Disease relevance of EPO

• Primary familial and congenital polycythemia (PFCP or familial erythrocytosis) is a rare proliferative disorder of erythroid progenitor cells, characterized by elevated erythrocyte mass and hemoglobin concentration, hypersensitivity of erythroid progenitors to erythropoietin (EPO), and autosomal dominant inheritance or sporadic occurrence [1].
• We used a transient global spinal ischemia model in rabbits to test whether exogenous EPO can cross the blood-spinal cord barrier and protect these motor neurons [2].
• The production of EPO by the kidneys in response to hypoxia and anemia is well documented [3].
• In addition to the HIF-1 complex, hepatocyte nuclear factor 4alpha (HNF4alpha) was found to be indispensable for hypoxia-induced EPO gene expression in hepatoma cells [4].
• Here we show that c-fps/fes proto-oncogene product (p92c-fes), nonreceptor tyrosine kinase, is tyrosine-phosphorylated on treatment with EPO in a human erythroleukemia cell line TF-1 that is responsive to granulocyte-macrophage colony-stimulating factor, interleukin-3, and EPO [5].

Psychiatry related information on EPO

• Although GATA-3 expression in hepatocytes increases during human development, erythropoietin mRNA accumulation is unaltered in mutant mice lacking GATA-3 [6].
• The administration of erythropoietin with and without preoperative autologous blood transfusion prior to cardiac surgery is associated with a significant risk reduction: RR = 0.28 (95% CI 0.18-0.44, P < 0.001) and RR = 0.53 (95% CI 0.32-0.88, P < 0.01), respectively [7].
• Recent studies show that erythropoietin receptors are widely distributed in human tissues, including the gastrointestinal tract, endothelial cells, spinal cord, and brain, suggesting that erythropoietin plays a wider role in infant development [8].
• The partial correction of ESRD anemia by recombinant human erythropoietin (EPO) has resulted both in generalized improvement in quality of life and physical activity and in reduced mortality and hospitalization rate [9].
• Administration of EPO prevented the reduction in enzyme activities observed during the progression of the renal insufficiency, thus preserving the erythrocyte defense mechanisms against oxidative stress [10].

High impact information on EPO

• These include regulation of vascular tone, monitoring of oxygen tension in the control of ventilation and erythropoietin production, and signal transduction from membrane receptors in various physiological processes [11].
• Epoetin for severe anemia in hepatoerythropoietic porphyria [12].
• Erythropoietin for end-stage renal disease [13].
• CONCLUSIONS: In patients with clinically evident congestive heart failure or ischemic heart disease who are receiving hemodialysis, administration of epoetin to raise their hematocrit to 42 percent is not recommended [14].
• CONCLUSIONS: Deregulated expression of Bcl-x may contribute to the erythropoietin-independent survival of erythroid-lineage cells in polycythemia vera and thereby contribute to the pathogenesis of this disease [15].

Chemical compound and disease context of EPO

• EPO treatment also failed to interfere with the antiproliferative and/or cytotoxic effects of Adriamycin, Taxol, and tamoxifen in breast tumor cells (or of cytarabine and daunorubicin in F-MEL cells) [16].
• However, mersalyl inhibited endogenous EPO mRNA expression induced by hypoxia, CoCl2, or DFO [17].
• Epo also enhanced immunoglobulin (IgG, IgM and IgA) production and thymidine uptake by purified tonsil small resting B cells stimulated by Staphylococcus aureus Cowan strain I (SAC) or by large activated B cells [18].
• Epoetin alfa also limited the extent of concussive brain injury, the immune damage in experimental autoimmune encephalomyelitis and excitotoxicity induced by kainate [19].
• Improved multilineage response of hematopoiesis in patients with myelodysplastic syndromes to a combination therapy with all-trans-retinoic acid, granulocyte colony-stimulating factor, erythropoietin and alpha-tocopherol [20].

Biological context of EPO

• This unliganded EPOR dimer is formed from self-association of the same key binding site residues that interact with EPO-mimetic peptide and EPO ligands [21].
• Furthermore, high concentrations of anti-EPO-neutralizing antibody abrogated erythropoiesis in cultures without exogenous EPO [22].
• Because rHu-EPO is currently used widely with an excellent safety profile, clinical trials evaluating its potential to prevent motor neuron apoptosis and the neurological deficits that occur as a consequence of ischemic injury are warranted [2].
• High concentrations of EPO occurred in patients experiencing significant hypotension despite routine transfusions for hematocrit < 42% [23].
• Inhibitors of phosphatidylinositide 3-kinase and Src kinases suppressed EPO-dependent phosphorylation of Gab2 [24].

Anatomical context of EPO

• Further in vitro analysis of the erythroid progenitor cells of this affected child revealed that the progenitor cells were hypersensitive to EPO (a hallmark of PFCP) suggesting the presence of the disease at the level of progenitor cells [1].
• EPO mRNA was detected in erythroid cells but not myeloid cells cultured in the presence of SCF, sIL-6R, and IL-6 [22].
• The mutant C5964G-EPOR exhibited hypersensitive EPO-dependent proliferation compared to the wild-type EPOR when tested in a murine interleukin-3-dependent myeloid cell line (FDC-P1) [1].
• These observations suggest both an acute as well as a delayed beneficial action of rHu-EPO in ischemic spinal cord injury [2].
• Stimulation of bone marrow mononuclear cells (BMMCs) with EMP upregulated EPO expression [3].

Associations of EPO with chemical compounds

• Although the EPO receptor has no kinase domain, EPO rapidly induces tyrosine phosphorylation of several proteins in EPO-responsive cells [5].
• Prostaglandin-E2 enhances EPO-mediated STAT5 transcriptional activity by serine phosphorylation of CREB [25].
• Transfection experiments showed that both Stat1alpha and Stat3 inhibited the induction by EPO of gamma-globin and erythroid-specific 5-aminolevulinate synthetase transcripts, resulting in a reduction of the percentage of hemoglobin-positive cells [26].
• Erythroid colony formation in response to erythropoietin (EPO) stimulation is enhanced by costimulating the cells with prostaglandin-E2 (PGE2) [25].
• NO activates soluble guanosine cyclase to produce cyclic guanosine monophosphate (cGMP), and we observed that EPO induced cGMP activity [27].

Physical interactions of EPO

• OBJECTIVE: Erythropoietin interacts with vascular endothelial growth factor (VEGF) and stimulates endothelial cell mitosis and motility; thus it may be of importance in the complex phenomenon of wound healing [28].
• Epo binding induces the stimulation of Jak2 tyrosine kinase [29].
• The gp130 receptor-ligand complexes are contrasted with the complex formed by erythropoietin (Epo) and its receptor, EpoR [30].
• EPO binds to an erythroid progenitor cell surface receptor that includes a p66 chain, and, when activated, the p66 protein becomes dimerized [31].
• Chromatin immunoprecipitation (ChIP) and sequential ChIP (re-ChIP) analysis showed that both Brm and Brg-1 associate with the enhancer region of the EPO gene in vivo in a hypoxia-dependent fashion and that each is present in a complex with HIF-1 [32].

Enzymatic interactions of EPO

• Finally, EPO-R was functional insofar as the receptor was phosphorylated on tyrosine residues in response to exogenous EPO treatment of cultured trophoblast or Jar cells [33].
• In this report, we demonstrate that insulin receptor substrate-2 (IRS-2) is phosphorylated on tyrosine following treatment of UT-7 cells with erythropoietin [34].
• Moreover Epo-activated Lyn phosphorylates in vitro PLC-gamma 2 immunoprecipitated from unstimulated cells [35].
• By using an antiserum against the GTPase-activating protein, we found that p120GAP is rapidly phosphorylated in tyrosine in response to erythropoietin [36].

Regulatory relationships of EPO

• Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells [27].
• In summary, these studies demonstrate that PGE2 enhancement of EPO-induced STAT5 transactivation is mediated by the cAMP/PKA/CREB pathway [25].
• TGF-beta also inhibited hypoxia-induced Epo production, but only by as much as 56% [37].
• Epo-induced tyrosine phosphorylation of GAB1 was also observed in normal human erythroid progenitors isolated from cord blood [38].
• Incubation with thapsigargin resulted in decreased EPO synthesis (P < 0.05) but stimulated VEGF secretion (P < 0.05) [39].

Other interactions of EPO

• However, structures of agonist and antagonist peptide complexes of EPOR, as well as an EPO-EPOR complex, have shown that the actual dimer configuration is critical for the biological response and signal efficiency [21].
• Thus, EPOR and JAK2 association seems to be important for EPO responsiveness in CTLL-2 cells [40].
• These