A “classical” homodimeric erythropoietin receptor is essential for the antiapoptotic effects of erythropoietin on differentiated neuroblastoma SH-SY5Y and pheochromocytoma PC-12 cells

Um, Moonkyoung; Gross, Alec W.; Lodish, Harvey F.

doi:10.1016/j.cellsig.2006.08.014

Cited by 133 publications

(123 citation statements)

References 74 publications

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“…In a recent study, no expression of the common beta-chain could be detected in neuronal cell lines that respond to EPO. 35 Furthermore, studies in mice harboring a brain specific genetic ablation of the classical EPOR have shown that expression of the EPOR is indispensable for EPO-induced neurogenesis and neuroprotection. 36 -38 In contrast, CEPO stimulates adult neurogenesis in the EPOR-knock-out mice suggesting that the cellular signaling by CEPO does not involve the classical EPOR.…”

Section: Epo Signaling In the Nervous Systemmentioning

confidence: 99%

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

et al. 2009

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Summary:The growth factor erythropoietin (EPO) and erythropoietin receptors (EPOR) are expressed in the nervous system. Neuronal expression of EPO and EPOR peaks during brain development and is upregulated in the adult brain after injury. Peripherally administered EPO, and at least some of its variants, cross the blood-brain barrier, stimulate neurogenesis, neuronal differentiation, and activate brain neurotrophic, antiapoptotic, anti-oxidant and anti-inflammatory signaling. These mechanisms underlie their tissue protective effects in nervous system disorders. As the tissue protective functions of EPO can be separated from its stimulatory action on hematopoiesis, novel EPO derivatives and mimetics, such as asialo-EPO and carbamoylated EPO have been developed. While the therapeutic potential of the novel EPO derivatives continues to be characterized in preclinical studies, the experimental findings in support for the use of recombinant human (rh)EPO in human brain disease have already been translated to clinical studies in acute ischemic stroke, chronic schizophrenia, and chronic progressive multiple sclerosis. In this review article, we assess the studies on EPO and, in particular, on its structural or functional variants in experimental models of nervous system disorders, and we provide a short overview of the completed and ongoing clinical studies testing EPO as neuroprotective/neuroregenerative treatment option in neuropsychiatric disease.

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Section: Epo Signaling In the Nervous Systemmentioning

confidence: 99%

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

et al. 2009

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“…It has been shown that non-hematopoietic tissues can express an atypical EPO-R beta-subunit heteroreceptor (Brines et al, 2004) that exhibits a non-classical EPOmediated signaling (Arcasoy, 2008). Other studies have demonstrated that the classic homodimeric EPO-R is essential for non-hematopoietic effects of EPO (Um et al, 2007). …”

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confidence: 99%

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

Lifshitz

Prutchi-Sagiv

Avneon

et al. 2009

Molecular Immunology

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Erythropoietin (EPO) is the main hormone that promotes proliferation and differentiation of erythroid progenitor cells via binding to its surface receptor (EPO-R). Recent studies suggest that this hormone may affect also other cell types, besides the red blood cell lineage. We have previously demonstrated that the immune system is a target of EPO; however, the direct target cells of EPO, as well as the molecular mechanisms underlying its role as an immunomodulator, are unknown. Here we present evidence for functional effects of EPO on dendritic cells (DCs), which are known to initiate the immune response. In-vivo experiments in EPO-injected mice and in transgenic mice over-expressing human EPO showed an increased splenic DC population with a higher cell surface expression of CD80 and CD86. Further analysis based on mouse models, showed that DCs derived in-vitro from bone marrow (BM-DCs) express EPO-R mRNA. In-vitro stimulation of these DCs with recombinant human EPO enhanced viability, upregulated CD80, CD86 and MHC class II and augmented the secretion of IL-12. Biochemical analysis of EPO mediated signaling in the BM-DCs showed activation of the AKT, MAPK and NF-kappaB pathways. EPO stimulation of the BM-DCs led to Tyr-phosphorylation of STAT3. The inability to detect EPO mediated activation of STAT5 in the BM-DCs, suggests that in DCs, STAT3 may play a more important role than STAT5 in EPO-R signaling. Taken together, our data support the premise that DCs are direct targets of EPO, thereby providing an insight to the immunomodulatory functions of EPO.

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“…11,13 However, unlike in positive control OCIM1 and UT7EPO cells (Figure 2a), the prior addition of Epo failed to diminish the intensity of FAB307P binding in primary myeloma cells (Figure 2b). This result is consistent with the notion that FAB307P is detecting a non-EpoR protein on the surface of myeloma cells.…”

Section: Evaluating Surface Erythropoietin Receptor In Multiple Myelomamentioning

confidence: 88%

“…A previous study failed to detect surface EpoR in primary Accepted article preview online 1 March 2012; advance online publication, 16 March 2012 myeloma samples using digoxigenin-labeled Epo binding detected by flow cytometry, however, this study was limited to four samples. 10 Moreover, the sensitivity of this assay was limited to 300 receptors per cell, whereas studies by Um et al 11 suggest that, at least in certain cell lines, surface EpoR expression below this level may be functionally relevant.…”

Section: Evaluating Surface Erythropoietin Receptor In Multiple Myelomamentioning

confidence: 99%

Evaluating surface erythropoietin receptor in multiple myeloma

et al. 2012

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In conclusion, our analysis in acute leukemia revealed mutations in the histone-modifying enzymes recently identified to be altered in other cancers, particularly UTX in ALL and MLL2 in AML, although not at a high incidence. Important to note is that UTX and MLL2 are part of the same protein complex and both MLL2 and UTX mutations may lead to similar phenotypic consequences in cancer cells. Also, MLL2 was not fully sequenced in our analysis, leaving open the possibility of additional mutations in AML. Nevertheless, our findings warrant further analyses within larger studies and most likely more comprehensive studies based on targeted or whole genome/exome next-generation sequencing approaches. Of interest, most of the UTX mutations observed in our study were found in clinically defined high-risk patients and at least 1 of those patients (05-046) eventually relapsed. Therefore, this observation might be of particular interest with regard to potential epigenetic treatment approaches, although the exact mechanisms of transformation in UTX-mutated ALL remain to be elucidated.

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A “classical” homodimeric erythropoietin receptor is essential for the antiapoptotic effects of erythropoietin on differentiated neuroblastoma SH-SY5Y and pheochromocytoma PC-12 cells

Cited by 133 publications

References 74 publications

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

Evaluating surface erythropoietin receptor in multiple myeloma

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