Turning cells red: signal transduction mediated by erythropoietin

Richmond, Terri D.; Chohan, Manprit; Barber, Dwayne L.

doi:10.1016/j.tcb.2005.01.007

Cited by 309 publications

(305 citation statements)

References 81 publications

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“…JAK2/STAT5 play a key role in initiating EPO-R activation and subsequent recruitment of signaling modules to the receptor (Richmond et al, 2005;Witthuhn et al, 1993).…”

Section: Epo Preferentially Activates Stat3 In Bm-dcsmentioning

confidence: 99%

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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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“…JAK2/STAT5 play a key role in initiating EPO-R activation and subsequent recruitment of signaling modules to the receptor (Richmond et al, 2005;Witthuhn et al, 1993).…”

Section: Epo Preferentially Activates Stat3 In Bm-dcsmentioning

confidence: 99%

“…For example, EPO stimulation of erythroid progenitors leads to STAT, MAPK and AKT activation, thus inducing cell proliferation (Richmond et al, 2005). EPO-R activates AKT signaling, which leads to the activation of enthothelial cells and to NO secretion by them (Marzo et al, 2008).…”

mentioning

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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“…EPO induces its biological effects through the interaction with the specific receptor whose expression is detectable in the central nervous system throughout the entire life. 96 Detailed studies in recent years have clearly suggested that EPO is neuroprotective in a wide variety of animal models ranging from acute diseases, such as traumatic brain injuries 97 or spinal cord lesions, 98 to chronic neurodegenerative disorders. To this regard, EPO has been shown to ameliorate the latency and severity of seizures induced by kainate 99 and to improve neurological function recovery in experimental autoimmune encephalomyelitis.…”

Section: Erythropoietinmentioning

confidence: 99%

Shedding light into the role of BDNF in the pharmacotherapy of Parkinson's disease

Fumagalli¹,

Racagni

Riva³

2006

Pharmacogenomics J

118

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Parkinson's disease (PD) is a chronic, neurodegenerative disease with a 1% incidence in the population over 55 years of age. Movement impairments represent undoubtedly the hallmark of the disorder; however, extensive evidence implicates cognitive deficits as concomitant peculiar features. Brainderived neurotrophic factor (BDNF) colocalizes with dopamine neurons in the substantia nigra, where dopaminergic cell bodies are located, and it has recently garnered attention as a molecule crucial for cognition, a function that is also compromised in PD patients. Thus, due to its colocalization with dopaminergic neurons and its role in cognition, BDNF might possess a dual role in PD, both as a neuroprotective molecule, since its inhibition leads to loss of nigral dopaminergic neurons, and as a neuromodulator, as its enhanced expression ameliorates cognitive processes. In this review, we discuss the mechanism of action of established as well as novel drugs for PD with a particular emphasis to those interfering with BDNF biosynthesis.

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“…This process involves concerted progression through different stages accompanied by temporally regulated changes in cell surface protein expression, a reduction in cell size, progressive hemoglobinization and nuclear condensation and extrusion. 1 Regulation of survival, expansion and differentiation of erythroid progenitors is dependent on several transcription factors and an intricate network of complex and finely tuned regulatory signaling pathways. 2,3 In vivo and in vitro studies have highlighted the importance of erythropoietin (Epo) receptor (EpoR) signaling through Janus kinase 2 (Jak2) tyrosine kinase in regulation of red blood cell production thereby preventing committed erythroid progenitors from undergoing apoptosis and facilitating proliferation and differentiation.…”

mentioning

confidence: 99%

“…2,3 In vivo and in vitro studies have highlighted the importance of erythropoietin (Epo) receptor (EpoR) signaling through Janus kinase 2 (Jak2) tyrosine kinase in regulation of red blood cell production thereby preventing committed erythroid progenitors from undergoing apoptosis and facilitating proliferation and differentiation. 1 In vivo knockout of either Epo or EpoR leads to a 5-to 20-fold reduction in number of circulating primitive erythroblasts during embryogenesis (day E11.5) and mice die because of severe anemia by day E13. 5.…”

mentioning

confidence: 99%

Epo-induced erythroid maturation is dependent on Plcγ1 signaling

et al. 2014

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Erythropoiesis is a tightly regulated process. Development of red blood cells occurs through differentiation of hematopoietic stem cells (HSCs) into more committed progenitors and finally into erythrocytes. Binding of erythropoietin (Epo) to its receptor (EpoR) is required for erythropoiesis as it promotes survival and late maturation of erythroid progenitors. In vivo and in vitro studies have highlighted the requirement of EpoR signaling through Janus kinase 2 (Jak2) tyrosine kinase and Stat5a/b as a central pathway. Here, we demonstrate that phospholipase C gamma 1 (Plcγ1) is activated downstream of EpoR-Jak2 independently of Stat5. Plcγ1-deficient pro-erythroblasts and erythroid progenitors exhibited strong impairment in differentiation and colony-forming potential. In vivo, suppression of Plcγ1 in immunophenotypically defined HSCs (Lin − Sca1 + KIT + CD48 − CD150 + ) severely reduced erythroid development. To identify Plcγ1 effector molecules involved in regulation of erythroid differentiation, we assessed changes occurring at the global transcriptional and DNA methylation level after inactivation of Plcγ1. The top common downstream effector was H2afy2, which encodes for the histone variant macroH2A2 (mH2A2). Inactivation of mH2A2 expression recapitulated the effects of Plcγ1 depletion on erythroid maturation. Taken together, our findings identify Plcγ1 and its downstream target mH2A2, as a 'non-canonical' Epo signaling pathway essential for erythroid differentiation.

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Turning cells red: signal transduction mediated by erythropoietin

Cited by 309 publications

References 81 publications

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

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

Shedding light into the role of BDNF in the pharmacotherapy of Parkinson's disease

Epo-induced erythroid maturation is dependent on Plcγ1 signaling

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