EPO receptor-mediated ERK kinase and NF-κB activation in erythropoietin-promoted differentiation of astrocytes

Lee, Sang Min; Nguyen, Thi Hong Nga; Park, Mi Hee; Kim, Kyung Soon; Cho, Kyoung Joo; Moon, Dong Cheul; Kim, Hee Young; Yoon, Do Young; Hong, Jin Tae

doi:10.1016/j.bbrc.2004.06.060

Cited by 58 publications

(35 citation statements)

References 39 publications

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“…These findings concur with the observation that a sustained activation of ERK1/2 in primary human astrocytes led to senescence and cell cycle arrest [47]. Interestingly, EPO promoted morphological differentiation and increased astrocyte specific GFAP expression in primary rat astrocyte cultures by inducing ERK1/2 [51]. Elongation of astrocytic processes upon induction of ERK1/2 in rat primary astrocytes has been reported previously [50], and could also be seen in the present study in response to both TPO and GCSF treatment (Fig.…”

Section: Discussionsupporting

confidence: 90%

Cell Type Specific Signalling by Hematopoietic Growth Factors in Neural Cells

et al. 2006

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Correct timing and spatial location of growth factor expression is critical for undisturbed brain development and functioning. In terminally differentiated cells distinct biological responses to growth factors may depend on cell type specific activation of signalling cascades. We show that the hematopoietic growth factors thrombopoietin (TPO) and granulocyte colony-stimulating factor (GCSF) exert cell type specific effects on survival, proliferation and the degree of phosphorylation of Akt1, ERK1/2 and STAT3 in rat hippocampal neurons and cortical astrocytes. In neurons, TPO induced cell death and selectively activated ERK1/2. GCSF protected neurons from TPO- and hypoxia-induced cell death via selective activation of Akt1. In astrocytes, neither TPO nor GCSF had any effect on cell viability but inhibited proliferation. This effect was accompanied by activation of ERK1/2 and inhibition of STAT3 activity. A balance between growth factors, their receptors and signalling proteins may play an important role in regulation of neural cell survival.

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Section: Discussionsupporting

confidence: 90%

Cell Type Specific Signalling by Hematopoietic Growth Factors in Neural Cells

et al. 2006

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“…ERK was reported to be unimportant in the mediation of EPO's neuroprotective effect against cerebral ischemia [58], cardiac ischemia [59] and Parkinson's disease [7]. In contrast, ERK was considered to be crucial for the neuroprotection of EPO against cerebral ischemia [60][61][62]. The relative contributions of ERK1/2 and PI3K in EPO-induced neuroprotection are ambiguous, depending on the model system examined.…”

Section: Discussionmentioning

confidence: 92%

Erythropoietin prevents PC12 cells from 1-methyl-4-phenylpyridinium ion-induced apoptosis via the Akt/GSK-3β/caspase-3 mediated signaling pathway

et al. 2007

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Apoptosis is a contributing cause of dopaminergic neuron loss in Parkinson disease. Recent work has shown that erythropoietin (EPO) offers protection against apoptosis in a wide variety of tissues. We demonstrate that exposure of PC12 cells to 1-methyl-4-phenylpyridinium ion (MPP(+)) with recombinant human EPO, significantly decreased apoptosis as measured by TUNEL and caspase-3 activity when compared to MPP(+) treatment alone. EPO induced sustained phosphorylation of Akt and its substrate, GSK-3beta, reduced caspase-3 activities in PC12 cells. The anti-apoptotic effect of EPO was abrogated by co-treatment with LY294002, the specific blocker of phosphatidylinositol 3-kinase (PI3K). The effects of EPO on GSK-3beta and caspase-3 activities were also blocked by LY294002. LiCl, the inhibitor of GSK-3beta, downregulated the caspase-3 activity and blocked the apoptosis induced by MPP(+). Finally, we determined that EPO transiently activated the ERK signaling pathway, but PD98059, a specific inhibitor of ERK, does not alter the survival effect of EPO in this model system. Thus, these findings indicate that EPO protects against apoptosis in PC12 cells exposed to MPP(+), through the Akt/GSK-3beta/caspase-3 signaling pathway, but the ERK pathway is not involved in the EPO-dependent survival enhancing effect in this model system.

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“…EPO exerts its biological functions through a cell surface receptor, which has been known to be expressed in the cerebral cortex, midbrain, and hippocampus of the CNS (1,3,26). EPO is expressed both in neurons and astrocytes and recent studies demonstrated that EPO receptor (EPOR) is expressed in cultured astrocytes (27). The EPO receptor belongs to a subfamily of the type I cytokine receptor superfamily, which also includes the ␤ common receptor (␤cR).…”

Section: Epo Inhibits Group I Mglur-induced Increase In Hypotonic Swementioning

confidence: 99%

Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection

Gunnarson

Song

Kowalewski

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Disturbed brain water homeostasis with swelling of astroglial cells is a common complication in stroke, trauma, and meningitis and is considered to be a major cause of permanent brain damage. Astroglial cells possess the water channel aquaporin 4 (AQP4). Recent studies from our laboratory have shown that glutamate, acting on group I metabotropic glutamate receptors (mGluRs), increases the permeability of astrocyte AQP4, which, in situations of hypoxia-ischemia, will increase astrocyte water uptake. Here we report that erythropoietin (EPO), which in recent years has emerged as a potent neuro-protective agent, antagonizes the effect of a group I mGluR agonist on astrocyte water permeability. Activation of group I mGluRs triggers fast and highly regular intracellular calcium oscillations and we show that EPO interferes with this signaling event by altering the frequency of the oscillations. These effects of EPO are immediate, in contrast to the neuroprotective effects of EPO that are known to depend upon gene activation. Our findings indicate that EPO may directly reduce the risk of astrocyte swelling in stroke and other brain insults. In support of this conclusion we found that EPO reduced the neurological symptoms in a mouse model of primary brain edema known to depend upon AQP4 water transport.aquaporin 4 ͉ brain edema ͉ glutamate E rythropoietin, the major haemopoietic growth factor, has in recent years emerged as one of the most efficient neuroprotective agents (1-3). It is well documented from both experimental and clinical studies that erythropoietin (EPO) attenuates the degree of brain damage after stroke (4-6). Stroke is associated with a massive release of glutamate and experimental studies have indicated that EPO also protects from glutamatetriggered neurotoxicity (7). EPO acts by preventing the destruction of viable tissue surrounding the site of an injury, that is, the penumbra that develops during the first 24-48 h after a brain insult (1). Cell swelling is one of the characteristic features of the penumbra (8, 9).Mounting evidence suggests that water uptake in astrocytes via the water channel aquaporin 4 (AQP4) is an important factor contributing to post-ischemic cell swelling (10, 11). Immunohistochemical studies have indicated a colocalization between EPO receptors and AQP4 in the brain (12, 13), particularly in glial cells at the interface between the brain parenchyma and the periphery. This raises the question whether EPO may modulate astrocyte water permeability and whether this effect may attenuate astrocyte water uptake after a brain insult. We have in a recent study demonstrated that glutamate increases astrocyte water permeability via activation of AQP4 (14). In the present study we have tested the possibility that EPO may counteract the effect of glutamate on astrocyte water permeability.To document the tissue protective role of EPO in brain edema, we first tested whether EPO reduces symptoms in a mouse model of water intoxication known to depend upon glial AQP4 (11). Observing a robust eff...

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EPO receptor-mediated ERK kinase and NF-κB activation in erythropoietin-promoted differentiation of astrocytes

Cited by 58 publications

References 39 publications

Cell Type Specific Signalling by Hematopoietic Growth Factors in Neural Cells

Cell Type Specific Signalling by Hematopoietic Growth Factors in Neural Cells

Erythropoietin prevents PC12 cells from 1-methyl-4-phenylpyridinium ion-induced apoptosis via the Akt/GSK-3β/caspase-3 mediated signaling pathway

Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection

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