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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The receptor-associated protein tyrosine kinase janus-kinase 2 (JAK2) is essential for normal red cell development and for erythropoietin receptor (EpoR) signaling. JAK2(-/-) embryos are severely deficient in erythropoiesis and die at an early stage of development from fetal anemia. The binding of erythropoietin (Epo) to the EpoR triggers the activation of JAK2, the phosphorylation of the EpoR, and the initiation of the EpoR signaling cascade. In addition to Epo binding to its receptor, signaling pathways downstream of the EpoR can also be stimulated by the BCR-ABL oncoprotein. This study explored whether JAK2 is required for BCR-ABL-mediated stimulation of erythropoiesis. Here, it is shown that JAK2 is constitutively tyrosine phosphorylated in cultured and primary erythroid cells expressing BCR-ABL. However, BCR-ABL effectively supports normal erythroid proliferation, differentiation, and maturation in JAK2-deficient fetal liver cells. Using mutants of BCR-ABL, this study shows that certain signaling pathways activated by BCR-ABL segments distinct from its tyrosine kinase domain are essential for rescue of erythropoiesis in JAK2(-/-) progenitors. The consequences of these multiple signaling pathways for normal erythroid development are discussed.
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PMID:Erythropoiesis in the absence of janus-kinase 2: BCR-ABL induces red cell formation in JAK2(-/-) hematopoietic progenitors. 1169 76

Novel erythropoiesis stimulating protein (NESP) is a supersialylated analogue of endogenous erythropoietin or recombinant human erythropoietin (rhuEPO). It contains a total of five N-linked consensus carbohydrate binding sites in the native protein. NESP has a higher molecular weight due to an increased content of carbohydrates, which, however, has no meaningful influence on the binding to and activation of the erythropoietin receptor. The major difference in comparison to rhuEPO is the up to threefold increase of the terminal half-life of NESP, which allows for less frequent dosing of NESP. Several clinical studies have shown that NESP is as safe and efficient as rhuEPO in correcting renal anaemia and in the maintenance therapy of renal anaemia.
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PMID:The clinical potential of novel erythropoiesis stimulating protein. 1172 8

Erythropoietin, known for its role in erythroid differentiation, has been shown to be neuroprotective during brain ischaemia in adult animal models. Although high levels of erythropoietin receptor are produced in embryonic brain, the role of erythropoietin during brain development is uncertain. We now provide evidence that erythropoietin acts to stimulate neural progenitor cells and to prevent apoptosis in the embryonic brain. Mice lacking the erythropoietin receptor exhibit severe anaemia and defective cardiac development, and die at embryonic day 13.5 (E13.5). By E12.5, in addition to apoptosis in foetal liver, endocardium and myocardium, the erythropoietin receptor null mouse shows extensive apoptosis in foetal brain. Lack of erythropoietin receptor affects brain development as early as E10.5, resulting in a reduction in the number of neural progenitor cells and increased apoptosis. Corresponding in vitro cultures of cortical cells from Epor(-/-) mice also exhibited decreases in neuron generation compared with normal controls and increased sensitivity to low oxygen tension with no surviving neurons in Epor(-/-) cortical cultures after 24 hour exposure to hypoxia. The viability of primary Epor(+/+) rodent embryonic cortical neurons was further increased by erythropoietin stimulation. Exposure of these cultures to hypoxia induced erythropoietin expression and a tenfold increase in erythropoietin receptor expression, increased cell survival and decreased apoptosis. Cultures of neuronal progenitor cells also exhibited a proliferative response to erythropoietin stimulation. These data demonstrate that the neuroprotective activity of erythropoietin is observed as early as E10.5 in the developing brain, and that induction of erythropoietin and its receptor by hypoxia may contribute to selective cell survival in the brain.
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PMID:Erythropoietin receptor signalling is required for normal brain development. 1180 41

Erythropoietic agents have transformed the management of renal anaemia. Two forms of recombinant human erythropoietin (rHuEPO) have been available since the early 1990s, and more recently, a second-generation erythropoietic agent, darbepoetin alfa, has been granted a licence for treating this condition. The endogenous erythropoietin molecule may contain anything from 4 to 14 sialic acid residues. The various isoforms have different biological potencies in vivo owing to their different metabolic clearance rates. However, there is a continuing debate about those organs potentially involved in the metabolism of the erythropoietin molecule; the kidneys, liver, and bone marrow have all been suggested as possible participants. Darbepoetin alfa contains two extra N-linked glycosylation consensus sequences increasing the potential maximum number of sialic acid residues from 14 up to 22. In vitro, the affinity of darbepoetin alfa for the erythropoietin receptor is less than for the natural ligand, but this is more than compensated for by the increased potency in vivo. One of the most important factors determining the biological activity of erythropoiesis-stimulating agents is the length of time that the serum concentration of the protein remains above the threshold necessary for erythropoiesis. The pharmacokinetic profile of darbepoetin alfa is distinct from that of rHuEPO, the major difference being the much longer elimination half-life and slower clearance in vivo of darbepoetin alfa leading to prolonged erythropoietic activity. Stimulation of erythropoiesis depends both on an ambient circulating level of erythropoietin and on the mechanisms governing the interaction of the hormone with its receptor. Our knowledge regarding the latter is limited and it is difficult to predict the optimum frequency of administration for an erythropoietic agent. In general, rHuEPO is given two or three times weekly. A small number of studies have supported the once-weekly use of rHuEPO. All clinical trials so far conducted on darbepoetin alfa have demonstrated success with once-weekly and once every other week dosing.
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PMID:Optimizing the use of erythropoietic agents-- pharmacokinetic and pharmacodynamic considerations. 1209 11

The Friend virus susceptibility gene 2 (Fv2) controls the polyclonal expansion of infected cells that occurs early during Friend erythroleukemia virus infection. Fv2 has recently been shown to encode a truncated form of the Stk receptor tyrosine kinase (Sf-Stk). This observation, coupled with earlier work, suggested that Sf-Stk drives the expansion of infected cells by forming a complex with the Friend virus envelope glycoprotein, gp55, and the erythropoietin receptor. Fv2 has also been implicated in the control of cell cycling in early erythroid progenitors (erythroid blast-forming units [BFU-Es]). Mouse strains that are homozygous for the resistant allele of Fv2 (Fv2(rr)) have few actively cycling BFU-Es. In this report, we demonstrate that the control of BFU-E cycling is encoded by a gene linked to, but distinct from, Fv2, and suggest that this gene is the dual-specific protein phosphatase Cdc25A, which regulates the G1- to S-phase transition of the cell cycle. We show that a naturally occurring allele of Cdc25A, which increases Cdc25A phosphatase activity and promotes cell-cycle progression, segregates in mouse strains that exhibit high levels of BFU-E cell cycling. In wild-type mice, this allele of Cdc25A does not overtly affect erythropoiesis; however, when this allele is combined with a mutation of the Kit receptor (Kit(WV)), the anemia of the mice is enhanced. Furthermore, overexpression of Cdc25A in bone marrow cells causes a defect in the BFU-E colony formation. These results suggest that proper regulation of the cell cycle through Cdc25A is required for normal erythropoiesis.
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PMID:A naturally occurring point substitution in Cdc25A, and not Fv2/Stk, is associated with altered cell-cycle status of early erythroid progenitor cells. 1241 23

Kit receptor tyrosine kinase and erythropoietin receptor (Epo-R) cooperate in regulating blood cell development. Mice that lack the expression of Kit or Epo-R die in utero of severe anemia. Stimulation of Kit by its ligand, stem cell factor activates several distinct early signaling pathways, including phospholipase C gamma, phosphatidylinositol 3-kinase, Src kinase, Grb2, and Grb7. The role of these pathways in Kit-induced growth, proliferation, or cooperation with Epo-R is not known. We demonstrate that inactivation of any one of these early signaling pathways in Kit significantly impairs growth and proliferation. However, inactivation of the Src pathway demonstrated the most profound defect. Combined stimulation with Epo also resulted in impaired cooperation between Src-defective Kit mutant and Epo-R and, to a lesser extent, with Kit mutants defective in the activation of phosphatidylinositol 3-kinase or Grb2. The impaired cooperation between the Src-defective Kit mutant and Epo-R was associated with reduced transphosphorylation of Epo-R and expression of c-Myc. Remarkably, restoration of only the Src pathway in a Kit receptor defective in the activation of all early signaling pathways demonstrated a 50% correction in proliferation in response to Kit stimulation and completely restored the cooperation with Epo-R. These data demonstrate an essential role for Src pathway in regulating growth, proliferation, and cooperation with Epo-R downstream from Kit.
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PMID:Functional and biochemical consequences of abrogating the activation of multiple diverse early signaling pathways in Kit. Role for Src kinase pathway in Kit-induced cooperation with erythropoietin receptor. 1248 28

Anemia is one of the characteristics of the frailty phenotype and is often observed in elderly patients. Although anemia in people of advancing age can often be attributed to underlying etiologies such as iron deficiency or chronic disease, some cases do not have any identifiable cause. Therefore, it has been suggested that the aging process itself might be an intrinsic factor in the development of anemia, possibly through the age-related dysregulation of certain proinflammatory cytokines such as interleukin-6 (IL-6). Although the mechanism underlying the association between increased IL-6 and anemia has not been fully elucidated, it has been suggested that, like with other cytokines, it involves direct inhibition of erythropoietin production or interaction with the erythropoietin receptor.
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PMID:Biological interactions of aging and anemia: a focus on cytokines. 1258 68

Erythropoietin is a hypoxia-induced hormone that is essential for normal erythropoiesis. The production of recombinant human erythropoietin (rHuEpo) has revolutionized the treatment of anemia associated with chronic renal failure and chemotherapy, and has been used as prophylaxis to prevent anemia after surgery. The erythropoietin receptor is widely distributed in the cardiovascular system, including endothelial cells, smooth muscle cells and cardiomyocytes. Epo has potentially beneficial effects on the endothelium including anti-apoptotic, mitogenic and angiogenic activities. On the other hand, some reports suggest that rHuEpo may have pro-thrombotic or platelet-activating effects. Hypertension develops in 20-30% of renal patients treated with rHuEpo. Many patients with heart failure have anemia. Despite some potential adverse effects, early studies in heart failure patients with anemia suggest that rHuEpo therapy is safe and effective in reducing left ventricular hypertrophy, enhancing exercise performance and increasing ejection fraction. Further studies are warranted to define the role of rHuEpo in chronic heart failure and other cardiovascular settings.
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PMID:The cardiovascular effects of erythropoietin. 1449 55

Erythropoietin is a hematopoietic cytokine that regulates the production of red blood cells. Erythropoietin is normally produced in the adult kidney in a hypoxia-inducible manner. The recombinant form of human erythropoietin is in clinical use for the prevention and treatment of anemia that is associated with cancer and its treatment with chemoradiation therapy. A series of recent studies from our laboratory and others have reported the expression of receptors for erythropoietin in several different types of human cancer cells. In the present study, we investigated the expression of erythropoietin receptor and its ligand erythropoietin in human prostate cancer. In clinical specimens of prostate cancer, we found abundant expression of erythropoietin receptor protein in all primary tumors examined using immunohistochemistry. Furthermore, we observed erythropoietin coexpression in prostate cancer cells by immunohistochemical analysis. To determine whether monolayer cultures of continuous cell lines derived from prostate cancer also express erythropoietin receptor and erythropoietin, we studied well-characterized hormone-responsive (LNCaP) and hormone-refractory (PC-3) prostate cancer cell lines. We performed reverse-transcription and polymerase chain reaction assays to detect erythropoietin receptor and erythropoietin mRNA transcripts, and also immunoprecipitation and immunoblotting to detect erythropoietin receptor protein expression in prostate cancer cells. These experiments revealed the expression of both erythropoietin receptor and erythropoietin in LNCaP and PC-3 cells suggesting that these prostate cancer cell lines may serve as useful experimental models for further studies of erythropoietin and erythropoietin receptor function in prostate cancer. The coexpression of erythropoietin receptor and its ligand erythropoietin in human prostate cancer cells suggests the potential for growth regulation by erythropoietin-erythropoietin receptor in an autocrine or paracrine manner.
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PMID:Erythropoietin and erythropoietin receptor expression in human prostate cancer. 1546 11

Anemia in cancer patients is associated with reduced quality of life and local failure after radiation treatment. However, the use of erythropoietin to correct cancer anemia and to improve radiation efficacy was disappointing. Erythropoietin-receptor signaling mainly acts via activation of STAT 5, but also crossactivates the antiapoptotic transcription factor NF-kappaB. This causes neuroprotection against oxidative stress and implies radioprotection. In order to investigate possible radioprotective effects of erythropoietin-receptor signaling, we used an in vitro model system employing HeLa TetOff cells, stably transfected with an expression vector for the erythropoietin-receptor gene. Using electrophoretic mobility shift assays, we could demonstrate strong activation of NF-kappaB by erythropoietin-receptor signaling in HeLa cells. Activation of NF-kappaB did not require degradation of IkappaBalpha and was not prevented by proteasome inhibition. Furthermore, stimulation with erythropoietin resulted in a 50% increased clonogenicity of erythropoietin-receptor-expressing cells but did not alter radiation sensitivity itself. As most human tumors express erythropoietin receptor, we advocate a restricted use erythropoietin to patients suffering from erythropoietin-receptor-expressing cancers.
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PMID:The erythropoietin-receptor pathway modulates survival of cancer cells. 1548 Apr 20


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