have distinct patterns of mRNA expression and regulation., Biochem Cell Biol, 80, 421, 10.1139/o02-115
Metzen, 2003, Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing., J Cell Sci, 116, 1319, 10.1242/jcs.00318
Appelhoff, 2004, Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor., J Biol Chem, 279, 38458, 10.1074/jbc.M406026200
Berra, 2003, HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia., EMBO J, 22, 4082, 10.1093/emboj/cdg392
Stiehl, 2006, Increased prolyl 4-hydroxylase domain proteins compensate for decreased oxygen levels. Evidence for an autoregulatory oxygen-sensing system., J Biol Chem, 281, 23482, 10.1074/jbc.M601719200
Takeda, 2006, Placental but not heart defects are associated with elevated hypoxia-inducible factor alpha levels in mice lacking prolyl hydroxylase domain protein 2., Mol Cell Biol, 26, 8336, 10.1128/MCB.00425-06
Takeda, 2007, Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system., Circulation, 116, 774, 10.1161/CIRCULATIONAHA.107.701516
Seibler, 2003, Rapid generation of inducible mouse mutants., Nucleic Acids Res, 31, e12, 10.1093/nar/gng012
Morrison, 1994, The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype., Immunity, 1, 661, 10.1016/1074-7613(94)90037-X
Spangrude, 1988, Purification and characterization of mouse hematopoietic stem cells., Science, 241, 58, 10.1126/science.2898810
Tian, 2006, Characterization of different isoforms of the HIF prolyl hydroxylase PHD1 generated by alternative initiation., Biochem J, 397, 179, 10.1042/BJ20051996
Berglund, 2002, Erythropoietin concentrations during 10 days of normobaric hypoxia under controlled environmental circumstances., Acta Physiol Scand, 174, 225, 10.1046/j.1365-201x.2002.00940.x
Lail, 1970, Effect of hypoxia on body weight, body water, and on hematological values of mice., Lab Anim Care, 20, 483
Mylrea, 1970, Hematologic responses of mice subjected to continuous hypoxia., Am J Physiol, 218, 1145, 10.1152/ajplegacy.1970.218.4.1145
Heinicke, 2003, Long-term exposure to intermittent hypoxia results in increased hemoglobin mass, reduced plasma volume, and elevated erythropoietin plasma levels in man., Eur J Appl Physiol, 88, 535, 10.1007/s00421-002-0732-z
Macdougall, 2006, Recent advances in erythropoietic agents in renal anemia., Semin Nephrol, 26, 313, 10.1016/j.semnephrol.2006.05.008
Hsieh, 2007, HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques., Blood, 110, 2140, 10.1182/blood-2007-02-073254
Richmond, 2005, Turning cells red: signal transduction mediated by erythropoietin., Trends Cell Biol, 15, 146, 10.1016/j.tcb.2005.01.007
Rankin, 2005, Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice., Mol Cell Biol, 25, 3163, 10.1128/MCB.25.8.3163-3172.2005
Gruber, 2007, Acute postnatal ablation of Hif-2alpha results in anemia., Proc Natl Acad Sci U S A, 104, 2301, 10.1073/pnas.0608382104
Scortegagna, 2005, HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner., Blood, 105, 3133, 10.1182/blood-2004-05-1695
Scortegagna, 2003, The HIF family member EPAS1/HIF-2alpha is required for normal hematopoiesis in mice., Blood, 102, 1634, 10.1182/blood-2003-02-0448
Rankin, 2007, Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo., J Clin Invest, 117, 1068, 10.1172/JCI30117
Warnecke, 2004, Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B and Kelly cells., FASEB J, 18, 1462, 10.1096/fj.04-1640fje
Sato, 2000, Erythroid progenitors differentiate and mature in response to endogenous erythropoietin., J Clin Invest, 106, 263, 10.1172/JCI9361
Parmar, 2007, Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia., Proc Natl Acad Sci U S A, 104, 5431, 10.1073/pnas.0701152104