Erythropoietin-dependent erythropoiesis: New insights and questions

Wojchowski, Don M.; Menon, Madhu P.; Sathyanarayana, Pradeep; Fang, Jing; Karur, Vinit; Houde, Estelle; Kapelle, William; Bogachev, Oleg

doi:10.1016/j.bcmd.2006.01.007

Cited by 38 publications

(33 citation statements)

References 33 publications

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“…4,[6][7][8] Consistent with this concept, EPO also has been demonstrated to exert cytoprotective effects in injured cardiac, renal, brain, and retinal cells. 10,11 In a distinct potential cancer cell context, EPO furthermore has been reported to increase mortality in patients with head and neck, and metastatic breast cancers.…”

Section: Discussionmentioning

confidence: 70%

“…[3][4][5][6][7][8]12 These interactions appear to evoke EPOR conformational events, 13 which are relayed to an upstream Janus kinase, JAK2 14 (and JAK2 likewise may preassemble with EPOR dimers at a juxtamembrane box1 domain). 15,16 JAK2, as activated via a Y1007 phosphorylation loop, 17 next stimulates 2 separable signal transduction pathways.…”

Section: Introductionmentioning

confidence: 99%

“…1,2 As a secreted monomeric sialoglycoprotein, EPO then targets developing erythroblasts, and is essential for red cell formation during definitive bone marrow and fetal liver erythropoiesis. [3][4][5][6][7][8] Prospective roles for EPO in promoting primitive red cell formation in yolk sac also have recently been described. 9 Beyond this, recombinant EPO has been demonstrated in ischemia and other cell damage models to provide cytoprotective effects for injured renal, cardiac, retinal, and neuronal tissues.…”

Section: Introductionmentioning

confidence: 99%

“…18 Second, JAK2 also mediates the phosphorylation of 8 conserved EPOR cytoplasmic PY sites, which can then form a scaffold for the binding of up to 20 SH2-or PTB-domain encoding signal transduction factors and molecular adaptors. [6][7][8][19][20][21] Among conserved EPOR cytoplasmic PY sites, 2 appear to act predominately to engage pathways to progenitor cell survival.First, EPOR-PY479 is a key binding site for p85-alpha and the corecruitment of PI3-kinase's p110 catalytic subunit. 22 PI3-kinase's antiapoptotic actions also involve AKT activation, and AKT's subsequent effects on mTOR, GSK3, and FOXO transcription factors.…”

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EPO receptor circuits for primary erythroblast survival

Sathyanarayana

Dev

Fang

et al. 2008

Blood

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EPO functions primarily as an erythroblast survival factor, and its antiapoptotic actions have been proposed to involve predominantly PI3-kinase and BCL-X pathways. Presently, the nature of EPOregulated survival genes has been investigated through transcriptome analyses of highly responsive, primary bone marrow erythroblasts. Two proapoptotic factors, Bim and FoxO3a, were rapidly repressed not only via the wild-type EPOR, but also by PY-deficient knocked-in EPOR alleles. In parallel, Pim1 and Pim3 kinases and Irs2 were induced. For this survival gene set, induction failed via a PY-null EPOR-HM allele, but was restored upon reconstitution of a PY343 STAT5-binding site within a related EPOR-H allele. Notably, EPOR-HM supports erythropoiesis at steady state but not during anemia, while EPOR-H exhibits near wildtype EPOR activities. EPOR-H and the wild-type EPOR (but not EPOR-HM) also markedly stimulated the expression of Trb3 pseudokinase, and intracellular serpin, Serpina-3G. For SERPINA-3G and TRB3, ectopic expression in EPOdependent progenitors furthermore significantly inhibited apoptosis due to cytokine withdrawal. BCL-XL and BCL2 also were studied, but in highly responsive Kit pos CD71 high Ter119 neg erythroblasts, neither was EPO modulated. EPOR survival circuits therefore include the repression of Bim plus IntroductionIn response to anemia, erythropoietin (EPO) is expressed by interstitial kidney and fetal liver cells via hypoxia-inducible transcription factor pathways. 1,2 As a secreted monomeric sialoglycoprotein, EPO then targets developing erythroblasts, and is essential for red cell formation during definitive bone marrow and fetal liver erythropoiesis. [3][4][5][6][7][8] Prospective roles for EPO in promoting primitive red cell formation in yolk sac also have recently been described. 9 Beyond this, recombinant EPO has been demonstrated in ischemia and other cell damage models to provide cytoprotective effects for injured renal, cardiac, retinal, and neuronal tissues. 10,11 Taken together, these considerations have heightened interest in the specific nature of key EPO action mechanisms, especially those associated with progenitor cell survival.EPO's prime effects are mediated via interactions with its dimeric single-transmembrane receptor (EPOR). [3][4][5][6][7][8]12 These interactions appear to evoke EPOR conformational events, 13 which are relayed to an upstream Janus kinase, JAK2 14 (and JAK2 likewise may preassemble with EPOR dimers at a juxtamembrane box1 domain). 15,16 JAK2, as activated via a Y1007 phosphorylation loop, 17 next stimulates 2 separable signal transduction pathways. First, JAK2 interestingly can support steady-state erythropoiesis via EPOR-PY-independent routes that, in part, may involve MEK1,2 and ERK1,2 stimulation. 18 Second, JAK2 also mediates the phosphorylation of 8 conserved EPOR cytoplasmic PY sites, which can then form a scaffold for the binding of up to 20 SH2-or PTB-domain encoding signal transduction factors and molecular adaptors. [6][7][8][19][20][21] Among conserve...

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Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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EPO receptor circuits for primary erythroblast survival

Sathyanarayana

Dev

Fang

et al. 2008

Blood

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“…The islets consist of a central macrophage with erythroblasts around it (Bessis and Breton-Gorius, 1962;Fruhman, 1970;Bernard, 1991). Studies on hematopoiesis of the red pulp have revealed that aging, pregnancy and hormone treatment with estrogen and erythropoietin have a signifi cant infl uence on erythropoiesis Wojchowski et al, 2006). Compared with studies on the erythroblasts in the red pulp, however, less attention has been paid to the islet macrophages.…”

Section: Introductionmentioning

confidence: 99%

Surface morphology of the central macrophages of erythroblastic islets in the spleen of aged and pregnant mice: an immunohistochemical light microscopic study

Sonoda

Sasaki

2008

Archives of Histology and Cytology

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Summary. This study used 100-m thick paraffin sections stained by the ER-HR3 antibody to examine the three-dimensional surface morphology of the central macrophages of erythroblastic islets in the splenic red pulp of aged and pregnant mice. The ER-HR3-positive cells were the macrophages located at the center of the erythroblastic islets, and the number per unit of splenic area was almost constant until 30 days of age, thereafter showing a marked decrease. In pregnant females, the ER-HR3-positive macrophage number significantly increased and became approximately eight times higher than the control value. In aged virgin females, the islet macrophages were generally ovoid in cell profile, and shallow cup-shaped dents were formed on their cell surface. However, in pregnant females, the macrophages became larger in size, and cell socket structures, formed by long finger-like cytoplasmic processes, became prominent on their cell surface. The 3-D images, obtained from 100-m thick paraffin sections, provided the clear morphological evidence of the activity of the islet macrophages in spleen erythropoiesis.

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Erythropoiesis

Olver¹

2022

Schalm's Veterinary Hematology

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Erythropoietin-dependent erythropoiesis: New insights and questions

Cited by 38 publications

References 33 publications

EPO receptor circuits for primary erythroblast survival

EPO receptor circuits for primary erythroblast survival

Surface morphology of the central macrophages of erythroblastic islets in the spleen of aged and pregnant mice: an immunohistochemical light microscopic study

Erythropoiesis

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